Nutrición contra el cancer

Foro general ciencia, medicina, nutrición, salud pública, política

Moderador: Fisio

Nutrición contra el cancer

Notapor Fisio » Lun, 08 Sep 2014, 08:40

Voy abriendo un hilo sobre este tema.

Según muchos autoproclamados científicos, suministrar una molécula química de síntesis para tratar de controlar un tumor es ciencia, pero si la molécula para controlar el tumor existe en la naturaleza, entonces es pseudociencia.

El cancer tiene múltiples rutas metabólicas que lo modulan, y una de las principales formas de modular las rutas metabólicas en el organismo es la alimentación. Hay que andar muy perdido si pensamos que una persona que se alimenta de comida occidental, inflamatoria y sustrato alimenticio del propio cancer, va a tener el mismo pronóstico que personas que toma nutrientes que activan rutas metabólicas que inhiben factores de transcripción, suprimen la inflamación, suprimen la angiogénesis, y demás dianas terapéuticas en cancer (que son muchas). Hay que estar MUY PERDIDO.

Se está dejando de lado intencionadamente toda la investigación clínica de muerte celular y control metabólico del cancer a partir de sustancias nutricionales en humanos. Voy a ir dejando constancia en este hilo de toda la investigación sobre mecanismos moleculares de nutrientes contra el cancer. Esto es una denuncia que han hecho varios científicos que se dedican a la investigación del cancer, que nunca se permite (o no se quiere financiar) para que sea probada en humanos, a pesar de que existen miles (MILES) de estudios que muestran la eficacia contra las células cancerígenas o de mejora de la calidad de vida en los pacientes de una gran diversidad de sustancias presentes en los alimentos.

"Because vitamin C has no patent potential, its development will not be supported by pharmaceutical companies," lead researcher Qi Chen told BBC News.

http://www.independent.co.uk/news/scien ... 17324.html



Tenemos pruebas a partir de ensayos clínicos, estudios in vitro y mediante xenoinjerto de tumores humanos en distintos animales de la capacidad de ciertos alimentos de combatir tumores. A veces ciertas sustancias ayudan a la propia quimioterapia sensibilizando las células al efecto de los fármacos. Pero la realidad a día de hoy en la investigación del cancer es que prácticamente solo se hacen estudios quimioterapia vs quimioterapia (así se justifica el uso de quimioterapia sí o sí). 4 ciclos vs 6 ciclos, como aumentación o coadyudante, etc. No se admiten otras investigaciones fuera del monopolio oncológico. No hay otros grupos comparadores: quimioterapia vs otra cosa. Ni siquiera hay grupos placebo, por lo que no hay datos objetivos de prácticamente nada. Atenta contra la ética privar a los pacientes de estrategias, como mínimo, complementarias y obligar a pacientes, científicos, docentes y médicos a tragar con las terapias del modelo biomédico y dejar el resto de terapias sin estudiar y sin financiación, para que así no tengan "evidencia".

Algunas quimioterapias usadas en la actualidad y con actividad terapéutica son precisamente extractos de plantas, como el Taxol, del arbol Taxus brevifolia que estudió un botánico: Arthur S. Barclay. Así que en realidad, algunos autodenominados científicos pasean una ignorancia de proporciones siderales.

Por otro lado, la respuesta de los nutricionistas que he observado en general es la misma creencia autoinducida e indocumentada de que no hay nada en la nutrición que pueda servir como terapia antitumoral, de la mano de la creencia autoinducida e indocumentada de que la quimioterapia cura el cancer. La terapia nutricional puede aportar tantos beneficios como la quimioterapia, pero además sin los efectos secundarios, añadiendo calidad de vida y ahorrando el coste económico enorme de muchos fármacos que solo aportan beneficios marginales. La quimioterapia solo es verdaderamente terapéutica para alargar la vida significativamente en una minoría de tipos de cancer (canceres hematológicos y alguno ginecológico principalmente). En el resto hay un beneficio generalmente muy pobre, y en una minoría de los pacientes de todos los tratados. Por ejemplo en cancer de mama en estadio temprano, la mayoría de las mujeres no obtendrán grandes beneficios de la quimioterapia, pero sí sus duros efectos secundarios. Solo una de cada tres tratadas verá incrementada su supervivencia. Es decir, si sumamos el sobrediagnóstico en mamografías y el sobretratamiento en quimioterapia, el resultado de las politicas oncológicas actuales en algunos tipos de cancer es que muchas mujeres están siendo innecesariamente dañadas por los tratamientos médicos, respecto a una minoría que se beneficia de estos tratamientos. Y ahí el quid: compensa dañar a muchos para beneficiar a unos pocos, sumado al coste económico? Se han valorado alternativas disponibles? Preguntas incómodas que molestan a gran parte de los autodenominados científicos y de las asociaciones médicas que viven de esto.

La industria siempre quiere documentar la eficacia de sus tratamientos retorciendo la estadística: a partir de surrogates, survival epidemiológicos, valores relativos por mortalidad específica como prueba absoluta, y eliminando de los estudios la estadística los daños producidos por los tratamientos. Se ocultan los daños producidos en la ecuación, y se suprimen las alternativas del análisis para que no existan comparadores.

http://annonc.oxfordjournals.org/conten ... ds636.full


Todo esto para reducir el análisis a un aparente valor absoluto: la "eficacia". Por ejemplo en las campañas de mamografías, la contrapartida de salvar una sola vida es sobrediagnosticar a nada menos que 10 mujeres (someter a tratamiento a 10 mujeres sanas con "falsos" bultos histológicamente positivos pero que no iban a progresar a cancer y que serán sometidas a un duro golpe diagnóstico de por vida, quimioterapia, cirugía, revisiones, e incluso verán sus senos mutilados). Esta es la parte que se quiere ocultar hablando solo de que se ha salvado una vida por cancer. No solo hay que medir la efectividad de las intervenciones a partir de estadística de mortalidad específica, sino a cuanta gente sana se daña innecesariamente para salvar una vida a una que verdaderamente se beneficia del tratamiento (NNT y mortalidad total). La medicina y la "divulgación científica" casi siempre muestra estadísticas parciales y análisis sesgados con la intención de manipular a la opinión pública.

La terapia nutricional tiene precisamente una doble ventaja en este terreno: puede ser efectiva en aumentar el tiempo de supervivencia y además aumentar la calidad de vida sin dañar a nadie. Sin embargo, no es honesto comparar la terapia nutricional y quimioterapia sin más. La quimioterapia ha recibido cientos de miles de millones para ser investigada, y un margen de más de 60 años de investigación prioritaria de extensión mundial. No caigamos en análisis superfluos de comparaciones sin más. Si la nutrición recibiera los miles de millones para investigación, medios y científicos que se le han dado a la quimioterapia, entonces podríamos hablar de una comparación en condiciones de igualdad. Llegado este caso, la quimio sería sin duda un tratamiento obsoleto en la inmensa mayoría de tipos de cancer, tendríamos tratamientos más efectivos y con menos efectos secundarios, por lo que se dañaría a menos pacientes.

Y no menos importante (de hecho el quid de la cuestión): el tratamiento contra el cancer cuesta mucho dinero del bolsillo de los ciudadanos, que, casualidad, va a parar a las farmacéuticas. Las propias guias NICE se cuestionan si el gobierno debe meter tanto dinero en fármacos que aportan un beneficio a menudo muy marginal (y hasta cientos de miles de euros el tratamiento, que es de lo que se trata).

http://www.med.mcgill.ca/epidemiology/c ... 0drugs.pdf

En los últimos 12 años, los tratamientos en conjunto han aumentado la supervivencia a tumores sólidos 2 meses... y queremos seguir así porque es más "científico"?

http://archotol.jamanetwork.com/article ... id=1891387

Los medios de divulgación siempre están sobrevalorando los posibles hallazgos surrogate en un futuro ("descubierta nueva proteina que podría algún día..."), y sin embargo no dan datos objetivos de la oncología hoy (y de estos 60 años), mostrando estadísticas de supervivencia epidemiológicas engañosas. El silencio de la prensa es un gran marcador del nivel de corrupción de un país. De la política de cancer actual se lucran en cadena jerárquicamente desde los accionistas en wall street de industria biotech y big farma, asociaciones médicas, laboratorios, gran parte con dinero público derivado con la excusa de "I+D", hasta los salarios de los médicos. Una cadena de conflicto de intereses brutal. Los consejos médicos que se dan coinciden con lo que les da dinero. Nos llevan vendiendo la cura biotecnológica y farmacológica del cancer desde hace... 60 años! Este documento es de 1958. Y así sigue todo.

Imagen

Si gastamos muchos millones de recursos económicos en pocos pacientes, en la mayoría de los casos no para salvar, sino para alargar la vida unos meses, dejamos de lado a muchos otros enfermos o personas en situación de vulnerabilidad a los que no se destinan recursos (no solo sanitarios, sino socioeconomicos) quienes se beneficiarian de muchísimos más años de vida por unidad económica invertida, y que se ven desatendidas porque su problema no implica la venta de biotecnología o farmacología. Pero es que los meses que se alargan a los primeros, probablemente se conseguirían con terapia nutricional sin fármacos que cuestan decenas de miles de euros. Ese dinero se podría invertir en cosas que salvarían la vida, de lejos, a mucha más gente, y añadirían más años de vida en otro lado.

Por el lado de los pacientes: la gente tiene derecho a tener opciones, no que se le imponga un tratamiento. La gente tiene derecho a información honesta, no a información parcial y sesgada, y a decidir sobre su propia salud y sobre su propio tratamiento, no a paternalismo médico que te dice lo que tienes que hacer, pero que justo lo que tienes que hacer es aquello que, casualidad, les da dinero. Este secuestro en la investigación hace que numerosos tratamientos queden sin investigar.


Las enfermedades tan complejas solo se pueden vencer (o más apropiadamente: controlar) desde una perspectiva multidisciplinar atacando todos los frentes:

-Sociológicas: una enfermedad es sociológica antes que biológica, enferma la gente vulnerable, la gente pobre, la gente con menor educación, etc. Por lo tanto hay que invertir más recursos en estas causas, en lugar de hacerlo en las consecuencias biológicas.

-Psicológicas: enferma la gente psicológicamente vulnerable.

-Nutricionales: enferma la gente con hábitos nutricionales pobres, hábitos que son irónicamente protegidos por el gobierno por sus intereses económicos con la industria. Ponemos una maquina de refrescos y bollos en cada oficina y en cada hospital. Y luego campañas de mamografías.

-Ambientales: enferma la gente que vive en ciudades hasta arriba de polución, legislación laxa con vertidos tóxicos a las aguas, se aprueban quimicos cuya repercusión sobre la salud es desconocida...

-Prevención: subvención de políticas de actividad física, clases de cocina en los colegios y campañas de concienciación de que el cancer no es cuestión de lazos rosas ni de quimioterapia, sino de salud pública.

-Terapias clínicas adicionales: que apoyen la biomedicina, como la nutrición clínica funcional que aquí expongo en lugar de suprimir opciones por intereses económicos.

La cura del cancer no va a llegar por un mecanismo. La única forma de ir avanzando es controlarlo desde todos los frentes. Es decir, no se puede dejar de lado la inversión en políticas de salud pública para invertir en biotecnología y farmacología. Llega un punto en el que invertir en biomedicina no salva vidas, sino que cuesta vidas, porque se destruye la inversión en el resto de políticas. Pero además, las propias tesis biomédicas quedan reducidas a un puñado de hipótesis que le interesan económicamente a la industria, lo mismo que se hizo al explicar aberrantemente la fisiología de la enfermedad cardiovascular a partir del colesterol, o la fisiología de la depresión con la serotonina. Esto es la anticiencia, desviar la investigación hacia cortinas de humo, y tirar medio siglo de políticas de salud y teledirigir la investigación hacia un falso objetivo teniendo a medio mundo investigando las mismas hipótesis. Un harakiri científico y un daño social irreparable. Que exista un efecto residual de un tratamiento (pura serendipia) y por lo tanto haya "evidencia científica" de un efecto que sucede a saber como, no indica que esto explique la fisiopatología subyacente, ni que el fármaco sea una línea terapéutica adecuada o que vaya a ir más allá del efecto por serendipia, y que debamos seguir investigando esta serendipia otros 60 años, y mucho menos indica que sea una política de salud beneficiosa para los pacientes. Es increible que los científicos, sanitarios y "divulgadores científicos" apoyen esto de forma irreflexiva. La política contra el cancer actual es una aberración, impulsada y mantenida por intereses económicos de industria, gobiernos, asociaciones médicas, etc.

PD: la línea de investigación biomédica más sólida en mi opinión es el desarrollo de transportadores (liposomas, etc) para que estos compuestos naturales tengan bioacumulación suficiente en los tejidos, que es una línea intermedia entre farmacología y nutrición funcional. Por lo que las farmacéuticas para mí siguen teniendo un papel, lo que no puede hacerse es continuar el monopolio hacia los tratamientos que les reportan beneficios a ellos y no a la sociedad.

PD2: esto no va de ciencia, sino de dinero. Pensar que los gobiernos y las farmacéuticas realizan inversiones en biomedicina pensando en la salud de los enfermos, y no en las rentabilidades que van a ganar con sus inversiones (las farmacéuticas son las empresas que más ganancias obtienen año tras año del mercado), es como pensar que los gobiernos y las inmobiliarias invertian mucho en ladrillo por el interés de proporcionar vivienda a los necesitados. ES ABSURDO!


Estudios en humanos





Vitamina C, último metaanálisis de 2014

Vitamin C and survival among women with breast cancer: a meta-analysis.
Harris HR1, Orsini N2, Wolk A2.
Author information

1Unit of Nutritional Epidemiology, Institute for Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden; Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA. Electronic address: holly.harris@ki.se.
2Unit of Nutritional Epidemiology, Institute for Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden.

Abstract
BACKGROUND:

The association between dietary vitamin C intake and breast cancer survival is inconsistent and few studies have specifically examined vitamin C supplement use among women with breast cancer. The purpose of this study was to summarise results from prospective studies on the association between vitamin C supplement use and dietary vitamin C intake and breast cancer-specific mortality and total mortality.
METHODS:

Studies were identified using the PubMed database through February 6, 2014 and by examining the references of retrieved articles. Prospective studies were included if they reported relative risks (RR) with 95% confidence intervals (95% CIs) for at least two categories or as a continuous exposure. Random-effects models were used to combine study-specific results.
RESULTS:

The ten identified studies examined vitamin C supplement use (n=6) and dietary vitamin C intake (n=7) and included 17,696 breast cancer cases, 2791 total deaths, and 1558 breast cancer-specific deaths. The summary RR (95% CI) for post-diagnosis vitamin C supplement use was 0.81 (95% CI 0.72-0.91) for total mortality and 0.85 (95% CI 0.74-0.99) for breast cancer-specific mortality. The summary RR for a 100mg per day increase in dietary vitamin C intake was 0.73 (95% CI 0.59-0.89) for total mortality and 0.78 (95% CI 0.64-0.94) for breast cancer-specific mortality.
CONCLUSION:

Results from this meta-analysis suggest that post-diagnosis vitamin C supplement use may be associated with a reduced risk of mortality. Dietary vitamin C intake was also statistically significantly associated with a reduced risk of total mortality and breast cancer-specific mortality.


http://www.ncbi.nlm.nih.gov/pubmed/24613622

Melatonina

Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis.
Mills E1, Wu P, Seely D, Guyatt G.
Author information
Abstract

Most observational studies show an association between melatonin and cancer in humans. We conducted a systematic review of randomized controlled trials (RCTs) of melatonin in solid tumor cancer patients and its effect on survival at 1 yr. With the aid of an information specialist, we searched 10 electronic databases from inception to October 2004. We included trials using melatonin as either sole treatment or as adjunct treatment. Prespecified criteria guided our assessment of trial quality. We conducted a meta-analysis using a random effects model. We included 10 RCTs published between 1992 and 2003 and included 643 patients. All trials included solid tumor cancers. All trials were conducted at the same hospital network, and were unblinded. Melatonin reduced the risk of death at 1 yr (relative risk: 0.66, 95% confidence interval: 0.59-0.73, I2=0%, heterogeneity P<or=0.56). Effects were consistent across melatonin dose, and type of cancer. No severe adverse events were reported. The substantial reduction in risk of death, low adverse events reported and low costs related to this intervention suggest great potential for melatonin in treating cancer. Confirming the efficacy and safety of melatonin in cancer treatment will require completion of blinded, independently conducted RCTs.

http://www.ncbi.nlm.nih.gov/pubmed/16207291



Carnitina

L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN)--a randomized multicentre trial.
Kraft M1, Kraft K, Gärtner S, Mayerle J, Simon P, Weber E, Schütte K, Stieler J, Koula-Jenik H, Holzhauer P, Gröber U, Engel G, Müller C, Feng YS, Aghdassi A, Nitsche C, Malfertheiner P, Patrzyk M, Kohlmann T, Lerch MM.
Author information

1Department of Medicine A, University Medicine Greifswald, Friedrich Löffler Straße 23a, Greifswald 17475, Germany.

Abstract
BACKGROUND:

Cachexia, a >10% loss of body-weight, is one factor determining the poor prognosis of pancreatic cancer. Deficiency of L-Carnitine has been proposed to cause cancer cachexia.
FINDINGS:

We screened 152 and enrolled 72 patients suffering from advanced pancreatic cancer in a prospective, multi-centre, placebo-controlled, randomized and double-blinded trial to receive oral L-Carnitine (4 g) or placebo for 12 weeks. At entry patients reported a mean weight loss of 12 ± 2.5 (SEM) kg. During treatment body-mass-index increased by 3.4 ± 1.4% under L-Carnitine and decreased (-1.5 ± 1.4%) in controls (p < 0.05). Moreover, nutritional status (body cell mass, body fat) and quality-of-life parameters improved under L-Carnitine. There was a trend towards an increased overall survival in the L-Carnitine group (median 519 ± 50 d versus 399 ± 43 d, not significant) and towards a reduced hospital-stay (36 ± 4d versus 41 ± 9d,n.s.).
CONCLUSION:

While these data are preliminary and need confirmation they indicate that patients with pancreatic cancer may have a clinically relevant benefit from the inexpensive and well tolerated oral supplementation of L-Carnitine.


http://www.ncbi.nlm.nih.gov/pubmed/22824168



Te verde

Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro.
McLarty J1, Bigelow RL, Smith M, Elmajian D, Ankem M, Cardelli JA.
Author information
Abstract

The purpose of this study was to determine the effects of short-term supplementation with the active compounds in green tea on serum biomarkers in patients with prostate cancer. Twenty-six men with positive prostate biopsies and scheduled for radical prostatectomy were given daily doses of Polyphenon E, which contained 800 mg of (-)-epigallocatechin-3-gallate (EGCG) and lesser amounts of (-)-epicatechin, (-)-epigallocatechin, and (-)-epicatechin-3-gallate (a total of 1.3 g of tea polyphenols), until time of radical prostatectomy. Serum was collected before initiation of the drug study and on the day of prostatectomy. Serum biomarkers hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-I, IGF binding protein-3 (IGFBP-3), and prostate-specific antigen (PSA) were analyzed by ELISA. Toxicity was monitored primarily through liver function enzymes. Changes in serum components were analyzed statistically using the Wilcoxon signed rank test. Cancer-associated fibroblasts were treated with EGCG, and HGF and VEGF protein and mRNA levels were measured. HGF, VEGF, PSA, IGF-I, IGFBP-3, and the IGF-I/IGFBP-3 ratio decreased significantly during the study. All of the liver function tests also decreased, five of them significantly: total protein, albumin, aspartate aminotransferase, alkaline phosphatase, and amylase. The decrease in HGF and VEGF was confirmed in prostate cancer-associated fibroblasts in vitro. Our results show a significant reduction in serum levels of PSA, HGF, and VEGF in men with prostate cancer after brief treatment with EGCG (Polyphenon E), with no elevation of liver enzymes. These findings support a potential role for Polyphenon E in the treatment or prevention of prostate cancer.

http://www.ncbi.nlm.nih.gov/pubmed/19542190/



Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study.
Bettuzzi S1, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A.
Author information
Abstract

Green tea catechins (GTCs) proved to be effective in inhibiting cancer growth in several experimental models. Recent studies showed that 30% of men with high-grade prostate intraepithelial neoplasia (HG-PIN) would develop prostate cancer (CaP) within 1 year after repeated biopsy. This prompted us to do a proof-of-principle clinical trial to assess the safety and efficacy of GTCs for the chemoprevention of CaP in HG-PIN volunteers. The purity and content of GTCs preparations were assessed by high-performance liquid chromatography [(-)-epigallocathechin, 5.5%; (-)-epicatechin, 12.24%; (-)-epigallocatechin-3-gallate, 51.88%; (-)-epicatechin-3-gallate, 6.12%; total GTCs, 75.7%; caffeine, <1%]. Sixty volunteers with HG-PIN, who were made aware of the study details, agreed to sign an informed consent form and were enrolled in this double-blind, placebo-controlled study. Daily treatment consisted of three GTCs capsules, 200 mg each (total 600 mg/d). After 1 year, only one tumor was diagnosed among the 30 GTCs-treated men (incidence, approximately 3%), whereas nine cancers were found among the 30 placebo-treated men (incidence, 30%). Total prostate-specific antigen did not change significantly between the two arms, but GTCs-treated men showed values constantly lower with respect to placebo-treated ones. International Prostate Symptom Score and quality of life scores of GTCs-treated men with coexistent benign prostate hyperplasia improved, reaching statistical significance in the case of International Prostate Symptom Scores. No significant side effects or adverse effects were documented. To our knowledge, this is the first study showing that GTCs are safe and very effective for treating premalignant lesions before CaP develops. As a secondary observation, administration of GTCs also reduced lower urinary tract symptoms, suggesting that these compounds might also be of help for treating the symptoms of benign prostate hyperplasia.


http://www.ncbi.nlm.nih.gov/pubmed/16424063/

Seguimiento del estudio

http://www.ncbi.nlm.nih.gov/pubmed/18406041


En desarrollo

Purpose

This randomized phase II trial studies how well green tea extract works in treating patients with low-risk prostate cancer. Green tea extract contains ingredients that may prevent or slow the growth of certain cancers.

Condition Intervention Phase
Stage I Prostate Cancer
Stage IIA Prostate Cancer
Stage IIB Prostate Cancer
Other: active surveillance
Drug: Sunphenon
Other: laboratory biomarker analysis
Other: Questionnaire Administration
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Study of Sunphenon Decaffeinated Capsules in Men With Low-Risk Prostate Cancer on Active Surveillance


http://clinicaltrials.gov/ct2/show/NCT0 ... non&rank=3



Preguntas:

1) el cancer es algo determinado genéticamente

No, el cancer se debe principalmente a factores ambientales, posiblemente hasta cifras del 95%. Algunos de esos factores, como la dieta, los podemos controlar. Otros no los conocemos (virus, etc).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515569/

2) el ejercicio previene el cancer, pero no lo cura.

El ejercicio previene el cancer, y una vez producido, lo combate atacando muchas de las dianas que tratan de alcanzarse con fármacos (NfKappaB, caspasas, P53, etc).

http://www.ncbi.nlm.nih.gov/pubmed/21610110

http://www.ncbi.nlm.nih.gov/pubmed/24470442

Si un fármaco tuviera la efectividad terapéutica del ejercicio físico abriría telediarios, las asociaciones médicas presionarían para su compra, y se vendería a decenas de miles de euros. El sistema de salud debe informar, promover, subvencionar y ofrecer a los pacientes esta terapia, al igual que promociona subvenciona y ofrece terapias biomédicas inefectivas y que cuestan decenas de miles de euros. En resumen, si quieres prevenir el cancer, haz ejercicio. Si quieres combatir el cancer, haz ejercicio.

3) la quimioterapia cura el cancer?

De los 100 o 200 tipos y subtipos de cancer, la quimioterapia es realmente efectiva (entendiendo como curación o prolongación significativa de años de vida significativos) en una minoría: linfoma y en canceres relativamente raros, de testiculos y ovarios. De hecho, la mayoría de los pacientes acaba desarrollando resistencia a la propia quimioterapia, quizás Darwinismo entre las células cancerígenas

http://www.medicaldaily.com/chemotherap ... wth-241770

La realidad es que la contribución de la quimioterapia a tumores sólidos es muy pobre

http://www.australianprescriber.com/magazine/29/1/2/3

Si tenemos en cuenta las limitaciones del estudio (quimioterapia como coadyudante, etc) en un escenario optimista se podría hablar de un 6%. Si quereis un 10%. Un 10% de un cancer que mataría en 3 años nos da algo más de 3 meses. Y esos 3 meses extra es vs no dar ningun otro tipo de alternativa y a menudo el precio son grandes efectos secundarios (y decenas de miles de euros...). En canceres avanzados, la propia quimioterpia llega a matar al 25% de los pacientes

http://www.abc.net.au/news/2008-11-13/c ... cer/204358

Otro riesgo es contribuir al desarrollo de otro cancer secundario al tratamiento

http://www.ncbi.nlm.nih.gov/pubmed/17374815

http://www.ncbi.nlm.nih.gov/pubmed/12852471


Y efectos secundarios graves e irreversibles como neuropatía en el 40% de los pacientes

http://www.cancer.gov/aboutnci/ncicance ... 2310/page6

Y otros potencialmente letales como cardiotoxicidad

http://www.ncbi.nlm.nih.gov/pubmed/22382639

Hepatotoxicidad

http://www.ncbi.nlm.nih.gov/pubmed/24099024

Fallo renal

http://www.ncbi.nlm.nih.gov/pubmed/15574506


Por lo tanto el uso, o no uso, de la quimioterapia no es algo sencillo. Nos gustan los heurísticos "para la enfermedad X hay una pastilla Y", pero lo siento, si la quimioterapia fuera a "curar" el cancer, lo habría hecho en estos 60 años. Esperemos que la terapia inmune y otro tipo de investigaciones logren mejores resultados.


4) pero he leido que ha aumentado la "supervivencia" en los ultimos 15 años

La "supervivencia" o survival rates son una estadística engañosa si no es de ensayos controlados. Se ha utilizado a menudo de manera deshonesta para confundir

http://jama.jamanetwork.com/article.asp ... eid=192788

La estadística de supervivencia aumenta aprentemente sobre todo porque diagnosticamos más tumores (inflando el denominador). Incluimos una mayor proporcion de pseudotumores o tumores histológicos benignos debido a las campañas de detección precoz y visibilidad. Es decir, bajamos el umbral de lo que consideramos un posible tumor hasta incluir tumores que no lo son, y eso aparentemente mejora la estadística de supervivencia (supervivientes/diagnosticos). Hace unas décadas los tumores diagnosticados eran sistemáticamente diferentes: la persona ya iba a la consulta con síntomas y por lo tanto eran tumores clínicos de peor pronóstico y peor estadística de supervivencia. También hay una mejor clasificación de tumores (hormonodependientes, etc) que reciben tratamientos más específicos, mejoras quirúrgicas, etc.

Para los interesados en los sesgos estadísticos, abrí un hilo explicando una parte aqui

viewtopic.php?f=13&t=2128


5) no es ético hacer ensayos clínicos con nutrición

La ética la deberían elegir los pacientes que son los implicados, los que van a sufrirlo, los que se ofrecen para formar parte de estudios y los que tienen su propia ética, no imponerles la suya las farmacéuticas ni las asociaciones médicas y científicas que ganan dinero con todo esto, ni tu ni yo por ellos. Se les debería dar la posibilidad de elegir, informandoles con honestidad y transparencia, cosa que precisamente no se hace ahora con muchos procedimientos. Ya se hacen ensayos clínicos con fármacos y procedimientos que se han demostrado poco o nada eficaces y además muy dañinos para los pacientes, como mamografias o PSA.

http://onlinelibrary.wiley.com/doi/10.1 ... 7.pub5/pdf

http://www.uspreventiveservicestaskforc ... eening.htm

Y ahí nunca hay conflictos "éticos". Los pacientes a menudo son cobayas engañadas, ya que piensan que están haciendo algo bueno por la medicina o por la sociedad cuando se prestan voluntarios para ensayos clínicos. El objetivo encubierto de muchos estudios no es el valor terapéutico de una sustancia, sino pasar el trámite regulatorio necesario para la aprobación de un fármaco que llena un hueco en el mercado detectado por los departamentos de márketing. El falso paternalismo de la ética tiene como fin preservar el status quo actual del modelo biomédico e impedir otros tratamientos que lo amenacen. La nutrición tiene evidencia preclínica de sobra como para ser puesta en marcha sin demora, como mínimo como coadyudante al tratamiento médico.

6) todos los médicos no pueden estar equivocados

Estudios recientes muestran que los médicos no entienden las estadísticas de cancer. No les culpo, puesto que todo se ha diseñado para confundir y en la universidad se excluyen sistemáticamente las cosas que molestan a la teoria oficial.

http://annals.org/article.aspx?articleid=1090696

Hay médicos que son conscientes de todo esto, pero si se expresan abiertamente en contra de ciertas prácticas, son sistemáticamente atacados por aquellos médicos y asociaciones médicas controlados y financiados por la industria. La carrera profesional y la vida de una persona se complica seriamente si se es crítico con la dinámica endogrupal industrial, clínica, profesional y política que está instalada en el sistema de salud. Hay una presión inimaginable en todo esto. De ahí la ciertamente llamativa escasez de voces críticas.

7) Lo hacemos por los pacientes. Una vida salvada está justificada, no importa el precio.

El argumento del altruismo, realmente cínico, no tiene en cuenta los daños producidos a pacientes sanos como expliqué anteriormente con las mamografías. Si por salvar una vida por cancer de prostata a partir de screening, matamos 0.3 vidas por secuelas de la cirugía, producimos 2 infartos, provocamos 1 trombo que hace peligrar otra vida, y dejamos sin próstata a 40 personas que quedarán impotentes e incontinentes, y todo esto le cuesta a la sociedad millones y millones de sus impuestos... esto es beneficio o provocar daños (datos a partir de USPTF). Tampoco tiene encuenta que si nos apropiamos de dinero para dar un beneficio residual para unas pocas personas, perdemos vidas por falta de inversiones en otras políticas que salvarían más vidas.

8) Vale, quizás la oncología no ha conseguido resultados espectaculares, pero es lo mejor que conocemos

Es lo mejor que conocemos, porque es lo único que se ha querido investigar. Lógica circular: no hay evidencia porque no se investiga. Y no se investiga para que precisamente no haya evidencia de otros tratamientos que supongan una amenaza. Y con esta estrategia, los autodenominados científicos acusan con cinismo de que no hay "evidencia" de nada más.

Las farmacéuticas hablando de ética (madre del amor hermoso), y los científicos dando generalmente una respuesta de exclusión intolerante cuando se les habla de testar objetivamente otras terapias con los mismos rigores que supuestamente propugnan, y acatar el resultado de los estudios. No puede ser más cínico el asunto. Creo que queda claro donde hay más prejuicios y anticiencia.

PD: urge (urge y mucho) enseñar en la facultad de medicina en particular, y de ciencias en general, dos asignaturas: sesgos en investigación, y sociología de la salud. Porque se está adiestrando paulovianamente a los sanitarios para solo mirar las causas biológicas, y a tener una estructura jerárquica de evidencia científica aberrante. Y por supuesto a olvidarse de las causas sociológicas de las enfermedades y de las políticas de salud pública, algo que salva más vida que todas las intervenciones científicas juntas.

PD2: está muy bien invertir en la "lucha contra el cancer" y la I+D. Pero ese dinero va a los intereses de la sociedad, o a los intereses de la industria?

PD3: lo repetiré una vez más. La salud no es cuestión de científicos. Sino de políticas de salud adecuadas. El culto al cientificismo es una creencia subjetiva, y tiene detrás los mismos mecanismos psicológicos como la creencia en grupos políticos o religiosos. La evidencia científica médica no determina objetivamente cuales son las políticas de salud idóneas. Que hay que invertir más en ciencia y medicina para mejorar la salud de las personas es una superstición muy extendida. Y hay mucho márketing disfrazado de ciencia para convencerte de ello.
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 5275
Registrado: Dom, 01 Sep 2013, 14:18

Re: Nutrición contra el cancer

Notapor Fisio » Lun, 08 Sep 2014, 08:40

Dieta cetogénica y restricción de carbohidratos

No es mi favorita en cancer (aunque sí para epilepsia y otras afecciones a nivel neurológico), pero empezamos por dieta cetogénica.

The low-carb, high-fat ketogenic diet can replace chemotherapy and radiation for even the deadliest of cancers, said Dr. Thomas Seyfried, a leading cancer researcher and professor at Boston College.





Is there a role for carbohydrate restriction in the treatment and prevention of cancer?
Klement RJ1, Kämmerer U.
Author information
Abstract

Over the last years, evidence has accumulated suggesting that by systematically reducing the amount of dietary carbohydrates (CHOs) one could suppress, or at least delay, the emergence of cancer, and that proliferation of already existing tumor cells could be slowed down. This hypothesis is supported by the association between modern chronic diseases like the metabolic syndrome and the risk of developing or dying from cancer. CHOs or glucose, to which more complex carbohydrates are ultimately digested, can have direct and indirect effects on tumor cell proliferation: first, contrary to normal cells, most malignant cells depend on steady glucose availability in the blood for their energy and biomass generating demands and are not able to metabolize significant amounts of fatty acids or ketone bodies due to mitochondrial dysfunction. Second, high insulin and insulin-like growth factor (IGF)-1 levels resulting from chronic ingestion of CHO-rich Western diet meals, can directly promote tumor cell proliferation via the insulin/IGF1 signaling pathway. Third, ketone bodies that are elevated when insulin and blood glucose levels are low, have been found to negatively affect proliferation of different malignant cells in vitro or not to be usable by tumor cells for metabolic demands, and a multitude of mouse models have shown anti-tumorigenic properties of very low CHO ketogenic diets. In addition, many cancer patients exhibit an altered glucose metabolism characterized by insulin resistance and may profit from an increased protein and fat intake.In this review, we address the possible beneficial effects of low CHO diets on cancer prevention and treatment. Emphasis will be placed on the role of insulin and IGF1 signaling in tumorigenesis as well as altered dietary needs of cancer patients.


http://www.ncbi.nlm.nih.gov/pubmed/22029671


Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial.
Schmidt M1, Pfetzer N, Schwab M, Strauss I, Kämmerer U.
Author information
Abstract
BACKGROUND:

Tumor patients exhibit an increased peripheral demand of fatty acids and protein. Contrarily, tumors utilize glucose as their main source of energy supply. Thus, a diet supplying the cancer patient with sufficient fat and protein for his demands while restricting the carbohydrates (CHO) tumors thrive on, could be a helpful strategy in improving the patients' situation. A ketogenic diet (KD) fulfills these requirements. Therefore, we performed a pilot study to investigate the feasibility of a KD and its influence on the quality of life of patients with advanced metastatic tumors.
METHODS:

Sixteen patients with advanced metastatic tumors and no conventional therapeutic options participated in the study. The patients were instructed to follow a KD (less than 70 g CHO per day) with normal groceries and were provided with a supply of food additives to mix a protein/fat shake to simplify the 3-month intervention period. Quality of life [assessed by EORTC QLQ-C30 (version 2)], serum and general health parameters were determined at baseline, after every two weeks of follow-up, or after drop out. The effect of dietary change on metabolism was monitored daily by measuring urinary ketone bodies.
RESULTS:

One patient did not tolerate the diet and dropped out within 3 days. Among those who tolerated the diet, two patients died early, one stopped after 2 weeks due to personal reasons, one felt unable to stick to the diet after 4 weeks, one stopped after 6 and two stopped after 7 and 8 weeks due to progress of the disease, one had to discontinue after 6 weeks to resume chemotherapy and five completed the 3 month intervention period. These five and the one who resumed chemotherapy after 6 weeks report an improved emotional functioning and less insomnia, while several other parameters of quality of life remained stable or worsened, reflecting their very advanced disease. Except for temporary constipation and fatigue, we found no severe adverse side effects, especially no changes in cholesterol or blood lipids.
CONCLUSIONS:

These pilot data suggest that a KD is suitable for even advanced cancer patients. It has no severe side effects and might improve aspects of quality of life and blood parameters in some patients with advanced metastatic tumors.


http://www.ncbi.nlm.nih.gov/pubmed/21794124

The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model.
Caso J1, Masko EM, Ii JA, Poulton SH, Dewhirst M, Pizzo SV, Freedland SJ.
Author information
Abstract
BACKGROUND:

No- and low-carbohydrate diets delay tumor growth compared to western diet (WD) in prostate cancer (PCa) xenograft studies. The effect of these diets in concert with androgen deprivation is unknown.
METHODS:

A total of 160 male SCID mice were injected with 1× 10(5) LAPC-4 human PCa cells. Of these, 150 mice were castrated and randomized to an ad libitum WD or fed via a paired-feeding protocol with a no-carbohydrate ketogenic diet (NCKD), 10% carbohydrate diet, or 20% carbohydrate diet. The remaining 10 mice were not castrated and were fed an ad libitum WD. The mice were sacrificed once volumes reached 1,000 mm3 and survival tested using the log-rank test. Serum from the median surviving 8 mice/group was assayed for insulin, IGF-1, and IGFBP-3.
RESULTS:

Body weights were roughly equal among groups. The 10 non-castrated mice experienced accelerated tumor growth. Among castrated mice, WD had the most rapid tumor growth; 20% carbohydrate diet the slowest (P = 0.046). Survival was not significantly different among the various carbohydrate restricted groups (P = 0.51). When pooled, there was a non-significant trend (P = 0.11) in improved survival among the carbohydrate restricted diets versus WD. No significant difference in serum insulin, IGF-1, and IGFBP-3 levels was noted among all groups at pre-randomization or at sacrifice.
CONCLUSIONS:

A 20% carbohydrate diet slowed tumor growth versus a WD. Though the benefit of carbohydrate restriction was somewhat less than in prior studies in non-castrate mice, these data still suggest diets achievable in humans may play a role in PCa management.


http://www.ncbi.nlm.nih.gov/pubmed/23038057



There have been no major advances in GBM management for over 50 years, though use of temozolomide
(Temodar) has produced marginal improvement in survival.1,47
We recently described how the current standard of care for GBM and
other high-grade brain tumors could actually accelerate tumor growth
thereby decreasing the probability of long-term patient survival.10,50
This prediction was based on new information regarding tumor energy
metabolism.

t is now recognized that glucose and glutamine are the
prime metabolic fuels for driving the growth of malignant tumors
including brain tumors.18,22,51-54. Indeed, some glioma cells can become dependent on glutamine for survival 55.
Ready access to glucose and glutamine will accelerate tumor growth thus enhancing the probability of
recurrence and reduced progression free survival.


http://rsg1foundation.com/docs/patient- ... native.pdf



The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer.
Poff AM1, Ari C, Seyfried TN, D'Agostino DP.
Author information
Abstract
INTRODUCTION:

Abnormal cancer metabolism creates a glycolytic-dependency which can be exploited by lowering glucose availability to the tumor. The ketogenic diet (KD) is a low carbohydrate, high fat diet which decreases blood glucose and elevates blood ketones and has been shown to slow cancer progression in animals and humans. Abnormal tumor vasculature creates hypoxic pockets which promote cancer progression and further increase the glycolytic-dependency of cancers. Hyperbaric oxygen therapy (HBO₂T) saturates tumors with oxygen, reversing the cancer promoting effects of tumor hypoxia. Since these non-toxic therapies exploit overlapping metabolic deficiencies of cancer, we tested their combined effects on cancer progression in a natural model of metastatic disease.
METHODS:

We used the firefly luciferase-tagged VM-M3 mouse model of metastatic cancer to compare tumor progression and survival in mice fed standard or KD ad libitum with or without HBO₂T (2.5 ATM absolute, 90 min, 3x/week). Tumor growth was monitored by in vivo bioluminescent imaging.
RESULTS:

KD alone significantly decreased blood glucose, slowed tumor growth, and increased mean survival time by 56.7% in mice with systemic metastatic cancer. While HBO₂T alone did not influence cancer progression, combining the KD with HBO₂T elicited a significant decrease in blood glucose, tumor growth rate, and 77.9% increase in mean survival time compared to controls.
CONCLUSIONS:

KD and HBO₂T produce significant anti-cancer effects when combined in a natural model of systemic metastatic cancer. Our evidence suggests that these therapies should be further investigated as potential non-toxic treatments or adjuvant therapies to standard care for patients with systemic metastatic disease.

http://www.ncbi.nlm.nih.gov/pubmed/23755243




Tumor-derived lactate and myeloid-derived suppressor cells: Linking metabolism to cancer immunology.
Husain Z, Seth P, Sukhatme VP.
Author information
Abstract

Many malignant cells produce increased amounts of lactate, which promotes the development of myeloid-derived suppressor cells (MDSCs). MDSCs, lactate, and a low pH in the tumor microenvironment inhibit the function of natural killer (NK) cells and T lymphocytes, hence allowing for disease progression. Ketogenic diets can deplete tumor-bearing animals from MDSCs and regulatory T cells, thereby improving their immunological profile.

http://www.ncbi.nlm.nih.gov/pubmed/24404426




Selectively starving cancer cells through dietary manipulation: methods and clinical implications.
Simone BA1, Champ CE, Rosenberg AL, Berger AC, Monti DA, Dicker AP, Simone NL.
Author information
Abstract

As the link between obesity and metabolic syndrome and cancer becomes clearer, the need to determine the optimal way to incorporate dietary manipulation in the treatment of cancer patients becomes increasingly important. Metabolic-based therapies, such as caloric restriction, intermittent fasting and a ketogenic diet, have the ability to decrease the incidence of spontaneous tumors and slow the growth of primary tumors, and may have an effect on distant metastases in animal models. Despite the abundance of preclinical data demonstrating the benefit of dietary modification for cancer, to date there are few clinical trials targeting diet as an intervention for cancer patients. We hypothesize that this may be due, in part, to the fact that several different types of diet modification exist with no clear recommendations regarding the optimal method. This article will delineate three commonly used methods of dietary manipulation to assess the potential of each as a regimen for cancer therapy.

http://www.ncbi.nlm.nih.gov/pubmed/23837760




Calorie or Carbohydrate Restriction? The Ketogenic Diet as Another Option for Supportive Cancer Treatment
Rainer J. Klement

The author agrees with Champ et al. that calorie reduction (CR) is a good supportive intervention for patients undergoing radiotherapy or chemotherapy. However, for those with cachexia or for those who are at risk for cachexia, CR may be problematic. Additionally, less food consumed means fewer nutrients. For these patients, the author suggests the addition of the ketogenic diet, which could be designed to include high-quality foods and could be combined with anticancer neutraceuticals.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3780638/




GLUT1 as a therapeutic target in hepatocellular carcinoma.
Amann T1, Hellerbrand C.
Author information
Abstract

Primary hepatocellular carcinoma (HCC) is one of the most fatal cancers in humans with rising incidence in many regions around the world. Currently, no satisfactory curative pharmacological treatment is available, and the outcome is mostly poor. Recently, we have shown that the glucose transporter GLUT1 is increased in a subset of patients with HCC and functionally affects tumorigenicity. GLUT1 is a rate-limiting transporter for glucose uptake, and its expression correlates with anaerobic glycolysis. This phenomenon is also known as the Warburg effect and recently became of great interest, since it affects not only glucose uptake and utilization but also has an influence on tumorigenic features like metastasis, chemoresistance and escape from immune surveillance. Consistent with this, RNA-interference-mediated inhibition of GLUT1 expression in HCC cells resulted in reduced tumorigenicity. Together, these findings indicate that GLUT1 is a novel and attractive therapeutic target for HCC. This review summarizes our current knowledge on the expression and function of GLUT1 in HCC, available drugs/strategies to inhibit GLUT1 expression or function, and potential side effects of such therapeutic strategies.

http://www.ncbi.nlm.nih.gov/pubmed/19874261




Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet.
Seyfried BT1, Kiebish M, Marsh J, Mukherjee P.
Author information
Abstract

Malignant brain tumors are a significant health problem in children and adults and are largely unmanageable. As a metabolic disorder involving the dysregulation of glycolysis and respiration (the Warburg effect), malignant brain cancer can be managed through changes in metabolic environment. In contrast to malignant brain tumors that are mostly dependent on glycolysis for energy, normal neurons and glia readily transition to ketone bodies (beta-hydroxybutyrate) for energy in vivo when glucose levels are reduced. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome, honed through millions of years of environmental forcing and variability selection, can transition from one energy state to another. We propose a different approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and less metabolically flexible tumor cells. This approach to brain cancer management is supported from recent studies in orthotopic mouse brain tumor models and in human pediatric astrocytoma treated with calorie restriction and the ketogenic diet. Issues of implementation and use protocols are discussed.

http://www.ncbi.nlm.nih.gov/pubmed/20009300




The Ketogenic Diet for the Treatment of Malignant Glioma

Eric C. Woolf and
Adrienne C. Scheck*

+ Author Affiliations

Barrow Neurological Institute, United States

↵* Corresponding author; email: adrienne.scheck@dignityhealth.org

Abstract

Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, thus reducing the efficacy of these treatments. In contrast, one trait shared by virtually all tumor cells is altered (dysregulated) metabolism. Tumor cells have an increased reliance on glucose, suggesting that treatments affecting cellular metabolism may be an effective method to improve current therapies. Indeed, metabolism has been a focus of cancer research in the last few years, as many pathways long associated with tumor growth have been found to intersect metabolic pathways in the cell. The ketogenic diet (high fat, low carbohydrate and protein), caloric restriction, and fasting all cause a metabolic change; specifically, a reduction in blood glucose and an increase in blood ketones. We, and others, have demonstrated that these metabolic changes improve survival in animal models of malignant gliomas and can potentiate the anti-tumor effect of chemotherapies and radiation treatment. In this review we discuss the use of metabolic alteration for the treatment of malignant brain tumors.

http://www.jlr.org/content/early/2014/0 ... 7.abstract




Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis.
Freedland SJ1, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson WJ, Cohen P, Hwang D, Peterson B, Fields T, Pizzo SV, Isaacs WB.
Author information
Abstract
BACKGROUND:

Recent evidence suggests carbohydrate intake may influence prostate cancer biology. We tested whether a no-carbohydrate ketogenic diet (NCKD) would delay prostate cancer growth relative to Western and low-fat diets in a xenograft model.
METHODS:

Seventy-five male SCID mice were fed a NCKD (84% fat-0% carbohydrate-16% protein kcal), low-fat (12% fat-72% carbohydrate-16% protein kcal), or Western diet (40% fat-44% carbohydrate-16% protein kcal). Low-fat mice were fed ad libitum and the other arms fed via a modified-paired feeding protocol. After 24 days, all mice were injected with LAPC-4 cells and sacrificed when tumors approached 1,000 mm(3).
RESULTS:

Despite consuming equal calories, NCKD-fed mice lost weight (up to 15% body weight) relative to low-fat and Western diet-fed mice and required additional kcal to equalize body weight. Fifty-one days after injection, NCKD mice tumor volumes were 33% smaller than Western mice (rank-sum, P = 0.009). There were no differences in tumor volume between low-fat and NCKD mice. Dietary treatment was significantly associated with survival (log-rank, P = 0.006), with the longest survival among the NCKD mice, followed by the low-fat mice. Serum IGFBP-3 was highest and IGF-1:IGFBP-3 ratio was lowest among NCKD mice while serum insulin and IGF-1 levels were highest in Western mice. NCKD mice had significantly decreased hepatic fatty infiltration relative to the other arms.
CONCLUSIONS:

In this xenograft model, despite consuming more calories, NCKD-fed mice had significantly reduced tumor growth and prolonged survival relative to Western mice and was associated with favorable changes in serum insulin and IGF axis hormones relative to low-fat or Western diet.

http://www.ncbi.nlm.nih.gov/pubmed/17999389




Decline of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients with head and neck cancer.
Schroeder U1, Himpe B, Pries R, Vonthein R, Nitsch S, Wollenberg B.
Author information
Abstract

In head and neck squamous cell carcinoma (HNSCC) aerobic glycolysis is the key feature for energy supply of the tumor. Quantitative microdialysis (μD) offers an online method to measure parameters of the carbohydrate metabolism in vivo. The aim was to standardize a quantitative μD-study in patients with HNSCC and to prove if a ketogenic diet would differently influence the carbohydrate metabolism of the tumor tissue. Commercially available 100 kDa-CMA71-μD- catheters were implanted in tumor-free and in tumor tissue in patients with HNSCC for simultaneous measurements up to 5 days. The metabolic pattern and circadian rhythm of urea, glucose, lactate, and pyruvate was monitored during 24 h of western diet and subsequent up to 4 days of ketogenic diet. After 3 days of ketogenic diet the mean lactate concentration declines to a greater extent in the tumor tissue than in the tumor-free mucosa, whereas the mean glucose and pyruvate concentrations rise. The in vivo glucose metabolism of the tumor tissue is clearly influenced by nutrition. The decline of mean lactate concentration in the tumor tissue after ketogenic diet supports the hypothesis that HNSCC tumor cells might use lactate as fuel for oxidative glucose metabolism.

http://www.ncbi.nlm.nih.gov/pubmed/23909728




Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme.
Champ CE1, Palmer JD, Volek JS, Werner-Wasik M, Andrews DW, Evans JJ, Glass J, Kim L, Shi W.
Author information
Abstract

Retrospective data suggests that low serum glucose levels during the treatment of glioblastoma multiforme (GBM) may improve clinical outcomes. As such, many patients are implementing a ketogenic diet (KD) in order to decrease serum glucose flux while simultaneously elevating circulating ketones during radiation therapy and chemotherapy for the treatment of GBM. With IRB approval, a retrospective review of patients with high-grade glioma treated with concurrent chemoradiotherapy and adjuvant chemotherapy was carried out from August 2010 to April 2013. Serum glucose and ketone levels, dexamethasone dose, and toxicity of patients undergoing a KD during treatment were also assessed. Blood glucose levels were compared between patients on an unspecified/standard diet and a KD. Toxicity was assessed by Common Terminology Criteria for Adverse Events version 4. In total, 53 patients were analyzed. Six underwent a KD during treatment. The diet was well tolerated with no grade III toxicity and one episode of grade II fatigue. No episodes of symptomatic hypoglycemia were experienced. Four patients are alive at a median follow-up of 14 months. The mean blood glucose of patients on a standard diet was 122 versus 84 mg/dl for those on a KD. Based on this retrospective study, a KD appears safe and well tolerated during the standard treatment of GBM. Dietary restriction of carbohydrates through a KD reduces serum glucose levels significantly, even in conjunction with high dose steroids, which may affect the response to standard treatment and prognosis. Larger prospective trials to confirm this relationship are warranted.

http://www.ncbi.nlm.nih.gov/pubmed/24442482




The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma.
Abdelwahab MG1, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, Scheck AC.
Author information
Abstract
INTRODUCTION:

The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4:1 (fat:carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas.
METHODS:

We used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging.
RESULTS:

Animals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days.
CONCLUSIONS:

KC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.

http://www.ncbi.nlm.nih.gov/pubmed/22563484

Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 5275
Registrado: Dom, 01 Sep 2013, 14:18

Re: Nutrición contra el cancer

Notapor Fisio » Lun, 08 Sep 2014, 08:41

Ácido betulínico

El ácido betulínico es un pentacíclico de origen natural que se encuentra en la corteza de varios especies de plantas, principalmente el abedul blanco Betula pubescens de la que recibe su nombre, sino también de Ziziphus mauritiana, Prunella vulgaris, las plantas carnívoras tropicales Triphyophyllum peltatum y Ancistrocladus heyneanus, Diospyros leucomelas, un miembro de la familia del caqui, Tetracera boiviniana, el jambul (Syzygium formosanum), del membrillo en flor (Chaenomeles sinensis), el romero, y Pulsatilla chinensis.

Betulin de extracto de corteza de abedul (Birch Bark)

Imagen

Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells.
Zuco V1, Supino R, Righetti SC, Cleris L, Marchesi E, Gambacorti-Passerini C, Formelli F.
Author information
Abstract

Betulinic acid is a triterpene with selective cytotoxicity against melanoma, neuroectodermal and malignant brain tumor cell lines. In this study the betulinic acid activity was evaluated, in comparison with doxorubicin, on different human neoplastic and non-neoplastic cell lines and on proliferating normal lymphocytes. Growth inhibition was evident in all the neoplastic cell lines independently on p53 status and histotype. Antiproliferative activity of betulinic acid was related to a cytotoxic effect on two p53 wild-type and on one p53 mutant cell lines and to a cytostatic effect on one p53 mutant melanoma clone. At the same concentrations, normal cells were unaffected indicating a selective effect of this agent. A cytotoxic activity of doxorubicin was evident on all the tested systems. In vivo experiments, performed on one of these cell lines, confirmed the antineoplastic activity of this drug. These data support further preclinical studies of betulinic acid not confined to melanoma and neuroectodermal tumors independently of p53 status.

http://www.ncbi.nlm.nih.gov/pubmed/11734332




Mitochondrion as a novel target of anticancer chemotherapy.
Costantini P1, Jacotot E, Decaudin D, Kroemer G.
Author information
Abstract

Mitochondrial membrane permeabilization is a critical event in the process leading to physiologic or chemotherapy-induced apoptosis (programmed cell death). This permeabilization event is, at least in part, under the control of the permeability transition pore complex (PTPC). Oncoproteins from the Bcl-2 family and tumor suppressor proteins from the Bax family interact with PTPC to inhibit or facilitate membrane permeabilization, respectively. Conventional chemotherapeutic agents elicit mitochondrial permeabilization in an indirect fashion by induction of endogenous effectors that are involved in the physiologic control of apoptosis. However, an increasing number of experimental anticancer drugs, including lonidamine, arsenite, betulinic acid, CD437, and several amphipathic cationic alpha-helical peptides, act directly on mitochondrial membranes and/or on the PTPC. Such agents may induce apoptosis in circumstances in which conventional drugs fail to act because endogenous apoptosis induction pathways, such as those involving p53, death receptors, or apical caspase activation, are disrupted. However, stabilization of the mitochondrial membrane by antiapoptotic Bcl-2-like proteins reduces the cytotoxic potential of most of these drugs. Targeting of specific PTPC components may overcome this Bcl-2-mediated apoptosis inhibition. One strategy involves cross-linking of critical redox-sensitive thiol groups within the PTPC; another involves the use of ligands to the mitochondrial benzodiazepine receptor. Thus, the design of mitochondrion-targeted cytotoxic drugs may constitute a novel strategy for overcoming apoptosis resistance.

http://www.ncbi.nlm.nih.gov/pubmed/10880547




Betulinic acid-induced Mcl-1 expression in human melanoma--mode of action and functional significance.
Selzer E1, Thallinger C, Hoeller C, Oberkleiner P, Wacheck V, Pehamberger H, Jansen B.
Author information
Abstract
BACKGROUND:

Currently there is no information on the regulation of expression and physiological role of the anti-apoptotic protein Mcl-1 in cells of the melanocytic lineage. This study investigates the regulation and expression of Mcl-1 in human melanoma cells, which was recently found to be induced by betulinic acid, a compound with anti-melanoma and apoptosis-inducing potential.
MATERIALS AND METHODS:

Mcl-1 phosphorthioate antisense oligonucleotides were used to investigate the effect of downregulating the expression of Mcl-1. Regulation of Mcl-1 expression was analyzed with the specific PI3-kinase inhibitors LY294002 and wortmannin and the inhibitor of MAP-kinase activation, PD98059. Western blot analysis was performed with anti ERK1/2, Mcl-1, Bak, Bcl-x and Bax antibodies. Activation status of PI-3 kinase and MAP-kinase pathways was investigated using phospho-Akt and phosphorylation-state independent Akt as well as phospho-MAP kinase, phospho-MEK and phospho-GSK-3alpha/beta antibodies.
RESULTS:

Upregulation of Mcl-1 in human melanoma cells by betulinic acid is mediated via a signal-transduction pathway that is inhibited by LY294002 and wortmannin. Betulinic acid-induced phosphorylation and activation of the Akt protein kinase was inhibited by LY294002. The inhibitor PD98059 reduced expression levels of Mcl-1 in melanoma cells and this effect was counteracted by betulinic acid. Downregulation of Mcl-1 by antisense oligodeoxynucleotides in combination with betulinic treatment led to a synergistic effect regarding growth inhibition.
CONCLUSIONS:

These results suggest that in human melanoma cells Mcl-1 is (i) of functional relevance for survival and (ii) subject to dual regulation by the MAP- kinase pathway and a pathway involving protein kinase B/Akt, the latter of which is modulated in response to betulinic acid. This study provides an experimental foundation for future therapeutic strategies using anti-Mcl-1 antisense oligonucleotides in human melanoma.

http://www.ncbi.nlm.nih.gov/pubmed/12606824



Screening of triterpenoids isolated from Phyllanthus flexuosus for DNA topoisomerase inhibitory activity.
Wada S1, Iida A, Tanaka R.
Author information
Abstract

DNA topoisomerases (Topos) are enzymes that play a crucial role in DNA metabolism events such as replication, transcription, recombination, and chromosome segregation at mitosis. Thus, Topo inhibitors could be expected to have antitumor effects. Naturally occurring lupane- and oleanane-type triterpenoids isolated from the bark of Phyllanthus flexuosus were screened for human Topos I and II inhibitory activities. Olean-12-en-3 beta,15 alpha-diol (1), olean-12-en-3 beta,15 alpha,24-triol (3), lupeol (4), and betulin (6) were found to be selective catalytic inhibitors of human Topo II activity with IC(50) values in the range of 10-39 microM.

http://www.ncbi.nlm.nih.gov/pubmed/11754608




Induction of p53 without increase in p21WAF1 in betulinic acid-mediated cell death is preferential for human metastatic melanoma.
Rieber M1, Strasberg Rieber M.
Author information
Abstract

Because betulinic acid was recently described as a melanoma-specific inducer of apoptosis, we investigated whether this agent was comparably effective against metastatic tumors and those in which metastatic ability and 92-kD gelatinase activity had been decreased by introduction of a normal chromosome 6. Human metastatic C8161 melanoma cells showed greater DNA fragmentation and growth arrest and earlier loss of viability in response to betulinic acid than their non-metastatic C8161/neo 6.3 counterpart. These effects involved induction of p53 without activation of p21WAF1 and were synergized by bromodeoxyuridine in metastatic Mel Juso, with no comparable responses in non-metastatic Mel Juso/neo 6 cells. Our data suggest that betulinic acid exerts its inhibitory effect partly by increasing p53 without a comparable effect on p21WAF1.

http://www.ncbi.nlm.nih.gov/pubmed/9628583



Enhanced cytotoxicity of some triterpenes toward leukemia L1210 cells cultured in low pH media: possibility of a new mode of cell killing.
Y Noda
Y Noda
T Kaiya
T Kaiya
K Kohda
K Kohda
Y Kawazoe
Y Kawazoe
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
CHEMICAL & PHARMACEUTICAL BULLETIN (Impact Factor: 1.56). 10/1997; 45(10):1665-70.
Source: PubMed

ABSTRACT Several triterpenes were tested for cytotoxicity by our contrived primary screening method using resting or dormant leukemia L1210 cells after 3 d-preculture without medium change. Some triterpenes were found to be more cytotoxic toward the 3 d-precultured resting cells than toward the growing cells in a fresh medium. These triterpenes are distinguished by highly selective cytotoxicity toward the starved resting cells unlike common anticancer agents. The highest selectivity was shown by betulinic acid, the ratio of its IC50 values toward the growing versus resting cells amounting to 175. It is suggested that this selective cytotoxicity is attributable to low pH (< or = 6.8) of the medium. It is noteworthy that betulinic acid is not cytotoxic at all in media of ordinary pH (> or = 7.0) even after a 48-h exposure. Betulinic acid might be promising as an antitumor agent toward solid tumors because the interior pH of tumor tissues is generally lower than in normal tissues.

http://www.researchgate.net/publication ... ll_killing




Sterol and triterpene derivatives from plants inhibit the effects of a tumor promoter, and sitosterol and betulinic acid inhibit tumor formation in mouse skin two-stage carcinogenesis.
Yasukawa K1, Takido M, Matsumoto T, Takeuchi M, Nakagawa S.
Author information
Abstract

A single topical application of 1 microgram of 12-O-tetradecanoylphorbol- 13-acetate (TPA) to the ears of mice was shown to induce edema, and this TPA-induced inflammation was inhibited by 4-methylsterol and triterpene derivatives. The ED50 of these compounds against TPA-induced inflammation was 0.1-3 mumol. Phytosterols had only slight inhibitory effects. Furthermore, application of 5 micrograms TPA to mouse skin rapidly caused accumulation of ornithine decarboxylase (ODC). Similarly, sitosterol and lupane-type triterpene derivatives markedly inhibited this TPA-induced ODC accumulation. In addition, 5 mumol betulinic acid markedly inhibited the promoting effect of 2.5 micrograms TPA applied twice weekly on skin tumor formation in mice initiated with 50 micrograms of 7,12-dimethylbenz[a]anthracene, and 5 mumol of sitosterol caused slight suppression. Thus, the inhibitory effects of sterol and triterpene derivatives on TPA-induced inflammation roughly parallelled their inhibitory activities against tumor promotion.

http://www.ncbi.nlm.nih.gov/pubmed/1898988



Pharmacokinetics and tissue distribution of betulinic acid in CD-1 mice.
Udeani GO1, Zhao GM, Geun Shin Y, Cooke BP, Graham J, Beecher CW, Kinghorn AD, Pezzuto JM.
Author information
Abstract

Betulinic acid is a naturally occurring pentacyclic triterpenoid. Betulinic acid has recently been selected by the National Cancer Institute for addition into the RAID (Rapid Access to Intervention in Development) programme. The agent exhibits potential anti-tumour activity and functions in this regard via apoptosis. The objective of the present study was to determine the pharmacokinetics of betulinic acid in CD-1 mice. Serum samples were obtained at designed times after a single 250 or 500 mg/kg intraperitoneal (IP) dose of betulinic acid. Tissue samples (skin, heart, liver, spleen, kidney, lung, brain, colon, caecum, ovary, uterus, thymus, lymph node, bladder, perirenal fat, mammary gland and small intestine) were collected after betulinic acid administration (500 mg/kg). Betulinic acid was extracted with methylene chloride and quantitatively analysed by HPLC/MS. Oleanolic acid and madecassic acid were used as internal standards. Pharmacokinetic parameters were calculated using the WinNonlin pharmacokinetic software package. A two-compartment, first-order model was selected for pharmacokinetic modelling. The results showed that after IP 250 and 500 mg/kg betulinic acid, the serum concentrations reached peaks at 0.15 and 0.23 h, respectively. The 250 and 500 mg/kg above betulinic acid IP doses were found to have elimination half-lives of 11.5 and 11.8 h and total clearances of 13.6 and 13.5 L/kg/h, respectively. The pharmacokinetic parameters observed for IP betulinic acid 500 mg/kg in the skin of mice were as follows: k(a) (h(-1)) 0.257, k(10) (h(-1)) 0.234, t(1/2(alpha)) (h) 2.63, t(1/2(beta)) (h) 20.2, V (L/kg) 0.61, AUC (microg/h/mL) 3504, T(max) (h) 3.90 and C(max) (microg/mL) 300.9. The distribution of betulinic acid in tissues at 24 h post-IP administration in a descending order was as follows: perirenal fat, ovary, spleen, mammary gland, uterus, bladder, lymph node, liver, small intestine, caecum, lung, thymus, colon, kidney, skin, heart and brain.

http://www.ncbi.nlm.nih.gov/pubmed/10870094



Effects of betulinic acid alone and in combination with irradiation in human melanoma cells.
Selzer E1, Pimentel E, Wacheck V, Schlegel W, Pehamberger H, Jansen B, Kodym R.
Author information
Abstract

Recently, betulinic acid was identified as a highly selective inhibitor of human melanoma growth and was reported to induce apoptosis in these cells. We have investigated the growth-inhibitory properties of this compound alone and in combination with ionizing radiation in a panel of established human melanoma cell lines as well as in normal human melanocytes. Betulinic acid strongly and consistently suppressed the growth and colony-forming ability of all human melanoma cell lines investigated. In combination with ionizing radiation the effect of betulinic acid on growth inhibition was additive in colony-forming assays. Betulinic acid also induced apoptosis in human melanoma cells as demonstrated by Annexin V binding and by the emergence of cells with apoptotic morphology. The growth-inhibitory action of betulinic acid was more pronounced in human melanoma cell lines than in normal human melanocytes. Notably, despite the induction of apoptosis, analysis of the expression of Bcl-2 family members in betulinic-acid-treated cells revealed that expression of the anti-apoptotic protein Mcl-1 was induced. Furthermore, the antiproliferative action of betulinic acid seemed to be independent of the p53 status. The properties of betulinic acid make it an interesting candidate, not only as a single agent but also in combination with radiotherapy. We conclude that the strictly additive mode of growth inhibition in combination with irradiation suggests that the two treatment modalities may function by inducing different cell death pathways or by affecting different target cell populations.

http://www.ncbi.nlm.nih.gov/pubmed/10771474



Betulinic acid induces apoptosis in human neuroblastoma cell lines.
Schmidt ML1, Kuzmanoff KL, Ling-Indeck L, Pezzuto JM.
Author information
Abstract

Neuroblastoma has long been recognized to show spontaneous regression during fetal development and in the majority of stage 4s infants < 1 year of age with disseminated disease. Stage 4s disease regresses with no chemotherapy in 50% of the patients. The mechanism by which this occurs is not understood but may be programmed cell death or apoptosis. Betulinic acid (BA) has been reported to induce apoptosis in human melanoma with in vitro and in vivo model systems. Melanoma, like neuroblastoma, is derived from the neural crest cell. We hypothesised that neuroblastoma cells have the machinery for programmed cell death and that apoptosis could be induced by betulinic acid. Nine human neuroblastoma cell lines were treated in vitro with BA at concentrations of 0-20 micrograms/ml for 0-6 days. Profound morphological changes were noted within 3 days. Cells withdrew their axonic-like extensions, became non-adherent and condensed into irregular dense spheroids typical of apoptotic cell death (ED50 = 14-17 micrograms/ml). DNA fragmentation analysis showed ladder formation in the 100-1200 bp region in 3/3 neuroblastoma cell lines treated with BA for 24-72 h. Thus, apparently BA does induce AP in neuroblastoma in vitro. This model will be utilised to investigate the role of apoptosis-related genes in neuroblastoma proliferation and to determine the therapeutic efficacy of BA in neuroblastoma in vivo.

http://www.ncbi.nlm.nih.gov/pubmed/9516843



Betulinic acid: a new chemotherapeutic agent in the treatment of neuroectodermal tumors.
Fulda S1, Jeremias I, Pietsch T, Debatin KM.
Author information
Abstract

We identified betulinic acid (BetA) as a new cytotoxic agent active against neuroectodermal tumor cells including neuroblastoma, medulloblastoma, glioblastoma and Ewing's sarcoma cells representing the most common solid tumors of childhood. BetA induced apoptosis independent of wild-type p53 protein and accumulation of death-inducing ligand/receptor systems such as CD95. BetA had a direct effect on mitochondria resulting in the release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-XL that blocked loss of the mitochondrial membrane potential and cytochrome c release from mitochondria conferred resistance to BetA at the level of mitochondrial dysfunction, protease activation and nuclear fragmentation. Neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis remained sensitive to treatment with BetA suggesting that BetA may bypass some forms of resistance. Moreover, BetA exhibited potent antitumor activity on primary tumor cell cultures from all neuroblastoma (4/4), all medulloblastoma (4/4) and most glioblastoma patients (20/24) ex vivo. These findings suggest that BetA may be a promising new agent in the treatment of neuroectodermal tumors in vivo.

http://www.ncbi.nlm.nih.gov/pubmed/10472570



The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis.
Raisova M1, Hossini AM, Eberle J, Riebeling C, Wieder T, Sturm I, Daniel PT, Orfanos CE, Geilen CC.
Author information
Abstract

Defective cytochrome c release and the resulting loss of caspase-3 activation was recently shown to be essential for the susceptibility of human melanoma cells to CD95/Fas-induced apoptosis. Cytochrome c release from mitochondria is regulated by the relative amounts of apoptosis-promoting and apoptosis-inhibiting Bcl-2 proteins in the outer membrane of these organelles. The assignment of Bax/Bcl-2 ratios by quantitative Western blotting in 11 melanoma cell populations revealed a relation to the susceptibility to CD95-mediated apoptosis. We could show that a low Bax/Bcl-2 ratio was characteristic for resistant cells and a high Bax/Bcl-2 ratio was characteristic for sensitive cells. Low Bax expression was not a consequence of mutations in the p53 coding sequence. The Bax/Bcl-2 ratio was also in clear correlation with sensitivity to another cell death inducer, N-acetylsphingosine. Furthermore, Bcl-2 overexpression abolished apoptosis triggered by both apoptotic stimuli, confirming the critical role of the Bax/Bcl-2 ratio as a rheostat that determines the susceptibility to apoptosis in melanoma cells by regulating mitochondrial function. Interestingly, some chemotherapeutics lead to the activation of death pathways by CD95L upregulation, ceramide generation, direct activation of upstream caspases, or upregulation of proapoptotic genes. Taken together, these signals enter the apoptotic pathway upstream of mitochondria, resulting in activation of this central checkpoint. We therefore assumed that apoptosis deficiency of malignant melanoma can be circumvented by drugs directly influencing mitochondrial functions. For this purpose we used betulinic acid, a cytotoxic agent selective for melanoma, straightly perturbing mitochondrial functions. In fact, betulinic acid induced mitochondrial cytochrome c release and DNA fragmentation in both CD95-resistant and CD95-sensitive melanoma cell populations, independent of the Bax/Bcl-2 ratio.

http://www.ncbi.nlm.nih.gov/pubmed/11511312



Betulinic acid reduces ultraviolet-C-induced DNA breakage in congenital melanocytic naeval cells: evidence for a potential role as a chemopreventive agent.
Salti GI1, Kichina JV, Das Gupta TK, Uddin S, Bratescu L, Pezzuto JM, Mehta RG, Constantinou AI.
Author information
Abstract

Melanoma transformation progresses in a multistep fashion from precursor lesions such as congenital naevi. Exposure to ultraviolet (UV) light promotes this process. Betulinic acid (BA) was identified by our group as a selective inhibitor of melanoma that functions by inducing apoptosis. The present study was designed to investigate the effect of BA and UV-C (254 nm) on cultured congenital melanocytic naevi (CMN) cells, using the single-cell gel electrophoresis (comet) assay to detect DNA damage. Exposure to UV light induced a 1.7-fold increase in CMN cells (P = 0.008) when compared with controls. When a p53 genetic suppressor element that encodes a dominant negative polypeptide (termed GSE56) was introduced into the CMN cells, the transfected cells were more sensitive to UV-induced DNA breakage. This suggests that p53 can protect against UV-induced DNA damage and subsequent melanoma transformation. Pretreatment with BA (3 microm) for 48 h resulted in a 25.5% reduction in UV-induced DNA breakage in the CMN cells (P = 0.023), but no changes were observed in the transfected cells. However, Western blot analysis revealed no changes in the p53 or p21 levels in BA-treated cells, suggesting that BA might mediate its action via a non-p53 pathway. These data indicate that BA may have an application as a chemopreventive agent in patients with congenital naevi.

http://www.ncbi.nlm.nih.gov/pubmed/11333133




Biologically active triterpenoids of Syncarpia glomulifera bark extract from Paluma, north Queensland, Australia.
Setzer WN, Setzer MC, Bates RB, Jackes BR.
Abstract

The crude chloroform bark extract of Syncarpia glomulifera (Myrtaceae) shows antibacterial and cytotoxic activity. Bioactivity-directed separation led to the isolation of oleanolic acid-3-acetate, ursolic acid-3-acetate and betulinic acid. The relatively large abundance (10% of the crude extract) and high degree of activity of betulinic acid are responsible for the bioactivity of the crude bark extract.

http://www.ncbi.nlm.nih.gov/pubmed/10763596



23-Hydroxybetulinic acid-mediated apoptosis is accompanied by decreases in bcl-2 expression and telomerase activity in HL-60 Cells.
Ji ZN1, Ye WC, Liu GG, Hsiao WL.
Author information
Abstract

23-Hydroxybetulinic acid, a derivative of betulinic acid, was investigated for its apoptotic effect and the associated telomerase activity in human leukemia HL-60 cells. Apoptosis and bcl-2 were determined by flow cytometry analysis. A PCR-based telomeric repeat amplification protocol assay was used to detect telomerase activity. Results showed that 23-hydroxybetulinic acid induced growth arrest and apoptotic cell death in HL-60 cells. The apoptotic events were associated with concurrent down-regulation of bcl-2 and the telomerase activity. Our data suggest that 23-hydroxybetulinic acid may be a potential cytotoxic agent for treatment of cancer.

http://www.ncbi.nlm.nih.gov/pubmed/12409140



Identification of three triterpenoids in almond hulls.
Takeoka G1, Dao L, Teranishi R, Wong R, Flessa S, Harden L, Edwards R.
Author information
Abstract

Three triterpenoids, betulinic acid, oleanolic acid, and ursolic acid, were isolated as their methyl esters (treatment with diazomethane) from diethyl ether extracts of almond hulls (Nonpareil variety) using flash chromatography and preparative high-performance liquid chromatography. The triterpenoids, which comprised approximately 1% of the hulls, were characterized using chromatographic and spectroscopic methods. These studies demonstrate that almond hulls are a rich source of these triterpenoids, which have reported anti-inflammatory, anti-HIV, and anti-cancer activities.

http://www.ncbi.nlm.nih.gov/pubmed/10956130



Differentiation- and apoptosis-inducing activities by pentacyclic triterpenes on a mouse melanoma cell line.
Hata K1, Hori K, Takahashi S.
Author information
Abstract

In a study to investigate the relationship between the chemical structure and the differentiation-inducing activity of pentacyclic triterpenes, several lupane, oleanane, and ursane triterpenes were prepared and their effects on B16 2F2 melanoma cell differentiation and growth were examined. Eleven lupane triterpenes used in this study acted on the melanoma cells as a melanogen, but no induction of melanogenesis of B16 2F2 cells by oleanane and ursane was detected. The differences at C-17 of the lupane series and acetylation of the OH group at C-3 did not markedly influence their activities. However, the ED(50) value for up-regulation of melanin biosynthesis was markedly decreased by the oxidation of the OH group at C-3 of lupeol (1). Betulinic acid (11), its methyl ester (12), lup-28-al-20(29)-ene-3beta-ol (9), and lup-28-al-20(29)-en-3-one (10) inhibited B16 2F2 cell proliferation by induction of apoptosis. These findings suggested that the carbonyl group at C-17 might be essential for the apoptotic effects of these compounds on B16 2F2 cells.

http://www.ncbi.nlm.nih.gov/pubmed/12027734



Betulinic acid: a new cytotoxic agent against malignant brain-tumor cells.
Fulda S1, Jeremias I, Steiner HH, Pietsch T, Debatin KM.
Author information
Abstract

Malignant brain tumors are the most common solid tumors in children. The overall prognosis for this group of patients is still poor, emphasizing the importance of more effective therapies. Betulinic acid (Bet A) has been described as a novel cytotoxic compound active against melanoma and neuroblastoma cells. Here we report that Bet A was active against medulloblastoma and glioblastoma cell lines. In addition, Bet A exerted cytotoxic activity against primary tumor cells cultured from patients in 4 of 4 medulloblastoma-tumor samples tested and in 20 of 24 glioblastoma-tumor samples. Since a small percentage of primary-glioblastoma-tumor cells (4/24) did not respond to Bet-A treatment, resistance to Bet A might occur. Induction of apoptosis by Bet A involved mitochondrial perturbations, since inhibition of the mitochondrial permeability transition by the mitochondrion-specific inhibitor bongkrekic acid (BA) reduced Bet-A-induced apoptosis. In addition, mitochondria undergoing Bet-A-induced permeability transition triggered DNA fragmentation in isolated nuclei. Cytochrome c was released from mitochondria of Bet-A-treated cells, and might be involved in activation of caspases. Following treatment with Bet A, caspase-8, caspase-3 and PARP were proteolytically processed. Inhibition of caspase cleavage by the broad-range caspase inhibitor zVAD.fmk strongly reduced Bet-A-induced apoptosis, indicating that apoptosis was mediated by activation of caspases. Since Bet A did not exhibit cytotoxicity against murine neuronal cells in vitro, these findings suggest that Bet A may be a promising new agent for the treatment of medulloblastoma and glioblastoma cells that clearly warrants further pre-clinical and clinical evaluation.

http://www.ncbi.nlm.nih.gov/pubmed/10399962



Tumor inhibitory agents from Vauquelinia corymbosa (Rosaceae).
Trumbull ER, Bianchi E, Eckert DJ, Wiedhopf RM, Cole JR.
Abstract

The chloroform extract of Vauquelinia corymbosa Correa has shown activity against the P-388 lymphocytic leukemia test system. The constituents responsible for this activity were identified as uvaol, ursolic acid, and betulinic acid. Their identity was proven by melting point; mixed melting point; elemental analysis; IR, PMR, and mass spectra; and preparation of derivatives.

http://www.ncbi.nlm.nih.gov/pubmed/966165



Microbial transformations of the antimelanoma agent betulinic acid.
Kouzi SA1, Chatterjee P, Pezzuto JM, Hamann MT.
Author information
Abstract

Microbial transformation studies of the antimelanoma agent betulinic acid (1) were conducted. Screening experiments showed a number of microorganisms capable of biotransforming 1. Three of these cultures, Bacillus megaterium ATCC 14581, Cunninghamella elegans ATCC 9244, and Mucor mucedo UI-4605, were selected for preparative scale transformation. Bioconversion of 1 with resting-cell suspensions of phenobarbital-induced B. megaterium ATCC 14581 resulted in the production of the known betulonic acid (2) and two new metabolites: 3beta,7beta-dihydroxy-lup-20(29)-en-28-oic acid (3) and 3beta,6alpha, 7beta-trihydroxy-lup-20(29)-en-28-oic acid (4). Biotransformation of 1 with growing cultures of C. elegans ATCC 9244 produced one new metabolite characterized as 1beta,3beta, 7beta-trihydroxy-lup-20(29)-en-28-oic acid (5). Incubation of 1 with growing cultures of M. mucedo UI-4605 afforded metabolite 3. Structure elucidation of all metabolites was based on NMR and HRMS analyses. In addition, the antimelanoma activity of metabolites 2-5 was evaluated against two human melanoma cell lines, Mel-1 (lymph node) and Mel-2 (pleural fluid).

http://www.ncbi.nlm.nih.gov/pubmed/11141108



Microbial transformations of two lupane-type triterpenes and anti-tumor-promoting effects of the transformation products.
Akihisa T1, Takamine Y, Yoshizumi K, Tokuda H, Kimura Y, Ukiya M, Nakahara T, Yokochi T, Ichiishi E, Nishino H.
Author information
Abstract

Microbial transformation of betulin (1), a lupane-type triterpene obtained from the bark extract of white birch (Betula platyphylla Sukatshev var. japonica), and its chemical oxidation product, betulonic acid (2), by the fungus Chaetomium longirostre yielded 4,28-dihydroxy-3,4-seco-lup-20(29)-en-3-oic acid (3) and 4-hydroxy-3,4-seco-lup-20(29)-ene-3,28-dioic acid (4) from 1, and 4,7beta,17-trihydroxy-3,4-seco-28-norlup-20(29)-en-3-oic acid (5) and 7 beta,15 alpha-dihydoxy-3-oxolup-20(29)-en-28-oic acid (6) from 2. The four metabolites, 3-6, along with 1 and 2, were evaluated for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells as a primary screening test for inhibitors of tumor promotion. All of the triterpenes tested showed potent inhibitory effects, with the four metabolites 3-6 exhibiting the more potent effects.

http://www.ncbi.nlm.nih.gov/pubmed/11908965




Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: identification of the inhibitory step, the major functional group responsible and development of more potent derivatives.
Chowdhury AR1, Mandal S, Mittra B, Sharma S, Mukhopadhyay S, Majumder HK.
Author information
Abstract
BACKGROUND:

Betulinic acid, a naturally abundant, plant derived, pentacyclic triterpenoid possesses anti-HIV, anti-malarial and anti-inflammatory properties and has recently emerged as a potent anti-tumor compound. This study explores the mode of action of betulinic acid on eukaryotic topoisomerase I and identifies the major functional group responsible along with more potent derivatives.
MATERIAL/METHODS:

Topoisomerase I relaxation activity was electrophoretically measured by the decreased mobility of the relaxed monomers followed by ethidium bromide staining. DNA cleavage was studied by electrophoretic separation of the nicked monomers from the relaxed and supercoiled monomers in presence of ethidium bromide. In-vivo DNA cleavage was studied in blasted mouse splenocytes by the SDS-K+ trapping of 3H-DNA-topoisomerase I-camptothecin ternary complex.
RESULTS:

Betulinic acid exerts its inhibitory effect by preventing topoisomerase I-DNA interaction as a result of which the 'cleavable complex' is not formed. In consequence, it also acts as an antagonist to camptothecin-mediated cleavage. A series of analogues modified at C-3, C-17 and C-20 positions of betulinic acid were subsequently assayed for inhibition of topoisomerase I catalytic activity. Replacement of the 17-carboxylic group reduces the inhibitory effect and decarboxylation leads to the complete loss of inhibitory effect.
CONCLUSIONS:

This study is the first detail report of betulinic acid as a very potent inhibitior of eukaryotic topoisomerase I and highlights the necessity of the carboxylic functional group. Dihydro betulinic acid is the most potent (IC50=0.5 mM) pentacyclic triterpenoid to inhibit eukaryotic topoisomerase I till date and can be exploited as a strong candidate for anti-tumor drug designing.

http://www.ncbi.nlm.nih.gov/pubmed/12118187



Preparation and cytotoxic effect of ceanothic acid derivatives.
Lee SS1, Chen WC, Huang CF, Su Y.
Author information
Abstract

Six ceanothane and 1-norceanothane derivatives (1, 2, 8-11) were prepared from ceanothic acid dibenzyl ester. These ring-A homologues of betulinic acid exhibited cytotoxic effects. Among these, 1-decarboxy-3-oxo-ceanothic acid (2) was found to be the most cytotoxic against OVCAR-3 and HeLa cancer cell lines, with an IC50 of 2.8 and 6.6 microg/mL, respectively, and an IC50 of 11.3 microg/mL against normal cell line FS-5.

http://www.ncbi.nlm.nih.gov/pubmed/9834149




Betulinic acid inhibits aminopeptidase N activity.
Melzig MF, Bormann H.
Abstract

The triterpene betulinic acid inhibits the activity of aminopeptidase N (EC 3.4.11.2) in a dose-dependent manner. An IC50 of 7.3 +/- 1.4 microM was determined for betulinic acid. This inhibitory activity is higher than that of bestatin' (IC50 = 16.9 +/- 4.1 microM), a well known inhibitor of this enzyme. The finding supports the idea that betulinic acid acts as anti-melanoma agent via inhibition of aminopeptidase N activity.

http://www.ncbi.nlm.nih.gov/pubmed/9810272



Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells.
Fulda S1, Susin SA, Kroemer G, Debatin KM.
Author information
Abstract

Apoptosis mediated by anticancer drugs may involve activation of death-inducing ligand/receptor systems such as CD95 (APO-1/Fas), cleavage of caspases, and perturbance of mitochondrial functions. We investigated the sequence of these events in SHEP neuroblastoma cells transfected with Bcl-2 or Bcl-X(L) using two different drugs, namely, doxorubicin (Doxo), which activates the CD95/CD95 ligand (CD95-L) system, and betulinic acid (Bet A), which does not enhance the expression of CD95 or CD95-L and which, as shown here, directly targets mitochondria. Apoptosis induced by both drugs was inhibited by Bcl-2 or Bcl-X(L) overexpression or by bongkrekic acid, an agent that stabilizes mitochondrial membrane barrier function, suggesting a critical role for mitochondria. After Doxo treatment, enhanced CD95/CD95-L expression and caspase-8 activation were not blocked by Bcl-2 or Bcl-X(L) and were found in cells with a mitochondrial transmembrane potential (delta psi(m)) that was still normal (delta psi(m)high cells). In marked contrast, after Bet A treatment, caspase-8 activation occurred in a Bcl-2- or Bcl-X(L)-inhibitable fashion and was confined to cells that had lost their delta psi(m) (delta psi(m)low cells). Mitochondria from cells treated with either Doxo or Bet A induced cleavage of both caspase-8 and caspase-3 in cytosolic extracts. Thus, caspase-8 activation may occur upstream or downstream of mitochondria, depending on the apoptosis-initiating stimulus. In contrast to caspase-8, cleavage of caspase-3 or poly(ADP-ribose)polymerase was always restricted to delta psi(m)low cells, downstream of the Bcl-2- or Bcl-X(L)-controlled checkpoint of apoptosis. Cytochrome c, released from mitochondria undergoing permeability transition, activated caspase-3 but not caspase-8 in a cell-free system. However, both caspases were activated by apoptosis-inducing factor, indicating that the mechanism of caspase-8 activation differed from that of caspase-3 activation. Taken together, our findings demonstrate that perturbance of mitochondrial function constitutes a central coordinating event in drug-induced cell death.

http://www.ncbi.nlm.nih.gov/pubmed/9766678



Synthesis of betulinic acid derivatives with activity against human melanoma.
Kim DS1, Pezzuto JM, Pisha E.
Author information
Abstract

Betulinic acid has been modified at C-3, C-20, and C-28 positions and the toxicity of the derivatives has been evaluated against cultured human melanoma (MEL-2) and human epidermoid carcinoma of the mouth (KB) cell lines. This preliminary investigation demonstrates that simple modifications of the parent structure of betulinic acid can produce potentially important derivatives, which may be developed as antitumor drugs.

http://www.ncbi.nlm.nih.gov/pubmed/9873420



Preparation of amino acid conjugates of betulinic acid with activity against human melanoma.
Jeong HJ1, Chai HB, Park SY, Kim DS.
Author information
Abstract

Betulinic acid has been coupled with a series of amino acids at C-28 carboxylic acid position and the toxicity of the derivatives has been evaluated against cultured human melanoma (MEL-2) and human epidermoid carcinoma of the mouth (KB) cell lines. A number of amino acid conjugates of betulinic acid showed improved water solubility as well as selective cytotoxicity. This investigation demonstrates that amino acid conjugates of betulinic acid can produce potentially important derivatives, which may be developed as antitumor agents.

http://www.ncbi.nlm.nih.gov/pubmed/10328313


Betulinic acid inhibits growth factor-induced in vitro angiogenesis via the modulation of mitochondrial function in endothelial cells.
Kwon HJ1, Shim JS, Kim JH, Cho HY, Yum YN, Kim SH, Yu J.
Author information
Abstract

Betulinic acid (BetA), a pentacyclic triterpene, is a selective apoptosis-inducing agent that works directly in mitochondria. Recent study has revealed that BetA inhibits in vitro enzymatic activity of aminopeptidase N (APN, EC 3.4.11.2), which is known to play an important role in angiogenesis, but the anti-angiogenic activity of BetA has not been reported yet. Data presented here show that BetA potently inhibited basic fibroblast growth factor (bFGF)-induced invasion and tube formation of bovine aortic endothelial cells (BAECs) at a concentration which had no effect on the cell viability. To access whether the anti-angiogenic nature of BetA originates from its inhibitory action against aminopeptidase N (APN) activity, the effect of BetA on APN was investigated. Surprisingly, BetA did not inhibit in vivo APN activity in endothelial cells or APN-positive tumor cells. On the other hand, BetA significantly decreased the mitochondrial reducing potential, and treatment with mitochondrial permeability transition (MPT) inhibitors attenuated BetA-induced inhibition of endothelial cell invasion. These results imply that anti-angiogenic activity of BetA occurs through a modulation of mitochondrial function rather than APN activity in endothelial cells.

http://www.ncbi.nlm.nih.gov/pubmed/11985792




Betulinic acid sensitization of low pH adapted human melanoma cells to hyperthermia.
Wachsberger PR1, Burd R, Wahl ML, Leeper DB.
Author information
Abstract

Betulinic acid is a known inducer of apoptosis in human melanoma that is most effective under conditions of low pH. It was hypothesized that betulinic acid, in combination with acute acidification and/or hyperthermia, would induce higher levels of apoptosis and cytotoxicity in low pH-adapted human melanoma cells than in cells grown at pH 7.3. DB-1 human melanoma cells, adapted to a tumour-like growth pH of 6.7, were exposed to hyperthermia (2h at 42 degrees C) and/or betulinic acid (4-10 microg/ml) and compared with cells grown at a physiological pH of 7.3 or after acute acidification from pH 7.3-6.3 or pH 6.7-6.3. Betulinic acid induced higher levels of apoptosis and cytotoxicity in low pH-adapted cells than in cells grown at pH 7.3, as measured by the terminal deoxynucleotidyl transferase (TdT) DNA fragmentation assay (TUNEL), the MTS cell viability assay, and single cell survival. Acute acidification of low pH adapted cells rendered them more susceptible to betulinic acid-induced apoptosis and cytotoxicity. In the presence of hyperthermia at 42 degrees C for 2 h, cells grown at pH 7.3 were not sensitized to heat killing by betulinic acid, whereas cells grown at pH 7.3 and acutely acidified to pH 6.3, cells adapted to growth at pH 6.7 and cells adapted to growth at pH 6.7 and acutely acidified to pH 6.3 were all similarly sensitized to heat killing by betulinic acid, with survival values of 5, 9 and 2%, respectively. It is concluded that betulinic acid may be useful in potentiating the therapeutic efficacy of hyperthermia as a cytotoxic agent in acidotic areas of tumours with minimal effect in normal tissues growing at pH 7.3.

http://www.ncbi.nlm.nih.gov/pubmed/11911485



[Are mitochondria targets of anticancer drugs responsible for apoptosis?].
[Article in French]
Marchetti P1, Mortier L, Beauvillain V, Formstecher P.
Author information
Abstract

The vast majority of both chemical and physical anticancer treatments act through the induction of apoptotic cell death in vitro and in vivo. In numerous experimental systems, the apoptotic processes can be divided into three different phases. In the first one, multiple pro-apoptotic signal transduction pathways (e.g. P53, ROS production, etc.) are activated by various factors including anti cancer drugs. This first step is followed by an intermediate phase in which pro-apoptotic signals converge to mitochondria which in turn can finally trigger the last degradation phase of apoptosis. Consequently, mitochondria, play a pivotal role in the executive phase of apoptosis and could represent a novel attractive target for pro-apoptotic drugs. Indeed, unlike conventional anti tumour drugs which trigger pro-apoptotic signal transduction pathways upstream mitochondria, several compounds were shown to act directly on mitochondria to induce apoptosis. These drugs include betulinic acid, lonidamine, arsenic trioxide and two retinoids like CD437/AHPN and fenretinide/4-HPR. This review summarizes new data concerning these drugs targetted to mitochondria and highlights the new perspective they may offer in cancer therapy.

http://www.ncbi.nlm.nih.gov/pubmed/12147443



Effect of three triterpenoids, lupeol, betulin, and betulinic acid on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils.
Yamashita K1, Lu H, Lu J, Chen G, Yokoyama T, Sagara Y, Manabe M, Kodama H.
Author information
Abstract
BACKGROUND:

The roots of Anemone raddeana are used in Chinese folk medicine for curing rheumatism and neuralgia.
METHODS:

The three triterpenoids lupeol, betulin and betulinic acid were isolated from ethanol extracts of the roots of A. raddeana. The effect of these triterpenoids on superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils was investigated.
RESULTS:

The superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was significantly suppressed by betulin and lupeol depending on the concentration of the triterpenoids. The suppressive effect of betulinic acid was low. The phorbol 12-myristate 13-acetate (PMA)-induced superoxide generation was suppressed by betulin in a concentration-dependent manner, but not by lupeol and betulinic acid. In contrast, the superoxide generation induced by arachidonic acid (AA) was suppressed by lupeol, while betulin and betulinic acid weakly enhanced the AA-induced superoxide generation. Lupeol and betulin suppressed tyrosyl phosphorylation of a 45.0-kDa protein in fMLP-treated human neutrophils in parallel to the suppression of fMLP-induced superoxide generation, but betulinic acid did not. Lupeol, betulin and betulinic acid showed no hemolytic effect even at a concentration of 500 micromol/l.
CONCLUSIONS:

Lupeol and betulin suppress superoxide generation by preventing tyrosyl phosphorylation of a 45.0-kDa protein in human neutrophils, and may have pharmaceutical applications.

http://www.ncbi.nlm.nih.gov/pubmed/12367771



Investigations on the steroidal anti-inflammatory activity of triterpenoids from Diospyros leucomelas.
Recio MC1, Giner RM, Máñez S, Gueho J, Julien HR, Hostettmann K, Ríos JL.
Author information
Abstract

Three triterpenes were isolated from Diospyros leucomelas and identified as betulin, betulinic acid, and ursolic acid. They showed anti-inflammatory activity in the carrageenan and serotonin paw edema tests and TPA and EPP ear edema tests. The blockade of their effects by progesterone, actinomycin D, and cycloheximide has served to determine the mechanism of action in relationship with that of glucocorticoids. Betulinic acid was the most affected and therefore a mode of action similar to these drugs may be postulated for it.

http://www.ncbi.nlm.nih.gov/pubmed/7701004




Activity-guided fractionation of the seeds of Ziziphus jujuba using a cyclooxygenase-2 inhibitory assay.
Su BN1, Cuendet M, Farnsworth NR, Fong HH, Pezzuto JM, Kinghorn AD.
Author information
Abstract

Bioactivity-guided fractionation of petroleum ether- and EtOAc-soluble extracts of the seeds of Ziziphus jujuba using a cyclooxygenase-2 assay as a monitor indicated that the triglyceride, 1,3-di-O-[9(Z)-octadecenoyl]-2-O-[9(Z),12(Z)-octadecadienoyl]glycerol (3), and a fatty acid mixture of linoleic, oleic and stearic acids, were the major active components. A new pentacyclic lupane-type triterpene derivative, 3-O-[9(Z)-octadecenoyl]betulinic acid (1), and betulinic acid (2) were also isolated and identified. All isolates as well as pure linoleic, oleic and stearic acids were evaluated for their inhibitory effects against both cyclooxygenases-1 (COX-1) and -2 (COX-2).

http://www.ncbi.nlm.nih.gov/pubmed/12494342



Constituents in evening primrose oil with radical scavenging, cyclooxygenase, and neutrophil elastase inhibitory activities.
Hamburger M1, Riese U, Graf H, Melzig MF, Ciesielski S, Baumann D, Dittmann K, Wegner C.
Author information
Abstract

Cold-pressed, non-raffinated evening primrose oil was found to contain lipophilic radical scavengers. A highly enriched fraction of these compounds could be obtained from the oil by extraction with aqueous ethanol and subsequent liquid-liquid partitioning with petroleum. LC-DAD-MS analysis revealed that the fraction contained three aromatic compounds with identical UV and ESI-MS spectra. The compounds were isolated by RP-HPLC and their structures established by chemical and spectroscopic means as 3-O-trans-caffeoyl derivatives of betulinic, morolic, and oleanolic acid. The morolic acid derivative was a new compound. The three esters exhibited pronounced radical scavenging activity against the stable 2,2-diphenyl-1-picrylhydrazyl radical and were potent inhibitors of neutrophil elastase and cyclooxygenase-1 and -2 in vitro. Commercial samples of evening primrose oils contained only traces of these lipophilic antioxidants.

http://www.ncbi.nlm.nih.gov/pubmed/12236675

Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 5275
Registrado: Dom, 01 Sep 2013, 14:18

Re: Nutrición contra el cancer

Notapor Fisio » Lun, 08 Sep 2014, 08:42

Ácido Betulínico


Betulinic acid as a potent and complex antitumor phytochemical: a minireview.
Gheorgheosu D, Duicu O, Dehelean C, Soica C, Muntean D1.
Author information
Abstract

Betulinic acid (BA), a natural compound with a lupan skeleton, has been highly investigated in the past decade for a plethora of beneficial properties, including anti-cancer, anti-inflammatory, anti-angiogenic, immune-modulatory, and anti-HIV effects. In particular, BA has been reported to be effective in vitro against tumor cell lines of different origins, and also in vivo, in animal models of cancer. The best characterized mechanism of its antitumor effect consists of triggering apoptosis via the mitochondrial pathway. BA has also an anti-metastatic effect via the prevention of the epithelial-to-mesencymal transition in highly aggressive melanoma cells. Furthermore, in the same model, BA is able to counteract the pro-invasive potential of the pro-tumoral protein neutrophil gelatinaseassociated lipocalin. The present review addresses the current state of knowledge regarding the anti-tumor effects of betulinic acid, a potent chemotherapeutic agent.

http://www.ncbi.nlm.nih.gov/pubmed/24568161



Proteomic Investigation into Betulinic Acid-Induced Apoptosis of Human Cervical Cancer HeLa Cells.
Xu T, Pang Q, Zhou D, Zhang A, Luo S, Wang Y, Yan X.
Author information
Abstract

Betulinic acid is a pentacyclic triterpenoid that exhibits anticancer functions in human cancer cells. This study provides evidence that betulinic acid is highly effective against the human cervical cancer cell line HeLa by inducing dose- and time-dependent apoptosis. The apoptotic process was further investigated using a proteomics approach to reveal protein expression changes in HeLa cells following betulinic acid treatment. Proteomic analysis revealed that there were six up- and thirty down-regulated proteins in betulinic acid-induced HeLa cells, and these proteins were then subjected to functional pathway analysis using multiple analysis software. UDP-glucose 6-dehydrogenase, 6-phosphogluconate dehydrogenase decarboxylating, chain A Horf6-a novel human peroxidase enzyme that involved in redox process, was found to be down-regulated during the apoptosis process of the oxidative stress response pathway. Consistent with our results at the protein level, an increase in intracellular reactive oxygen species was observed in betulinic acid-treated cells. The proteins glucose-regulated protein and cargo-selection protein TIP47, which are involved in the endoplasmic reticulum pathway, were up-regulated by betulinic acid treatment. Meanwhile, 14-3-3 family proteins, including 14-3-3β and 14-3-3ε, were down-regulated in response to betulinic acid treatment, which is consistent with the decrease in expression of the target genes 14-3-3β and 14-3-3ε. Furthermore, it was found that the antiapoptotic bcl-2 gene was down-regulated while the proapoptotic bax gene was up-regulated after betulinic acid treatment in HeLa cells. These results suggest that betulinic acid induces apoptosis of HeLa cells by triggering both the endoplasmic reticulum pathway and the ROS-mediated mitochondrial pathway.

http://www.ncbi.nlm.nih.gov/pubmed/25148076



Inhibition of estrogen signaling through depletion of estrogen receptor alpha by ursolic acid and betulinic acid from Prunella vulgaris var. lilacina.
Kim HI1, Quan FS2, Kim JE1, Lee NR1, Kim HJ1, Jo SJ1, Lee CM1, Jang DS3, Inn KS4.
Author information
Abstract

Extracts of Prunella vulgaris have been shown to exert antiestrogenic effects. To identify the compounds responsible for these actions, we isolated the constituents of P. vulgaris and tested their individual antiestrogenic effects. Rosmarinic acid, caffeic acid, ursolic acid (UA), oleanolic acid, hyperoside, rutin and betulinic acid (BA) were isolated from the flower stalks of P. vulgaris var. lilacina Nakai (Labiatae). Among these constituents, UA and BA showed significant antiestrogenic effects, measured as a decrease in the mRNA level of GREB1, an estrogen-responsive protein; the effects of BA were stronger than those of UA. UA and BA were capable of suppressing estrogen response element (ERE)-dependent luciferase activity and expression of estrogen-responsive genes in response to exposure to estradiol, further supporting the suppressive role of these compounds in estrogen-induced signaling. However, neither UA nor BA was capable of suppressing estrogen signaling in cells ectopically overexpressing estrogen receptor α (ERα). Furthermore, both mRNA and protein levels of ERα were reduced by treatment with UA or BA, suggesting that UA and BA inhibit estrogen signaling by suppressing the expression of ERα. Interestingly, both compounds enhanced prostate-specific antigen promoter activity. Collectively, these findings demonstrate that UA and BA are responsible for the antiestrogenic effects of P. vulgaris and suggest their potential use as therapeutic agents against estrogen-dependent tumors.

http://www.ncbi.nlm.nih.gov/pubmed/25088993



Antioxidant value and antiproliferative efficacy of mitragynine and a silane reduced analogue.
Goh TB1, Koh RY, Mordi MN, Mansor SM.
Author information
Abstract
BACKGROUND:

To investigate the antioxidant value and anticancer functions of mitragynine (MTG) and its silane-reduced analogues (SRM) in vitro.
MATERIALS AND METHODS:

MTG and SRM was analyzed for their reducing power ability, ABTS radical inhibition and 1,1-diphenyl-2-picryl hydrazylfree radicals scavenging activities. Furthermore, the antiproliferation efficacy was evaluated using MTT assay on K 562 and HCT116 cancer cell lines versus NIH/3T3 and CCD18-Co normal cell lines respectively.
RESULTS:

SRM and MTG demonstrate moderate antioxidant value with ABTS assay (Trolox equivalent antioxidant capacity (TEAC): 2.25±0.02 mmol trolox / mmol and 1.96±0.04 mmol trolox / mmol respectively) and DPPH (IC50=3.75±0.04 mg/mL and IC50=2.28±0.02 mg/mL respectively). Both MTG and SRM demonstrate equal potency (IC50=25.20±1.53 and IC50= 22.19±1.06 respectively) towards K 562 cell lines, comparable to control, betulinic acid (BA) (IC5024.40±1.26). Both compounds showed concentration-dependent cytototoxicity effects and exert profound antiproliferative efficacy at concentration > 100 μM towards HCT 116 and K 562 cancer cell lines, comparable to those of BA and 5-FU (5-Fluorouracil). Furthermore, both MTG and SRM exhibit high selectivity towards HCT 116 cell lines with selective indexes of 3.14 and 2.93 respectively compared to 5-FU (SI=0.60).
CONCLUSIONS:

These findings revealed that the medicinal and nutitional values of mitragynine obtained from ketum leaves that growth in tropical forest of Southeast Asia and its analogues does not limited to analgesic properties but could be promising antioxidant and anticancer or chemopreventive compounds.

http://www.ncbi.nlm.nih.gov/pubmed/25081682




Interesante tocoferoles inhibiendo la actividad apoptótica, insisto, cuidado con los antioxidantes.

Betulinic Acid-Induced Cytotoxicity in Human Breast Tumor Cell Lines MCF-7 and T47D and its Modification by Tocopherol.
Tiwari R1, Puthli A, Balakrishnan S, Sapra BK, Mishra KP.
Author information
Abstract

Betulinic acid (BA) has been shown to cause apoptosis in neuroblastoma and melanoma cell lines. We evaluated the cytotoxicity of BA in two breast cancer cell lines MCF-7 and T47D differing in their p53 status. Treatment with BA resulted in a dose dependent inhibition of cell proliferation and induction of apoptosis. This indicates p53-independent apoptotic pathway, because response of both p53 mutant and wild type cell line were found unaffected after treatment with pifithrin-α, an inhibitor of p53. Cells were significantly protected when treated by tocopherol suggesting involvement of membrane centered lipid peroxidation-mediated mechanism in BA-induced apoptosis.

http://www.ncbi.nlm.nih.gov/pubmed/25019212



Strong anticancer potential of nano-triterpenoid from Phytolacca decandra against A549 adenocarcinoma via a Ca(2+)-dependent mitochondrial apoptotic pathway.
Das J1, Das S1, Paul A1, Samadder A1, Khuda-Bukhsh AR2.
Author information

1Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani 741235, India.
2Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani 741235, India. Electronic address: prof_arkb@yahoo.co.in.

Abstract

We isolated a triterpenoid from an ethanolic extract of Phytolacca decandra and nanoencapsulated it with biodegradable nontoxic polymers of poly(lactide-co-glycolide) to examine if the nanoform of this hitherto unexplored betulinic-acid derivative (NdBA) could produce a stronger anticancer effect by rendering better drug bioavailability and targeted delivery than the nonencapsulated betulinic-acid derivative (dBA). The nanoparticles were characterized with the help of physicochemical and morphological studies involving dynamic light scattering and atomic force microscopy. A549 cancer cells were exposed to NdBA and dBA at the IC50 doses of 50 μg/mL and 100 μg/mL, respectively. Mitochondrial dysfunction-mediated apoptosis was determined by examining the changes in the intracellular calcium content, the reactive oxygen species accumulation, the cytochrome c release, the upregulation of Bcl-2-associated-X protein (Bax) and caspase 3, the downregulation of B cell lymphoma 2, and the mitochondrial membrane potential (ΔΨm) depolarization. Apoptosis was also verified by acridine orange staining observed under fluorescence microscopy and annexin V-fluorescein isothiocyanate/propidium iodide staining through flow cytometric studies. The levels of intracellular adenosine triphosphate/adenosine diphosphate ratio decreased, and the ATPase activity increased more strikingly in A549 cells exposed to NdBA than in A549 cells exposed to dBA. Overall results showed that both drugs directly target the mitochondrial oxidative phosphorylation system, with NdBA having a stronger effect, indicating NdBA to be a better candidate for the development of an anticancer drug for use against lung adenocarcinomas.

http://www.ncbi.nlm.nih.gov/pubmed/24929458




Betulinic acid-induced mitochondria-dependent cell death is counterbalanced by an autophagic salvage response.
Potze L, Mullauer FB, Colak S, Kessler JH, Medema JP.
Author information
Abstract

Betulinic acid (BetA) is a plant-derived pentacyclic triterpenoid that exerts potent anti-cancer effects in vitro and in vivo. It was shown to induce apoptosis via a direct effect on mitochondria. This is largely independent of proapoptotic BAK and BAX, but can be inhibited by cyclosporin A (CsA), an inhibitor of the permeability transition (PT) pore. Here we show that blocking apoptosis with general caspase inhibitors did not prevent cell death, indicating that alternative, caspase-independent cell death pathways were activated. BetA did not induce necroptosis, but we observed a strong induction of autophagy in several cancer cell lines. Autophagy was functional as shown by enhanced flux and degradation of long-lived proteins. BetA-induced autophagy could be blocked, just like apoptosis, with CsA, suggesting that autophagy is activated as a response to the mitochondrial damage inflicted by BetA. As both a survival and cell death role have been attributed to autophagy, autophagy-deficient tumor cells and mouse embryo fibroblasts were analyzed to determine the role of autophagy in BetA-induced cell death. This clearly established BetA-induced autophagy as a survival mechanism and indicates that BetA utilizes an as yet-undefined mechanism to kill cancer cells.

http://www.ncbi.nlm.nih.gov/pubmed/24722294




Betulinic acid isolated from Vitis amurensis root inhibits 3-isobutyl-1-methylxanthine induced melanogenesis via the regulation of MEK/ERK and PI3K/Akt pathways in B16F10 cells.
Jin KS1, Oh YN1, Hyun SK2, Kwon HJ3, Kim BW4.
Author information
Abstract

Previously, betulinic acid was identified as one of the main compounds responsible for the anti-melanogenic effect in Vitis amurensis root. In this study, we investigated the precise mechanism underlying the anti-melanogenic activity of betulinic acid in B16F10 cells. Betulinic acid significantly attenuated 3-isobutyl-1-methylxanthine (IBMX)-induced melanin production by inhibiting tyrosinase, tyrosinase related protein (TRP)-1, and TRP-2 expression through the modulation of their corresponding transcription factors, microphthalamia associated transcription factor (MITF) and cAMP response element binding protein (CREB), in B16F10 cells. In addition, phosphorylation of mitogen-activated protein kinase kinase (MEK)/extracellular regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt, involved in the melanogenic processes, were ameliorated by betulinic acid treatment. Role of MEK/ERK and PI3K/Akt signaling pathway in the melanogenesis was confirmed by using specific inhibitors, PD98059 (for MEK/ERK) and LY294002 (for PI3K/Akt), respectively. As a result, betulinic acid inhibited melanin production by tyrosinase, TRP-1, and TRP-2 inhibition through the regulation of CREB and MITF, which was accompanied with MEK/ERK and PI3K/Akt inactivation in IBMX-stimulated B16F10 cells. Consequently, these results demonstrate a novel molecular function of betulinic acid derived from V. amurensis root in melanogenesis, which in turn enhances our understanding on the application of cosmetic therapy for reducing skin hyperpigmentation.

http://www.ncbi.nlm.nih.gov/pubmed/24632067



Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment.
Park SY1, Kim HJ1, Kim KR1, Lee SK1, Lee CK1, Park KK2, Chung WY3.
Author information
Abstract

Many breast cancer patients experience bone metastases and suffer skeletal complications. The present study provides evidence on the protective and therapeutic potential of betulinic acid on cancer-associated bone diseases. Betulinic acid is a naturally occurring triterpenoid with the beneficial activity to limit the progression and severity of cancer, diabetes, cardiovascular diseases, atherosclerosis, and obesity. We first investigated its effect on breast cancer cells, osteoblastic cells, and osteoclasts in the vicious cycle of osteolytic bone metastasis. Betulinic acid reduced cell viability and the production of parathyroid hormone-related protein (PTHrP), a major osteolytic factor, in MDA-MB-231 human metastatic breast cancer cells stimulated with or without tumor growth factor-β. Betulinic acid blocked an increase in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin ratio by downregulating RANKL protein expression in PTHrP-treated human osteoblastic cells. In addition, betulinic acid inhibited RANKL-induced osteoclastogenesis in murine bone marrow macrophages and decreased the production of resorbed area in plates with a bone biomimetic synthetic surface by suppressing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Furthermore, oral administration of betulinic acid inhibited bone loss in mice intra-tibially inoculated with breast cancer cells and in ovariectomized mice causing estrogen deprivation, as supported by the restored bone morphometric parameters and serum bone turnover markers. Taken together, these findings suggest that betulinic acid may have the potential to prevent bone loss in patients with bone metastases and cancer treatment-induced estrogen deficiency.

http://www.ncbi.nlm.nih.gov/pubmed/24463094




A-ring modified betulinic acid derivatives as potent cancer preventive agents.
Hung HY1, Nakagawa-Goto K2, Tokuda H3, Iida A4, Suzuki N3, Bori ID5, Qian K6, Lee KH7.
Author information
Abstract

Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1×10(3) mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5×10(2), 1×10(2), and 1×10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.

http://www.ncbi.nlm.nih.gov/pubmed/24411124




Design, synthesis, and anti-tumor activity of novel betulinic acid derivatives.
Liu JH1, Tang J, Zhu ZF, Chen L.
Author information
Abstract

Seventeen new derivatives of betulinic acid (BA) with potential anti-tumor activity have been synthesized. In order to improve the bioactivity of BA, we connected BA and nitric oxide donors together via different linkers. The results of the biological activity of these derivatives showed that four compounds exhibited obvious cytotoxicity against human hepatocellular carcinoma cells in vitro.

http://www.ncbi.nlm.nih.gov/pubmed/24350921




Lamin B1 is a novel therapeutic target of betulinic acid in pancreatic cancer.
Li L1, Du Y, Kong X, Li Z, Jia Z, Cui J, Gao J, Wang G, Xie K.
Author information
Abstract
PURPOSE:

Betulinic acid, a naturally occurring pentacyclic triterpenoid, exhibits potent antitumor activities, whereas the underlying mechanisms remain unclear. In the current study, we sought to determine the role and regulation of lamin B1 expression in human pancreatic cancer pathogenesis and betulinic acid-based therapy.
EXPERIMENTAL DESIGN:

We used cDNA microarray to identify betulinic acid target genes and used tissue microarray to determine the expression levels of lamin B1 in pancreatic cancer tissues and to define their relationship with the clinicopathologic characteristics of pancreatic cancer. We also used in vitro and in vivo models to determine the biologic impacts of altered lamin B1 expression on and mechanisms underlying lamin B1 overexpression in human pancreatic cancer.
RESULTS:

We found that lamin B1 was significantly downregulated by betulinic acid treatment in pancreatic cancer in both in vitro culture and xenograft models. Overexpression of lamin B1 was pronounced in human pancreatic cancer, and increased lamin B1 expression was directly associated with low-grade differentiation, increased incidence of distant metastasis, and poor prognosis of patients with pancreatic cancer. Furthermore, knockdown of lamin B1 significantly attenuated the proliferation, invasion, and tumorigenicity of pancreatic cancer cells.
CONCLUSIONS:

Lamin B1 plays an important role in pancreatic cancer pathogenesis and is a novel therapeutic target of betulinic acid treatment.

http://www.ncbi.nlm.nih.gov/pubmed/23857605




Betulinic acid selectively increases protein degradation and enhances prostate cancer-specific apoptosis: possible role for inhibition of deubiquitinase activity.
Reiner T1, Parrondo R, de Las Pozas A, Palenzuela D, Perez-Stable C.
Author information
Abstract

Inhibition of the ubiquitin-proteasome system (UPS) of protein degradation is a valid anti-cancer strategy and has led to the approval of bortezomib for the treatment of multiple myeloma. However, the alternative approach of enhancing the degradation of oncoproteins that are frequently overexpressed in cancers is less developed. Betulinic acid (BA) is a plant-derived small molecule that can increase apoptosis specifically in cancer but not in normal cells, making it an attractive anti-cancer agent. Our results in prostate cancer suggested that BA inhibited multiple deubiquitinases (DUBs), which resulted in the accumulation of poly-ubiquitinated proteins, decreased levels of oncoproteins, and increased apoptotic cell death. In normal fibroblasts, however, BA did not inhibit DUB activity nor increased total poly-ubiquitinated proteins, which was associated with a lack of effect on cell death. In the TRAMP transgenic mouse model of prostate cancer, treatment with BA (10 mg/kg) inhibited primary tumors, increased apoptosis, decreased angiogenesis and proliferation, and lowered androgen receptor and cyclin D1 protein. BA treatment also inhibited DUB activity and increased ubiquitinated proteins in TRAMP prostate cancer but had no effect on apoptosis or ubiquitination in normal mouse tissues. Overall, our data suggests that BA-mediated inhibition of DUBs and induction of apoptotic cell death specifically in prostate cancer but not in normal cells and tissues may provide an effective non-toxic and clinically selective agent for chemotherapy.

http://www.ncbi.nlm.nih.gov/pubmed/23424652




Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro.
Yang LJ1, Chen Y, He J, Yi S, Wen L, Zhao J, Zhang BP, Cui GH.
Author information
Abstract
AIM:

To investigate the effects of betulinic acid (BA) on apoptosis and autophagic flux in multiple myeloma cells and the relationship between the two processes.
METHODS:

The proliferation of human multiple myeloma KM3 cells was measured with MTT assay. FITC/PI double-labeled flow cytometry (FCM) and Hoechst 33258 staining were used to analyze the cell apoptosis. Caspase 3, PARP, Beclin1, LC3-II, and P62 were detected using Western blotting.
RESULTS:

Treatment of KM3 cells with BA (5-25 μg/mL) suppressed the cell proliferation in time- and dose-dependent manners. The IC(50) values at 12, 24, and 36 h were 22.29, 17.36, and 13.06 μg/mL, respectively. BA treatment dose-dependently induced apoptosis of KM3 cells, which was associated with the activation of caspase 3. However, Z-DEVD-FMK, a specific inhibitor of caspase 3, did not decrease, but rather sensitized the cells to BA-induced apoptosis, suggesting an alternative mechanism involved. On other hand, BA treatment dose-dependently increased the accumulation of LC3-II and P62 in KM3 cells, representing the inhibition of autophagic flux. Furthermore, BA treatment dose-dependently downregulated the expression of Beclin 1, an important inducer of autophagy, in KM3 cells. In the presence of BA, Z-DEVD-FMK induced autophagy and increased the amount of LC3-II in KM3 cells, which may occur via attenuating BA-induced decrease in the level of Beclin 1. Similarly, rapamycin, an autophagy inducer, increased the amount of LC3-II in KM3 cells. In the presence of BA, rapamycin caused further increase in the amount of LC3-II. Furthermore, rapamycin sensitized BA-treated KM3 cells to apoptosis.
CONCLUSION:

The results demonstrate that BA induces apoptosis and blocks autophagic flux in KM3 cells. Furthermore, in addition to activation of caspase 3, the inhibition of autophagic flux also contributes to the BA-mediated apoptosis of KM3 cells.

http://www.ncbi.nlm.nih.gov/pubmed/23064721




Puede revertir hasta la farmacorresistencia

BBA, a derivative of 23-hydroxybetulinic acid, potently reverses ABCB1-mediated drug resistance in vitro and in vivo.
Zhang DM1, Shu C, Chen JJ, Sodani K, Wang J, Bhatnagar J, Lan P, Ruan ZX, Xiao ZJ, Ambudkar SV, Chen WM, Chen ZS, Ye WC.
Author information
Abstract

23-O-(1,4'-Bipiperidine-1-carbonyl)betulinic acid (BBA), a synthetic derivative of 23-hydroxybetulinic acid (23-HBA), shows a reversal effect on multidrug resistance (MDR) in our preliminary screening. Overexpression of ATP-binding cassette (ABC) transporters such as ABCB1, ABCG2, and ABCC1 has been reported in recent studies to be a major factor contributing to MDR. Our study results showed that BBA enhanced the cytotoxicity of ABCB1 substrates and increased the accumulation of doxorubicin or rhodamine123 in ABCB1 overexpressing cells, but had no effect on non ABCB1 substrate, such as cisplatin; what's more, BBA slightly reversed ABCG2-mediated resistance to SN-38, but did not affect the ABCC1-mediated MDR. Further studies on the mechanism indicated that BBA did not alter the expression of ABCB1 at mRNA or protein levels, but affected the ABCB1 ATPase activity by stimulating the basal activity at lower concentrations and inhibiting the activity at higher concentrations. In addition, BBA inhibited the verapamil-stimulated ABCB1 ATPase activity and the photolabeling of ABCB1 with [(125)I] iodoarylazidoprazosin in a concentration-dependent manner, indicating that BBA directly interacts with ABCB1. The docking study confirmed this notion that BBA could bind to the drug binding site(s) on ABCB1, but its binding position was only partially overlapping with that of verapamil or iodoarylazidoprazosin. Importantly, BBA increased the inhibitory effect of paclitaxel in ABCB1 overexpressing KB-C2 cell xenografts in nude mice. Taken together, our findings suggest that BBA can reverse ABCB1-mediated MDR by inhibiting its efflux function of ABCB1, which supports the development of BBA as a novel potential MDR reversal agent used in the clinic.

http://www.ncbi.nlm.nih.gov/pubmed/23046348




Betulinic acid exerts immunoregulation and anti-tumor effect on cervical carcinoma (U14) tumor-bearing mice.
Wang P1, Li Q, Li K, Zhang X, Han Z, Wang J, Gao D, Li J.
Author information
Abstract

Phytochemicals used in cancer therapy and prevention are an important source. Betulinic acid (BetA), a lupine-type pentacyclic triterpenoid saponin from plants, has shown anti-tumor activity in some cell lines in previous studies. In this paper, its anti-tumor effect and the possible mechanisms were investigated in U14 tumor-bearing mice. The results showed that BetA (100 mg/kg and 200 mg/kg) effectively suppressed tumor growth in vivo. Compared with the control group, BetA significantly improved the levels of IL-2 and TNF-alpha in tumor-bearing mice and increased the number of CD4+ lymphocytes subsets, as well as the ratio of CD4+/CD8+ at a dose of 200 mg/kg. Furthermore, treatment with BetA induced cells apoptosis in dose-dependent manner in tumor bearing mice, and inhibited the expression of Bcl-2 and Ki-67 protein while upregulated the expression of caspase-8 protein. The mechanisms by which BetA exerted anti-tumor effects might involve the induction of tumor cell apoptosis. This process is also related to improvement of body's immune response.

http://www.ncbi.nlm.nih.gov/pubmed/22957441




Betulinic acid decreases specificity protein 1 (Sp1) level via increasing the sumoylation of sp1 to inhibit lung cancer growth.
Hsu TI1, Wang MC, Chen SY, Huang ST, Yeh YM, Su WC, Chang WC, Hung JJ.
Author information
Abstract

Previous studies have shown that the inhibitory effect of betulinic acid (BA) on specificity protein 1 (Sp1) expression is involved in the prevention of cancer progression, but the mechanism of this effect remains to be delineated. In this study, we determined that BA treatment in HeLa cells increased the sumoylation of Sp1 by inhibiting sentrin-specific protease 1 expression. The subsequent recruitment of E3 ubiquitin-protein ligase RING finger protein 4 resulted in ubiquitin-mediated degradation in a 26S-proteosome-dependent pathway. In addition, both BA treatment and mithramycin A (MMA) treatment inhibited lung tumor growth and down-regulated Sp1 protein expression in Kras(G12D)-induced lung cancers of bitransgenic mice. In gene expression profiles of Kras(G12D)-induced lung cancers in bitransgenic mice with and without Sp1 inhibition, 542 genes were affected by MMA treatment. One of the gene products, cyclin A2, which was involved in the S and G(2)/M phase transition during cell cycle progression, was investigated in detail because its expression was regulated by Sp1. The down-regulation of cyclin A2 by BA treatment resulted in decreased retinoblastoma protein phosphorylation and cell cycle G(2)/M arrest. The BA-mediated cellular Sp1 degradation and antitumor effect were also confirmed in a xenograft mouse model by using H1299 cells. The knockdown of Sp1 in lung cancer cells attenuated the tumor-suppressive effect of BA. Taken together, the results of this study clarify the mechanism of BA-mediated Sp1 degradation and identify a pivotal role for Sp1 in the BA-induced repression of lung cancer growth.

http://www.ncbi.nlm.nih.gov/pubmed/22956772



Betulin induces mitochondrial cytochrome c release associated apoptosis in human cancer cells.
Li Y1, He K, Huang Y, Zheng D, Gao C, Cui L, Jin YH.
Author information
Abstract

We examined whether betulin, a naturally abundant compound, has anticancer functions in human cancer cells. The results showed that betulin significantly inhibited cell viability in cervix carcinoma HeLa cells, hepatoma HepG2 cells, lung adenocarcinoma A549 cells, and breast cancer MCF-7 cells with IC(50) values ranging from 10 to 15 microg/mL. While betulin exhibited only moderate anticancer activity in other human cancer cells such as hepatoma SK-HEP-1 cells, prostate carcinoma PC-3, and lung carcinoma NCI-H460, with IC(50) values ranging from 20 to 60 microg/mL, it showed minor growth inhibition in human erythroleukemia K562 cells (IC(50) > 100 microg/mL). We further investigated the mechanism of anticancer activity by betulin, using HeLa cells as an experimental model. Betulin (10 microg/mL) induces apoptotic cell death, as evidenced by morphological characteristics such as membrane phosphatidylserine translocation, nuclear condensation/fragmentation, and apoptotic body formation. A kinetics analysis showed that the depolarization of mitochondrial membrane potential and the release of mitochondrial cytochrome c occurred as early as 30 min after treatment with betulin. Betulin, unlike its chemical derivative betulinic acid, did not directly trigger mitochondrial cytochrome c release in isolated mitochondria. Importantly, Bax and Bak were rapidly translocated to the mitochondria 30 min after betulin treatment. The sequential activation of caspase-9 and caspase-3/-7 and the cleavage of poly(ADP-ribose) polymerase (PARP) were observed behind those mitochondrial events. Furthermore, specific downregulation of either caspase-9, Bax, or Bak by siRNA effectively reduced PARP cleavage and caspase-3 activation. Taken together, the lines of evidence demonstrate that betulin triggers apoptosis of human cancer cells through the intrinsic apoptotic pathway.

http://www.ncbi.nlm.nih.gov/pubmed/20564340



Betulinic acid, a natural compound with potent anticancer effects.
Mullauer FB1, Kessler JH, Medema JP.
Author information
Abstract

New therapies using novel mechanisms to induce tumor cell death are needed with plants playing a crucial role as a source for potential anticancer compounds. One highly promising class of natural compounds are the triterpenoids with betulinic acid (BetA) as the most prominent representative. In-vitro studies have identified this agent as potently effective against a wide variety of cancer cells, also those derived from therapy-resistant and refractory tumors, whereas it has been found to be relatively nontoxic for healthy cells. In-vivo preclinically applied BetA showed some remarkable anticancer effects and a complete absence of systemic toxicity in rodents. BetA also cooperated with other therapies to induce tumor cell death and several potent derivatives have been discovered. Its antitumor activity has been related to its direct effects on mitochondria where it induces Bax/Bak-independent cytochrome-c release.

http://www.ncbi.nlm.nih.gov/pubmed/20075711



Lupane triterpenoids--betulin and betulinic acid derivatives induce apoptosis in tumor cells.
Kommera H1, Kaluđerović GN, Kalbitz J, Paschke R.
Author information
Abstract

In the present investigation the antiproliferative activity of thirteen derivatives of betulinic acid and betulin was tested against five different tumor cell lines. The toxicity against normal human fibroblasts (WWO70327) and the mode of cell death on HT-29 (colon cancer) as well as caspase activity induced by the most active compounds, 9 (3-O-chloroacetylbetulinic acid) and 15 (28-O-chloroacetylbetulin) were determined. Investigated derivatives exerted a dose dependent antiproliferative action at micromolar concentrations toward target tumor cell lines. Treatment of HT-29 cells for 24 h with 9 and 15 induced apoptosis, as observed by dye exclusion test (trypan blue) and confirmed by the appearance of a typical ladder pattern in the DNA fragmentation assay.

http://www.ncbi.nlm.nih.gov/pubmed/19957199




Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells.
Pandey MK1, Sung B, Aggarwal BB.
Author information
Abstract

STAT3 activation has been associated with survival, proliferation and invasion of various human cancers. Whether betulinic acid, a pentacyclic triterpene, can modulate the STAT3 pathway, was investigated in human multiple myeloma (MM) cells. We found that betulinic acid inhibited constitutive activation of STAT3, Src kinase, JAK1 and JAK2. Pervanadate reversed the betulinic acid-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Furthermore, betulinic acid induced the expression of the PTP SHP-1 and silencing of the SHP-1 gene abolished the ability of betulinic acid to inhibit STAT3 activation and rescued betulinic acid-induced cell death. Betulinic acid also downregulated the expression of STAT3-regulated gene products such as bcl-xL, bcl-2, cyclin D1 and survivin. This correlated with an increase in apoptosis as indicated by an increase in the sub-G1 cell population and an increase in caspase-3-induced PARP cleavage. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the betulinic acid-induced apoptosis. Betulinic acid also enhanced the apoptosis induced by thalidomide (from 10 to 55%) and bortezomib (from 5 to 70%) in MM cells. Overall, our results suggest that betulinic acid downregulates STAT3 activation through upregulation of SHP-1, and this may have potential in sensitization of STAT3 overexpressing tumors to chemotherapeutic agents.

http://www.ncbi.nlm.nih.gov/pubmed/19937797



[Effect of betulinic acid on inducing apoptosis of human multiple myeloma cell line RPMI-8226].
[Article in Chinese]
Cheng YQ1, Chen Y, Wu QL, Fang J, Yang LJ.
Author information
Abstract

The aim of this study was to investigate the effect of betulinic acid on inducing apoptosis of human multiple myeloma RPMI-8226 cell line. The inhibitory effect of betulinic acid on proliferation and its inducing apoptosis effect, influence on cell cycle and induced morphological changes of RPMI-8226 were evaluated by MTT, flow cytometry Annexin-V/PI double staining, flow cytometry with PI staining and fluorescence microscopy with Hoechst33258 staining, respectively. The transcription level changes of bcl-xl gene and caspase 3 which are two kinds of apoptosis related protein gene were determined by RT-PCR. The results showed that within a certain range of concentration (0, 5, 10, 15, 20 microg/ml), IC50 of betulinic acid to RPMI-8226 at 24 hours was 10.156+/-0.659 microg/ml, while the IC50 at 48 hours was 5.434+/-0.212 microg/ml, and its inhibiting effect on proliferation of RPMI-8226 showed both time-and dose-dependent manners. Flow cytometry with Annexin-V/PI double staining revealed that apoptotic rate of RPMI-8226 cells increased as betulinic acid concentration increased. Flow cytometry with PI staining showed that the ratio of cells in G0/G1 phase increased, while it in S phase decreased, and ratio of cells at G2/M phase did not present a significant change. Morphological differences were typical and obvious between cells in treated and control groups under fluorescence microscope using Hoechst33258 staining. RT-PCR detection of caspase 3 gene indicated that its transcription level showed an increasing trend as the concentration of betulinic acid increased, while the bcl-xl showed the opposite trend. It is concluded that the betulinic acid can induce apoptosis of RPMI-8226 within a certain range of concentration in a time- and dose-dependent manners. This phenomenon may be related to the transcriptional level increase of caspase 3 gene and decrease of bcl-xl. Betulinic acid also affects G1/S in cell cycle which arrests cells at phase G0/G1.

http://www.ncbi.nlm.nih.gov/pubmed/19840455




Betulinic acid treatment promotes apoptosis in hepatoblastoma cells.
Eichenmüller M1, von Schweinitz D, Kappler R.
Author information
Abstract

Hepatoblastoma (HB) represents the most common malignant liver tumor in children with a dismal prognosis for patients with advanced disease. This study provides evidence that the naturally occurring pentacyclic triterpenoid betulinic acid (BA) is highly effective against HB. We demonstrate that BA has a strong cytotoxic effect on HB cells in a dose-dependent manner by impinging on cell viability and causing massive induction of programmed cell death. Apoptotic features including morphological changes, membrane asymmetry and proteolytic cleavage of caspase 3 and poly(ADP-ribose) polymerase were frequently found in BA-treated HB cells, which is suggestive of the mitochondrial intrinsic apoptotic pathway. In contrast, the hepatocellular carcinoma (HCC) cell line HepG2 was resistant to BA treatment. This insensitivity was dependent on the high expression of survival factors, such as Survivin and BCL2. Interestingly, BA treatment led to a significant decrease in expression of the hedgehog target genes GLI1, PTCH1 and IGF2 in HepT3 cells. In conclusion, we demonstrate that BA is capable of inducing apoptosis in HB cells and thereby might be a hopeful new strategy for treating HB, especially those with an activated hedgehog signaling pathway.

http://www.ncbi.nlm.nih.gov/pubmed/19724925




Betulinic acid exhibits stronger cytotoxic activity on the normal melanocyte NHEM-neo cell line than on drug-resistant and drug-sensitive MeWo melanoma cell lines.
Surowiak P1, Drag M, Materna V, Dietel M, Lage H.
Author information
Abstract

Betulinic acid is a triterpene isolated from the bark of many plants that exhibits cytotoxicity in several cancer cell lines and is capable of inducing apoptosis. In this study, we examined the cytotoxic activity and apoptotic ability of betulinic acid in the drug-sensitive (MeWo) and drug-resistant melanoma MeWo CIS (cisplatin), MeWo ETO (etoposide), MeWo VIN (vinblastin) and MeWo FOTE (fotemusine) cell lines, as well as in the normal melanocyte NHEM-neo cell line. The results show that betulinic acid exhibited significant cytotoxicity on all the cell lines. However, a sulphorhodamine B cell proliferation assay and immunocytochemical analysis of Ki67 expression revealed the strongest cytotoxicity on the normal melanocyte cell line, NHEM-neo. Flow cytometry and immunocytochemical analysis of caspase 3 expression was used to confirm cell death by apoptosis. In conclusion, betulinic acid is a potential candidate for anticancer research, and may also have an application in the cosmetics industry.

http://www.ncbi.nlm.nih.gov/pubmed/21475863



Aumenta la eficacia de quimioterapia

Effect of betulinic acid on anticancer drug-resistant colon cancer cells.
Jung GR1, Kim KJ, Choi CH, Lee TB, Han SI, Han HK, Lim SC.
Author information
Abstract

Primary or acquired resistance of tumours to established chemotherapeutic regimens is a major concern in oncology. Attempts to improve the survival of cancer patients largely depend on strategies to prevent tumour cell resistance. 5-Fluorouracil (5-FU)-based chemotherapy with a combination of other drugs such as irinotecan (IRT) and oxaliplatin (OXT) has been reported to be effective, even though an optimal regimen has yet to be defined due to the relatively high toxicity of the procedure. The aim of this study was to examine the effect of betulinic acid (BetA) as a chemosensitizer for anticancer drug treatment in chemoresistant colon cancer cell lines. A chemoresistant cell line to 5-fluorouracil (SNU-C5/5FU-R), irinotecan (SNU-C5/IRT-R) and oxaliplatin (SNU-C5/OXT-R) treatment were derived from the wild-type colon adenocarcinoma cell line (SNU-C5/WT). The effect of BetA or a combination of anticancer drugs and BetA on the multidrug resistance-related genes, caspases, Bcl-2, Bad and cell death in the SNU-C5/WT and SNU-C5/R cell lines was analysed. BetA alone was an effective chemotherapeutic drug for the SNU-C5/WT, SNU-C5/5FU-R and SNU-C5/OXT-R cells. The combination of BetA with IRT or OXT was effective against SNU-C5/5FU-R cells, and the combination of BetA with 5-fluorouracil, IRT or OXT was effective against SNU-C5/OXT-R cells. BetA induced cancer cell death by apoptosis through the mitochondrial pathway. These findings indicate that the use of BetA as a chemosensitizer may be a new strategy to enhance the efficacy of chemotherapy. However, further studies will be needed for confirmation.

http://www.ncbi.nlm.nih.gov/pubmed/17845510


Sensitization for anticancer drug-induced apoptosis by betulinic Acid.
Fulda S1, Debatin KM.
Author information
Abstract

We previously described that betulinic acid (BetA), a naturally occurring pentacyclic triterpenoid, induces apoptosis in tumor cells through the mitochondrial pathway. Here, for the first time, we provide evidence that BetA cooperated with anticancer drugs to induce apoptosis and to inhibit clonogenic survival of tumor cells. Combined treatment with BetA and anticancer drugs acted in concert to induce loss of mitochondrial membrane potential and the release of cytochrome c and Smac from mitochondria, resulting in activation of caspases and apoptosis. Overexpression of Bcl-2, which blocked mitochondrial perturbations, also inhibited the cooperative effect of BetA and anticancer drugs, indicating that cooperative interaction involved the mitochondrial pathway. Notably, cooperation of BetA and anticancer drugs was found for various cytotoxic compounds with different modes of action (e.g., doxorubicin, cisplatin, Taxol, VP16, or actino-mycin D). Importantly, BetA and anticancer drugs cooperated to induce apoptosis in different tumor cell lines, including p53 mutant cells, and also in primary tumor cells, but not in human fibroblasts indicating some tumor specificity. These findings indicate that using BetA as sensitizer in chemotherapy-based combination regimens may be a novel strategy to enhance the efficacy of anticancer therapy, which warrants further investigation.

http://www.ncbi.nlm.nih.gov/pubmed/15802021




Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors.
Chintharlapalli S1, Papineni S, Ramaiah SK, Safe S.
Author information
Abstract

Betulinic acid is a pentacyclic triterpene natural product initially identified as a melanoma-specific cytotoxic agent that exhibits low toxicity in animal models. Subsequent studies show that betulinic acid induces apoptosis and antiangiogenic responses in tumors derived from multiple tissues; however, the underlying mechanism of action is unknown. Using LNCaP prostate cancer cells as a model, we now show that betulinic acid decreases expression of vascular endothelial growth (VEGF) and the antiapoptotic protein survivin. The mechanism of these betulinic acid-induced antiangiogenic and proapoptotic responses in both LNCaP cells and in tumors is due to activation of selective proteasome-dependent degradation of the transcription factors specificity protein 1 (Sp1), Sp3, and Sp4, which regulate VEGF and survivin expression. Thus, betulinic acid acts as a novel anticancer agent through targeted degradation of Sp proteins that are highly overexpressed in tumors.

http://www.ncbi.nlm.nih.gov/pubmed/17363604




Broad in vitro efficacy of plant-derived betulinic acid against cell lines derived from the most prevalent human cancer types.
Kessler JH1, Mullauer FB, de Roo GM, Medema JP.
Author information
Abstract

Betulinic acid (BA) is a widely available plant-derived triterpene with reported activity against cancer cells of neuroectodermal origin and leukaemias. Treatment with BA was shown to protect mice against transplanted human melanoma and led to tumor regression. In contrast, cells from healthy tissues were resistant to BA and toxic side-effects in animals were absent. These findings have raised interest in the chemotherapeutical anti-cancer potential of BA. A comprehensive assessment of the efficacy of BA against the clinically most important cancer types is currently lacking. Therefore, we tested the in vitro sensitivity of broad cell line panels derived from lung, colorectal, breast, prostate and cervical cancer, which are the prevalent cancer types characterized with highest mortalities in woman and men. Multiple assays were used in order to allow a reliable assessment of anti-cancer efficacy of BA. After 48 h of treatment with BA, cell viability as assessed with MTT and cell death as measured with propidium iodide exclusion showed clear differences in sensitivity between cell lines. However, in all cell lines tested colony formation was completely halted at remarkably equal BA concentrations that are likely attainable in vivo. Our results substantiate the possible application of BA as a chemotherapeutic agent for the most prevalent human cancer types.

http://www.ncbi.nlm.nih.gov/pubmed/17169485




Betulinic acid induces apoptosis in skin cancer cells and differentiation in normal human keratinocytes.
Galgon T1, Wohlrab W, Dräger B.
Author information
Abstract

Betulinic acid (BA), a pentacyclic triterpene of plant origin, induces cell death in melanoma cells and other malignant cells of neuroectodermal origin. Little is known about additional biological effects in normal target cells. We show, in this study, that BA induces differentiation as well as cell death in normal human keratinocytes (NHK). Cytotoxicity profiles of BA are compared among normal human keratinocytes, HaCaT cells, IGR1 melanoma cells and normal melanocytes. As expected, BA is toxic to all cell types, normal and malignant, but varies in its cytotoxic potency and in the extent of induction of apoptotic vs. necrotic cell death in the four different skin cell types. Apoptosis is proved by annexin V and Apo2.7 binding and by DNA fragmentation. Induction of differentiation-associated antigens in keratinocytes--filaggrin and involucrin--is demonstrated, together with specific morphological changes in treated cell cultures. BA, apart from its cytotoxic activities in cellular systems, is capable of inducing differentiation of NHK into corneocytes without immediately provoking apoptotic cell death.

http://www.ncbi.nlm.nih.gov/pubmed/16176281

Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 5275
Registrado: Dom, 01 Sep 2013, 14:18

Re: Nutrición contra el cancer

Notapor Fisio » Lun, 08 Sep 2014, 08:43

Ácido betulínico

Curiosamente no funciona con inhibidores de NfKappaB

Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy.
Kasperczyk H1, La Ferla-Brühl K, Westhoff MA, Behrend L, Zwacka RM, Debatin KM, Fulda S.
Author information
Abstract

Recent evidence demonstrates that the anticancer activity of betulinic acid (BetA) can be markedly increased by combination protocols, for example with chemotherapy, ionizing radiation or TRAIL. Since nuclear factor-kappaB (NF-kappaB), a key regulator of stress-induced transcriptional activation, has been implicated in mediating apoptosis resistance, we investigated the role of NF-kappaB in BetA-induced apoptosis. Here, we provide for the first time evidence that BetA activates NF-kappaB in a variety of tumor cell lines. NF-kappaB DNA-binding complexes induced by BetA consisted of p50 and p65 subunits. Nuclear translocation of p65 was also confirmed by immunofluorescence microscopy. BetA-induced NF-kappaB activation involved increased IKK activity and phosphorylation of IkappaB-alpha at serine 32/36 followed by degradation of IkappaB-alpha. Reporter assays revealed that NF-kappaB activated by BetA is transcriptionally active. Interestingly, inhibition of BetA-induced NF-kappaB activation by different chemical inhibitors (proteasome inhibitor, antioxidant, IKK inhibitor) attenuated BetA-induced apoptosis. Importantly, specific NF-kappaB inhibition by transient or stable expression of IkappaB-alpha super-repressor inhibited BetA-induced apoptosis in SH-EP neuroblastoma cells, while transient expression of IkappaB-alpha super-repressor had no influence on BetA-induced apoptosis in two other cell lines. Thus, our findings that activation of NF-kappaB by BetA promotes BetA-induced apoptosis in a cell type-specific fashion indicate that NF-kappaB inhibitors in combination with BetA would have no therapeutic benefit or could even be contraproductive in certain tumors, which has important implications for the design of BetA-based combination protocols.

http://www.ncbi.nlm.nih.gov/pubmed/16007147

NF-kappaB activation enhances cell death by antimitotic drugs in human prostate cancer cells.
Parrondo R1, de las Pozas A, Reiner T, Rai P, Perez-Stable C.
Author information

1Geriatric Research, Education, and Clinical Center and Research Service, Bruce W, Carter Veterans Affairs Medical Center, Miami, FL 33125, USA.

Abstract
BACKGROUND:

NF-kappaB is a transcription factor that promotes inhibition of apoptosis and resistance to chemotherapy. It is commonly believed that inhibition of NF-kappaB activity can increase sensitivity of cancer cells to chemotherapy. However, there is evidence that NF-kappaB activation can sensitize cells to apoptosis and that inhibition of NF-kappaB results in resistance to chemotherapy. In prostate cancer, it is not clear in the different cell types (androgen-dependent and castration-resistant) if activation or inhibition of NF-kappaB is required for stimulation of apoptosis by chemotherapy.
RESULTS:

Our data indicate that the response of prostate cancer (PC) cells to the antimitotic drugs docetaxel (Doc) and 2-methoxyestradiol (2ME2) is dependent on the levels of NF-kappaB activity. In androgen-dependent LNCaP cells, Doc and 2ME2 treatment increased the low basal NF-kappaB activity, as determined by Western blot analysis of phospho-IkappaBalpha/p65, NF-kappaB promoter reporter assays, and p65 localization. Treatment of LNCaP cells with parthenolide, a pharmacologic inhibitor of NF-kappaB, or introduction of dominant-negative IkappaBalpha, or an shRNA specific for p65, a component of the NF-kappaB heterodimer, blocked apoptosis induced by Doc and 2ME2. In castration-resistant DU145 and PC3 cells, Doc and 2ME2 had little effect on the high basal NF-kappaB activity and addition of parthenolide did not enhance cell death. However, the combination of Doc or 2ME2 with betulinic acid (BA), a triterpenoid that activates NF-kappaB, stimulated apoptosis in LNCaP and non-apoptotic cell death in DU145 and PC3 cells. Increased sensitivity to cell death mediated by the Doc or 2ME2 + BA combination is likely due to increased NF-kappaB activity.
CONCLUSIONS:

Our data suggest that the combination of antimitotic drugs with NF-kappaB inhibitors will have antagonistic effects in a common type of PC cell typical of LNCaP. However, combination strategies utilizing antimitotic drugs with BA, an activator of NF-kappaB, will universally enhance cell death in PC cells, notably in the aggressive, castration-resistant variety that does not respond to conventional therapies.

http://www.ncbi.nlm.nih.gov/pubmed/20618955




Betulinic acid induces apoptosis in human chronic myelogenous leukemia (CML) cell line K-562 without altering the levels of Bcr-Abl.
Raghuvar Gopal DV1, Narkar AA, Badrinath Y, Mishra KP, Joshi DS.
Author information
Abstract

Betulinic acid (BA), a plant derived triterpenoid, isolated from various sources shows cytotoxicity in cell lines of melanoma, neuroectodermal and malignant brain tumors. Chronic myelogenous leukemia (CML) is characterized by Philadelphia chromosome (Bcr-Abl), a molecular abnormality leading to the intrinsic tyrosine kinase activity that provides growth and survival advantage to the cells. Present study describes the cytotoxicity of BA on human CML cell line K-562, positive for Bcr-Abl. The decrease in the viability of K-562 cells treated with BA at different concentrations and time intervals was assessed using MTT assay. Cell death induced by BA was determined to be apoptotic as measured by FACS analysis of PI stained nuclei, PS externalization by Annexin-V fluorescence and characteristic DNA fragmentation. DiOC6(3) fluorescent probe determined alterations in the mitochondrial membrane potential (MMP). RT-PCR confirmed the expression levels of Bcr-Abl in controls and K-562 cells treated with BA. The rapid loss of MMP of K-562 cells upon treatment with BA shows the direct activation of apoptosis at the level of mitochondria, overcoming the resistance of the high levels of expression of Bcr-Abl.


http://www.ncbi.nlm.nih.gov/pubmed/15649617


Betulinic acid-induced apoptosis in leukemia cells.
Ehrhardt H1, Fulda S, Führer M, Debatin KM, Jeremias I.
Author information
Abstract

Betulinic acid (BA), a natural component isolated from Birch trees, effectively induces apoptosis in neuroectodermal and epithelial tumor cells and exerts little toxicity in animal trials. Here, we show that BA-induced marked apoptosis in 65% of primary pediatric acute leukemia cells and all leukemia cell lines tested. When compared for in vitro efficiency with conventionally used cytotoxic drugs, BA was more potent than nine out of 10 standard therapeutics and especially efficient in tumor relapse. No crossresistances were found between BA and any cytotoxic drug. Intracellular apoptosis signaling in leukemia tumor cells paralleled the pathway found in neuroectodermal cells involving caspases, but not death receptors. In isolated mitochondria, BA induced release of both cytochrome c and Smac. Taken together, BA potently induces apoptosis in leukemia cells and should be further evaluated as a future drug to treat leukemia.

http://www.ncbi.nlm.nih.gov/pubmed/15201849




Antiangiogénico

Betulinic acid and its derivatives as anti-angiogenic agents.
Mukherjee R1, Jaggi M, Rajendran P, Siddiqui MJ, Srivastava SK, Vardhan A, Burman AC.
Author information
Abstract

Betulinic acid (1) significantly caused cytotoxicity to endothelial cell line ECV304 (IC(50) 1.26+/-0.44 microg/mL) in a 5-day MTT assay. Novel and more potent derivatives of betulinic acid (2, 4, 6-8) have been synthesized with IC(50) less than 0.4 microg/mL. The endothelial cell specificity against human tumor cell lines DU145, L132, A549, and PA-1 were determined. Further betulinic acid (1) inhibited TLS formation of ECV304 cells on Matrigel(TM) by 5.5% while its derivatives caused an inhibition of 13.1-49.2%.

http://www.ncbi.nlm.nih.gov/pubmed/15081004




Betulinic acid: a promising anticancer candidate.
Eiznhamer DA1, Xu ZQ.
Author information
Abstract

Betulinic acid is a naturally occurring pentacyclic triterpenoid which has demonstrated selective cytotoxicity against a number of specific tumor types, a variety of infectious agents such as HIV, malaria and bacteria, and the inflammatory process in general. Biological activity was first demonstrated in melanoma cell lines and was confirmed in mice bearing human melanoma xenografts. These in vivo studies also established a favorable safety margin for betulinic acid, as systemic side effects were not observed at any dose. Recently, considerable in vitro evidence has demonstrated that betulinic acid is effective against small- and non-small-cell lung, ovarian, cervical, and head and neck carcinomas. Published data suggest that betulinic acid induces apoptosis in sensitive cells in a p53- and CD95-independent fashion. While the precise molecular target and mechanism of action remain elusive and are the focus of a number of ongoing research programs, accumulated experimental evidence indicates that betulinic acid functions through a mitochondrial-mediated pathway. Supplemental reports suggest that the generation of reactive oxygen species, inhibition of topoisomerase I, activation of the MAP kinase cascade, inhibition of angiogenesis, and modulation of pro-growth transcriptional activators and aminopeptidase N activity may play a role in betulinic acid-induced apoptosis. These potential mechanisms of action may enable betulinic acid to be effective in cells resistant to other chemotherapeutic agents. Arguments supporting the role of this agent in the treatment of cancers and other infectious conditions will be reviewed.

http://www.ncbi.nlm.nih.gov/pubmed/15057642




New betulinic acid derivatives induce potent and selective antiproliferative activity through cell cycle arrest at the S phase and caspase dependent apoptosis in human cancer cells.
Santos RC1, Salvador JA, Cortés R, Pachón G, Marín S, Cascante M.
Author information
Abstract

New semisynthetic derivatives of betulinic acid (BA) RS01, RS02 and RS03 with 18-45 times improved cytotoxic activity against HepG2 cells, were tested for their ability to induce apoptosis and cell cycle arrest in HepG2, HeLa and Jurkat cells. All the compounds induced significant increase in the population at the S phase more effectively than BA. RS01, RS02 and RS03 were also found to be potent inducers of apoptosis with RS01 being markedly more potent than BA, suggesting that the introduction of the imidazolyl moiety is crucial for enhancing the induction of apoptosis and the cell cycle arrest. The mechanism of apoptosis induction has been studied in HepG2 cells and found to be mediated by activation of the postmitochondrial caspases-9 and -3 cascade and possibly by mitochondrial amplification loop involving caspase-8. These facts were corroborated by detection of mitochondrial cytochrome c release and DNA fragmentation. Because RS01, RS02 and RS03 exhibited significant improved antitumor activity with respect to BA, they may be promising new agents for the treatment of cancer. In particular, RS01 is the most promising compound with an IC(50) value 45 times lower than BA on HepG2 cells and 61 times lower than the one found for the non-tumoral Chang liver cells.

http://www.sciencedirect.com/science/ar ... 8411000708




[Influence of betulinic acid on proliferation, migration, cell cycle and apoptosis of pancreatic cancer cells].
[Article in Chinese]
Jiang M1, Zhou Y, Yang M, Zhang R, Zou M, Cai G, Pan D.
Author information
Abstract
OBJECTIVE:

To investigate the effect of betulinic acid (BA) on the proliferation, migration, apoptosis and cell cycle of pancreatic cancer cells (BxPC-3) in vitro and elucidate the underlying.
METHOD:

The effect of BA on the proliferation of BxPC-3 was measured by using sulforhodamine B (SRB) assay. Migratory ability of BxPC3 cells were detected by wound healing assay, and the morphological change was observed with light microscope. The influence of BA on cell cycle of BxPC-3 cells was tested by flow cytometry (FCM). Apoptosis was analyzed by using Hochest33342-PI double staining. Western blot technologies were applied to detect the expression of Bcl-2 and Bax.
RESULT:

BA exhibited significant cell proliferation and migration inhibition, as well as its potency of inducing apoptosis in BxPC-3 cells in vitro in a dose-dependent manner. The IC50 value for 72 h was 16.54 mg x L(-1). Cell migration was significantly inhibited at 5 mg x L(-1) of BA. Cells treated with BA showed increased cell population in G0 phase, with decreased G2/M phase population. The expression of Bax and Bcl-2 was up and down-regulated respectively in BA-treated BxPC-3 cells in a dose-dependent manner.
CONCLUSION:

BA exerted potent effect on growth inhibition, G0 cell cycle arrest and induction of apoptosis in BxPC-3 cells in vitro, possibly associated with the down-regulation of Bcl-2 and up-regulation of Bax expression. The potent antitumor capacity of BA suggested that it could be a promising new anticancer agent in human pancreatic cancer treatment.

http://www.ncbi.nlm.nih.gov/pubmed/21355282




Betulinic acid delivered in liposomes reduces growth of human lung and colon cancers in mice without causing systemic toxicity.
Mullauer FB1, van Bloois L, Daalhuisen JB, Ten Brink MS, Storm G, Medema JP, Schiffelers RM, Kessler JH.
Author information
Abstract

Betulinic acid (BetA) is a plant-derived pentacyclic triterpenoid with potent anticancer capacity that targets the mitochondrial pathway of apoptosis. BetA has a broad efficacy in vitro against prevalent cancer types, including lung, colorectal, prostate, cervix and breast cancer, melanomas, neuroblastomas, and leukemias. The cytotoxic effects of the compound against healthy cells are minimal, rendering BetA a promising potential anticancer drug. However, because of the weak hydrosolubility of BetA, it has been difficult to study its efficacy in vivo and a pharmaceutical formulation is not yet available. We report the development of a liposome formulation of BetA and show its successful application in mice. Large liposomes, assembled without cholesterol to reduce their rigidity, efficiently incorporated BetA. Nude mice xenografted with human colon and lung cancer tumors were treated intravenously with the BetA-containing liposomes. Tumor growth was reduced to more than 50% compared with the control treatment, leading to an enhanced survival of the mice. Oral administration of the liposomal formulation of BetA also slowed tumor growth. Any signs of systemic toxicity caused by BetA treatment were absent. Thus, liposomes are an efficient formulation vehicle for BetA, enabling its preclinical development as a nontoxic compound for the treatment of cancers.

http://www.ncbi.nlm.nih.gov/pubmed/21263311




Inmunidad

Immunomodulatory effects of betulinic acid from the bark of white birch on mice.
Yi JE1, Obminska-Mrukowicz B, Yuan LY, Yuan H.
Author information
Abstract

The objective of this study was to explore the immunomodulatory effects of betulinic acid (BA) extracted from the bark of white birch on mice. Female mice were orally administered BA for 14 days in doses of 0, 0.25, 0.5, and 1 mg/kg body weight. We found that BA significantly enhanced the thymus and spleen indices, and stimulated lymphocyte proliferation induced by Concanavalin A and lipopolysaccharide as shown by MTT assay. Flow cytometry revealed that BA increased the percentage of CD4(+) cells in thymus as well as the percentage of CD19(+) and the ratios of CD4(+)/CD8(+) in spleen. BA increased the number of plaque-forming cell and macrophage phagocytic activity as indicated by a neutral red dye uptake assay, and the peritoneal macrophages levels of TNF-α were also increased. In contrast, serum levels of IgG and IgM and serum concentrations of IL-2 and IL-6 were significantly decreased in BA-treated mice compared to the control as assayed by haemagglutination tests and ELISA, respectively. Taken together, these results suggest that BA enhances mouse cellular immunity, humoral immunity, and activity of macrophages. Thus, BA is a potential immune stimulator and may strengthen the immune response of its host.

http://www.ncbi.nlm.nih.gov/pubmed/21113099



Antitumor effect of betulinic acid on human acute leukemia K562 cells in vitro.
Wu Q1, He J, Fang J, Hong M.
Author information
Abstract

The effects of betulinic acid (BA), a pentacyclic lupane-type triterpene, on the cell viability, cell cycle and apoptosis in human leukemia K562 cells were investigated. The effects of BA on the growth of K562 cells were studied by MTT assay. Apoptosis was assayed through Annexin V/propidium iodide (PI) double-labeled cytometry. The effects of BA on the cell cycle of K562 cells were studied by a PI method. The expression of Bax and capase-3 was detected by using Western blot. The results showed that BA was cytotoxic to K562 cells with an IC50 of 21.26 microg/mL at 24 h. After treating K562 cells with 10 microg/mL BA for 72 h, the number of cells was reduced by 58%. BA induced apoptosis of K562 cells in a time- and dose-dependent manner. The proportion of cells in G0/G1 and G2/M phases was decreased and that in S phase was increased after K562 cells were treated with BA for 24 h. BA treatment also increased the expression of the pro-apoptotic proteins Bax and caspase-3. It suggested that BA could inhibit the proliferation of K562 cells through the induction of cell cycle arrest and apoptosis. The antitumor effects of BA were related with up-regulation of the expression of Bax and caspase-3 proteins. BA may qualify for the development of new therapies for leukemia.

http://www.ncbi.nlm.nih.gov/pubmed/20714869




Antiproliferative effect of extracts from Aristolochia baetica and Origanum compactum on human breast cancer cell line MCF-7.
Chaouki W1, Leger DY, Eljastimi J, Beneytout JL, Hmamouchi M.
Author information

1Service of Laboratory, National Institute for Oncology, Rabat, Morocco. wchaouki@yahoo.fr

Abstract

Aristolochia baetica L. (Aristolochiaceae) and Origanum compactum Benth. (Lamiaceae) are native plants of Morocco used in traditional medicine. In order to systematically evaluate their potential activity on human breast cancer, four different polarity extracts from each plant were assessed in vitro for their antiproliferative effect on MCF-7 cells. As a result, several extracts of those plants showed potent cell proliferation inhibition on MCF-7 cells. Chloroform extract of A. baetica (IC50: 216.06 +/- 15 microg/mL) and ethyl acetate of O. compactum (IC50: 279.51 +/- 16 microg/mL) were the most active. Thin layer chromatography examination of the bioactive extracts of A. baetica and O. compactum showed the presence of aristolochic acid and betulinic acid, respectively. These results call for further studies of these extracts.

http://www.ncbi.nlm.nih.gov/pubmed/20645812




Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors.
Chintharlapalli S1, Papineni S, Lei P, Pathi S, Safe S.
Author information
Abstract
BACKGROUND:

Betulinic acid (BA) inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells.
METHODS:

The effects of BA on colon cancer cell proliferation and apoptosis and tumor growth in vivo were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a) and ZBTB10 mRNA expression.
RESULTS:

BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS), ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10.
CONCLUSIONS:

These results suggest that the anticancer activity of BA in colon cancer cells

http://www.ncbi.nlm.nih.gov/pubmed/21864401




Suppression of STAT3 and HIF-1 alpha mediates anti-angiogenic activity of betulinic acid in hypoxic PC-3 prostate cancer cells.
Shin J1, Lee HJ, Jung DB, Jung JH, Lee HJ, Lee EO, Lee SG, Shim BS, Choi SH, Ko SG, Ahn KS, Jeong SJ, Kim SH.
Author information
Abstract
BACKGROUND:

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that betulinic acid (BA), a triterpene from the bark of white birch, had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells.
METHODOLOGY/PRINCIPAL FINDINGS:

BA inhibited the protein expression and the transcriptional activities of hypoxia-inducible factor-1α (HIF-1α) under hypoxic condition. Consistently, BA blocked hypoxia-induced phosphorylation, DNA binding activity and nuclear accumulation of STAT3. In addition, BA significantly reduced cellular and secreted levels of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Furthermore, BA prevented in vitro capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxic PC-3 cells, implying anti-angiogenic activity of BA under hypoxic condition. Of note, chromatin immunoprecipitation (ChiP) assay revealed that BA inhibited binding of HIF-1α and STAT3 to VEGF promoter. Furthermore, silencing STAT3 using siRNA transfection effectively enhanced the reduced VEGF production induced by BA treatment under hypoxia.
CONCLUSIONS/SIGNIFICANCE:

Taken together, our results suggest that BA has anti-angiogenic activity by disturbing the binding of HIF-1α and STAT3 to the VEGF promoter in hypoxic PC-3 cells.

http://www.ncbi.nlm.nih.gov/pubmed/21731766




Betulinic acid decreases ER-negative breast cancer cell growth in vitro and in vivo: role of Sp transcription factors and microRNA-27a:ZBTB10.
Mertens-Talcott SU1, Noratto GD, Li X, Angel-Morales G, Bertoldi MC, Safe S.
Author information
Abstract

Betulinic acid (BA), a pentacyclic triterpenoid isolated from tree bark is cytotoxic to cancer cells. There is evidence that specificity proteins (Sps), such as Sp1, Sp3, and Sp4, are overexpressed in tumors and contribute to the proliferative and angiogenic phenotype associated with cancer cells. The objective of this study was to determine the efficacy of BA in decreasing the Sps expression and underlying mechanisms. Results show that BA decreased proliferation and induced apoptosis of estrogen-receptor-negative breast cancer MDA-MB-231 cells. The BA-induced Sp1, Sp3, and Sp4 downregulation was accompanied by increased zinc finger ZBTB10 expression, a putative Sp-repressor and decreased microRNA-27a levels, a microRNA involved in the regulation of ZBTB10. Similar results were observed in MDA-MB-231 cells transfected with ZBTB10 expression plasmid. BA induced cell cycle arrest in the G2/M phase and increased Myt-1 mRNA (a microRNA-27a target gene), which causes inhibition in G2/M by phosphorylation of cdc2. The effects of BA were reversed by transient transfection with a mimic of microRNA-27a. In nude mice with xenografted MDA-MB-231 cells, tumor size and weight were significantly decreased by BA treatment. In tumor tissue, ZBTB10 mRNA was increased while mRNA and protein of Sp1, Sp3 and Sp4, as well as mRNA of vascular endothelial growth factor receptor (VEGFR), survivin and microRNA-27a were decreased by BA. In lungs of xenografted mice, human β2-microglobulin mRNA was decreased in BA-treated animals. These results show that the anticancer effects of BA are at least in part based on interactions with the microRNA-27a-ZBTB10-Sp-axis causing increased cell death.

http://www.ncbi.nlm.nih.gov/pubmed/22407812

Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 5275
Registrado: Dom, 01 Sep 2013, 14:18

Re: Nutrición contra el cancer

Notapor Fisio » Lun, 08 Sep 2014, 08:43

Otros triterpenoides del hibisco

Imagen

Imagen

Hibiscus is a genus of flowering plants in the mallow family, Malvaceae. It is quite large, containing several hundred species that are native to warm-temperate, subtropical and tropical regions throughout the world. Member species are often noted for their showy flowers and are commonly known simply as hibiscus, or less widely known as rose mallow. The genus includes both annual and perennial herbaceous plants, as well as woody shrubs and small trees. The generic name is derived from the Greek word ἱβίσκος (hibískos), which was the name Pedanius Dioscorides gave to Althaea officinalis.

Cytotoxic effect of triterpenoids from the root bark of Hibiscus syriacus.
Shi LS1, Wu CH2, Yang TC3, Yao CW4, Lin HC5, Chang WL6.
Author information
Abstract

In this study, 4 new triterpenoids-3β- acetoxy-olean-11-en,28,13β-olide (1), 3β- acetoxy-11α,12α-epoxy-olean-28,13β-olide (2), 19α-epi-betulin (3), and 20, 28-epoxy-17β,19β-lupan-3β-ol (4)-and 12 known compounds, were isolated from the root bark of Hibiscus syriacus L. by using acetone extraction. Their structures were characterized by extensive spectroscopic analysis. To investigate cytotoxicity, A549 human lung cancer cells were exposed to the extract and the compounds identified from it. Significantly reduced cell viability was observed with betulin-3-caffeate (12) (IC50, 4.3 μM). The results of this study indicate that betulin-3-caffeate (12) identified from H. syriacus L. may warrant further investigation for potential as anticancer therapies.

http://www.ncbi.nlm.nih.gov/pubmed/24862067



Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer.
Yadav VR1, Prasad S, Sung B, Kannappan R, Aggarwal BB.
Author information

1Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston 77030, TX, USA. vryadav@mdanderson.org

Abstract

Traditional medicine and diet has served mankind through the ages for prevention and treatment of most chronic diseases. Mounting evidence suggests that chronic inflammation mediates most chronic diseases, including cancer. More than other transcription factors, nuclear factor-kappaB (NF-κB) and STAT3 have emerged as major regulators of inflammation, cellular transformation, and tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Thus, agents that can inhibit NF-κB and STAT3 activation pathways have the potential to both prevent and treat cancer. In this review, we examine the potential of one group of compounds called triterpenes, derived from traditional medicine and diet for their ability to suppress inflammatory pathways linked to tumorigenesis. These triterpenes include avicins, betulinic acid, boswellic acid, celastrol, diosgenin, madecassic acid, maslinic acid, momordin, saikosaponins, platycodon, pristimerin, ursolic acid, and withanolide. This review thus supports the famous adage of Hippocrates, "Let food be thy medicine and medicine be thy food".


http://www.ncbi.nlm.nih.gov/pubmed/22069560
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 5275
Registrado: Dom, 01 Sep 2013, 14:18

Re: Nutrición contra el cancer

Notapor Fisio » Lun, 08 Sep 2014, 08:43

Dejo aquí también la marihuana.

Marihuana

Imagen


La marihuana no solo tiene actividad anticancerígena, sino que también alivia el dolor, mejora el sueño, inhibe las nauseas, reduce la ansiedad y muchas cosas en pacientes con cancer y otras enfermedades. Así que, la marihuana puede eliminar muchos fármacos peligrosos y mal tolerados (por eso entre otras cosas la marihuana molesta tanto y es tan "peligrosa": dejan de vender muchos fármacos).

El cannabis detiene la metástasis de diferentes tipos de cancer agresivos

http://www.huffingtonpost.com/2012/09/1 ... lp00000003


Cancer de cerebro

British Journal of Cancer (2006) 95, 197–203. doi:10.1038/sj.bjc.6603236 http://www.bjcancer.com
Published online 27 June 2006
A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme

M Guzmán1, M J Duarte2, C Blázquez1, J Ravina2, M C Rosa2, I Galve-Roperh1, C Sánchez1, G Velasco1 and L González-Feria2

1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid 28040, Spain
2Department of Neurosurgery, Hospital Universitario de Canarias, La Laguna, Tenerife 38320, Spain

Correspondence: Professor M Guzmán, E-mail: mgp@bbm1.ucm.es; Professor L González-Feria, E-mail: lgferia@yahoo.es

Revised 15 May 2006; Accepted 5 June 2006
Advance online publication 27 June 2006
Top of page
Abstract

Δ9-Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of cannabinoids has never been tested in humans. Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. We also evaluated THC action on the length of survival and various tumour-cell parameters. A dose escalation regimen for THC administration was assessed. Cannabinoid delivery was safe and could be achieved without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15–33). Δ9-Tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.




Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor.
Sánchez C, de Ceballos ML, Gomez del Pulgar T, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Ramón y Cajal S, Guzmán M.
Source

Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.
Abstract

The development of new therapeutic strategies is essential for the management of gliomas, one of the most malignant forms of cancer. We have shown previously that the growth of the rat glioma C6 cell line is inhibited by psychoactive cannabinoids (I. Galve-Roperh et al., Nat. Med., 6: 313-319, 2000). These compounds act on the brain and some other organs through the widely expressed CB(1) receptor. By contrast, the other cannabinoid receptor subtype, the CB(2) receptor, shows a much more restricted distribution and is absent from normal brain. Here we show that local administration of the selective CB(2) agonist JWH-133 at 50 microg/day to Rag-2(-/-) mice induced a considerable regression of malignant tumors generated by inoculation of C6 glioma cells. The selective involvement of the CB(2) receptor in this action was evidenced by: (a) the prevention by the CB(2) antagonist SR144528 but not the CB(1) antagonist SR141716; (b) the down-regulation of the CB(2) receptor but not the CB(1) receptor in the tumors; and (c) the absence of typical CB(1)-mediated psychotropic side effects. Cannabinoid receptor expression was subsequently examined in biopsies from human astrocytomas. A full 70% (26 of 37) of the human astrocytomas analyzed expressed significant levels of cannabinoid receptors. Of interest, the extent of CB(2) receptor expression was directly related with tumor malignancy. In addition, the growth of grade IV human astrocytoma cells in Rag-2(-/-) mice was completely blocked by JWH-133 administration at 50 microg/day. Experiments carried out with C6 glioma cells in culture evidenced the internalization of the CB(2) but not the CB(1) receptor upon JWH-133 challenge and showed that selective activation of the CB(2) receptor signaled apoptosis via enhanced ceramide synthesis de novo. These results support a therapeutic approach for the treatment of malignant gliomas devoid of psychotropic side effects.




Neuroprotection by Δ9-Tetrahydrocannabinol, the Main Active Compound in Marijuana, against Ouabain-Induced In Vivo Excitotoxicity


Excitotoxicity is a paradigm used to explain the biochemical events in both acute neuronal damage and in slowly progressive, neurodegenerative diseases. Here, we show in a longitudinal magnetic resonance imaging study that Δ9-tetrahydrocannabinol (Δ9-THC), the main active compound in marijuana, reduces neuronal injury in neonatal rats injected intracerebrally with the Na+/K+-ATPase inhibitor ouabain to elicit excitotoxicity. In the acute phase Δ9-THC reduced the volume of cytotoxic edema by 22%. After 7 d, 36% less neuronal damage was observed in treated rats compared with control animals. Coadministration of the CB1 cannabinoid receptor antagonist SR141716 prevented the neuroprotective actions of Δ9-THC, indicating that Δ9-THC afforded protection to neurons via the CB1 receptor. In Δ9-THC-treated rats the volume of astrogliotic tissue was 36% smaller. The CB1 receptor antagonist did not block this effect. These results provide evidence that the cannabinoid system can serve to protect the brain against neurodegeneration.




Antitumor Effects of Cannabidiol, a Nonpsychoactive Cannabinoid, on Human Glioma Cell Lines

Department of Pharmacology, Chemotherapy and Toxicology (P.M., A.C.), and Department of Pharmacological Sciences, School of Pharmacy, and Center of Excellence for Neurodegenerative Diseases, University of Milan, Milan, Italy (S.C., M.P.A.); and Department of Structural and Functional Biology, Pharmacology Unit and Center of Neuroscience, University of Insubria, Busto Arsizio (Varese), Italy (A.V., D.P.)

Address correspondence to:
Daniela Parolaro, Dept. of Structural and Functional Biology, Pharmacology Unit and Center of Neuroscience, University of Insubria, Via A. da Giussano 10, 21052 Busto Arsizio (Varese), Italy. E-mail: daniela.parolaro@uninsubria.it

Abstract

Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC50 of 25 μM. The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; SR2) and α-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.



A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma

Sofía Torres1,
Mar Lorente1,
Fátima Rodríguez-Fornés1,
Sonia Hernández-Tiedra1,
María Salazar1,2,
Elena García-Taboada1,
Juan Barcia3,
Manuel Guzmán1,2 and
Guillermo Velasco1,2

+ Author Affiliations

Authors' Affiliations: 1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 2Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), and 3Department of Neurosurgery, Hospital Clínico San Carlos, Madrid, Spain

Corresponding Author:
Guillermo Velasco, Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, C/José Antonio Novais s/n, 28040 Madrid, Spain. Phone: 34-913944668; Fax: 34-913944672; E-mail: gvd@bbm1.ucm.es

S. Torres and M. Lorente contributed equally to the work.

Abstract

Glioblastoma multiforme (GBM) is highly resistant to current anticancer treatments, which makes it crucial to find new therapeutic strategies aimed at improving the poor prognosis of patients suffering from this disease. Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoid receptor agonists inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, we show that the combined administration of THC and temozolomide (TMZ; the benchmark agent for the management of GBM) exerts a strong antitumoral action in glioma xenografts, an effect that is also observed in tumors that are resistant to TMZ treatment. Combined administration of THC and TMZ enhanced autophagy, whereas pharmacologic or genetic inhibition of this process prevented TMZ + THC-induced cell death, supporting that activation of autophagy plays a crucial role on the mechanism of action of this drug combination. Administration of submaximal doses of THC and cannabidiol (CBD; another plant-derived cannabinoid that also induces glioma cell death through a mechanism of action different from that of THC) remarkably reduces the growth of glioma xenografts. Moreover, treatment with TMZ and submaximal doses of THC and CBD produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors. Altogether, our findings support that the combined administration of TMZ and cannabinoids could be therapeutically exploited for the management of GBM. Mol Cancer Ther; 10(1); 90–103. ©2011 AACR.




http://www.nature.com/bjc/journal/v95/n ... 3236a.html

http://www.ncbi.nlm.nih.gov/pubmed/11479216

http://www.jneurosci.org/content/21/17/6475.abstract

http://jpet.aspetjournals.org/content/3 ... 8.abstract

http://mct.aacrjournals.org/content/10/1/90.abstract




Cancer de mama

Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis.
McAllister SD, Murase R, Christian RT, Lau D, Zielinski AJ, Allison J, Almanza C, Pakdel A, Lee J, Limbad C, Liu Y, Debs RJ, Moore DH, Desprez PY.
Source

California Pacific Medical Center, Research Institute, San Francisco, CA 94107, USA. mcallis@cpmcri.org
Erratum in

Breast Cancer Res Treat. 2012 May;133(1):401-4.

Abstract

Invasion and metastasis of aggressive breast cancer cells are the final and fatal steps during cancer progression. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Therefore, effective, targeted, and non-toxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. We previously reported that cannabidiol (CBD), a cannabinoid with a low toxicity profile, down-regulated Id-1 gene expression in aggressive human breast cancer cells in culture. Using cell proliferation and invasion assays, cell flow cytometry to examine cell cycle and the formation of reactive oxygen species, and Western analysis, we determined pathways leading to the down-regulation of Id-1 expression by CBD and consequently to the inhibition of the proliferative and invasive phenotype of human breast cancer cells. Then, using the mouse 4T1 mammary tumor cell line and the ranksum test, two different syngeneic models of tumor metastasis to the lungs were chosen to determine whether treatment with CBD would reduce metastasis in vivo. We show that CBD inhibits human breast cancer cell proliferation and invasion through differential modulation of the extracellular signal-regulated kinase (ERK) and reactive oxygen species (ROS) pathways, and that both pathways lead to down-regulation of Id-1 expression. Moreover, we demonstrate that CBD up-regulates the pro-differentiation factor, Id-2. Using immune competent mice, we then show that treatment with CBD significantly reduces primary tumor mass as well as the size and number of lung metastatic foci in two models of metastasis. Our data demonstrate the efficacy of CBD in pre-clinical models of breast cancer. The results have the potential to lead to the development of novel non-toxic compounds for the treatment of breast cancer metastasis, and the information gained from these experiments broaden our knowledge of both Id-1 and cannabinoid biology as it pertains to cancer progression.




Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells.
McAllister SD, Christian RT, Horowitz MP, Garcia A, Desprez PY.
Source

California Pacific Medical Center, Research Institute, 475 Brannan Street, San Francisco, CA 94107, USA. mcallis@cpmcri.org
Abstract

Invasion and metastasis of aggressive breast cancer cells is the final and fatal step during cancer progression, and is the least understood genetically. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Clearly, effective and nontoxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. Using a mouse model, we previously determined that metastatic breast cancer cells became significantly less invasive in vitro and less metastatic in vivo when Id-1 was down-regulated by stable transduction with antisense Id-1. It is not possible at this point, however, to use antisense technology to reduce Id-1 expression in patients with metastatic breast cancer. Here, we report that cannabidiol (CBD), a cannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion. These effects seemed to occur as the result of an inhibition of the Id-1 gene at the promoter level. Importantly, CBD did not inhibit invasiveness in cells that ectopically expressed Id-1. In conclusion, CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness.



Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion.
Nasser MW, Qamri Z, Deol YS, Smith D, Shilo K, Zou X, Ganju RK.
Source

Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
Abstract
BACKGROUND:

Cannabinoids bind to cannabinoid receptors CB(1) and CB(2) and have been reported to possess anti-tumorigenic activity in various cancers. However, the mechanisms through which cannabinoids modulate tumor growth are not well known. In this study, we report that a synthetic non-psychoactive cannabinoid that specifically binds to cannabinoid receptor CB(2) may modulate breast tumor growth and metastasis by inhibiting signaling of the chemokine receptor CXCR4 and its ligand CXCL12. This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis.
METHODOLOGY/PRINCIPAL FINDINGS:

We observed high expression of both CB(2) and CXCR4 receptors in breast cancer patient tissues by immunohistochemical analysis. We further found that CB(2)-specific agonist JWH-015 inhibits the CXCL12-induced chemotaxis and wound healing of MCF7 overexpressing CXCR4 (MCF7/CXCR4), highly metastatic clone of MDA-MB-231 (SCP2) and NT 2.5 cells (derived from MMTV-neu) by using chemotactic and wound healing assays. Elucidation of the molecular mechanisms using various biochemical techniques and confocal microscopy revealed that JWH-015 treatment inhibited CXCL12-induced P44/P42 ERK activation, cytoskeletal focal adhesion and stress fiber formation, which play a critical role in breast cancer invasion and metastasis. In addition, we have shown that JWH-015 significantly inhibits orthotopic tumor growth in syngenic mice in vivo using NT 2.5 cells. Furthermore, our studies have revealed that JWH-015 significantly inhibits phosphorylation of CXCR4 and its downstream signaling in vivo in orthotopic and spontaneous breast cancer MMTV-PyMT mouse model systems.
CONCLUSIONS/SIGNIFICANCE:

This study provides novel insights into the crosstalk between CB(2) and CXCR4/CXCL12-signaling pathways in the modulation of breast tumor growth and metastasis. Furthermore, these studies indicate that CB(2) receptors could be used for developing innovative therapeutic strategies against breast cancer.




Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma.
Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V.
Source

Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche Pozzuoli, Italy.
Abstract

Delta(9)-Tetrahydrocannabinol (THC) exhibits antitumor effects on various cancer cell types, but its use in chemotherapy is limited by its psychotropic activity. We investigated the antitumor activities of other plant cannabinoids, i.e., cannabidiol, cannabigerol, cannabichromene, cannabidiol acid and THC acid, and assessed whether there is any advantage in using Cannabis extracts (enriched in either cannabidiol or THC) over pure cannabinoids. Results obtained in a panel of tumor cell lines clearly indicate that, of the five natural compounds tested, cannabidiol is the most potent inhibitor of cancer cell growth (IC(50) between 6.0 and 10.6 microM), with significantly lower potency in noncancer cells. The cannabidiol-rich extract was equipotent to cannabidiol, whereas cannabigerol and cannabichromene followed in the rank of potency. Both cannabidiol and the cannabidiol-rich extract inhibited the growth of xenograft tumors obtained by s.c. injection into athymic mice of human MDA-MB-231 breast carcinoma or rat v-K-ras-transformed thyroid epithelial cells and reduced lung metastases deriving from intrapaw injection of MDA-MB-231 cells. Judging from several experiments on its possible cellular and molecular mechanisms of action, we propose that cannabidiol lacks a unique mode of action in the cell lines investigated. At least for MDA-MB-231 cells, however, our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis via: direct or indirect activation of cannabinoid CB(2) and vanilloid transient receptor potential vanilloid type-1 receptors and cannabinoid/vanilloid receptor-independent elevation of intracellular Ca(2+) and reactive oxygen species. Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.




Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition

ErbB2-positive breast cancer is characterized by highly aggressive phenotypes and reduced responsiveness to standard therapies. Although specific ErbB2-targeted therapies have been designed, only a small percentage of patients respond to these treatments and most of them eventually relapse. The existence of this population of particularly aggressive and non-responding or relapsing patients urges the search for novel therapies. The purpose of this study was to determine whether cannabinoids might constitute a new therapeutic tool for the treatment of ErbB2-positive breast tumors. We analyzed their antitumor potential in a well established and clinically relevant model of ErbB2-driven metastatic breast cancer: the MMTV-neu mouse. We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors.
Results

Our results show that both Δ9-tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH-133, a non-psychotropic CB2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu mice. Histological analyses of the tumors revealed that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis. Cannabinoid antitumoral action relies, at least partially, on the inhibition of the pro-tumorigenic Akt pathway. We also found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB2.
Conclusions

Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.




Cannabinoids: a new hope for breast cancer therapy?
Caffarel MM, Andradas C, Pérez-Gómez E, Guzmán M, Sánchez C.
Source

Dept. Biochemistry and Molecular Biology I, School of Biology, Complutense University-CIBERNED-IRYCIS, Madrid, Spain.
Abstract

Breast cancer is a very common disease that affects approximately 1 in 10 women at some point in their lives. Importantly, breast cancer cannot be considered a single disease as it is characterized by distinct pathological and molecular subtypes that are treated with different therapies and have diverse clinical outcomes. Although some highly successful treatments have been developed, certain breast tumors are resistant to conventional therapies and a considerable number of them relapse. Therefore, new strategies are urgently needed, and the challenge for the future will most likely be the development of individualized therapies that specifically target each patient's tumor. Experimental evidence accumulated during the last decade supports that cannabinoids, the active components of Cannabis sativa and their derivatives, possess anticancer activity. Thus, these compounds exert anti-proliferative, pro-apoptotic, anti-migratory and anti-invasive actions in a wide spectrum of cancer cells in culture. Moreover, tumor growth, angiogenesis and metastasis are hampered by cannabinoids in xenograft-based and genetically-engineered mouse models of cancer. This review summarizes our current knowledge on the anti-tumor potential of cannabinoids in breast cancer, which suggests that cannabinoid-based medicines may be useful for the treatment of most breast tumor subtypes.





The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation

Anandamide was the first brain metabolite shown to act as a ligand of “central” CB1 cannabinoid receptors. Here we report that the endogenous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently inhibited the proliferation of MCF-7 and EFM-19 cells with IC50 values between 0.5 and 1.5 μM and 83–92% maximal inhibition at 5–10 μM. The proliferation of several other nonmammary tumoral cell lines was not affected by 10 μM anandamide. The anti-proliferative effect of anandamide was not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the S phase of the cell cycle. A stable analogue of anandamide (R)-methanandamide, another endogenous cannabinoid, 2-arachidonoylglycerol, and the synthetic cannabinoid HU-210 also inhibited EFM-19 cell proliferation, whereas arachidonic acid was much less effective. These cannabimimetic substances displaced the binding of the selective cannabinoid agonist [3H]CP 55,940 to EFM-19 membranes with an order of potency identical to that observed for the inhibition of EFM-19 cell proliferation. Moreover, anandamide cytostatic effect was inhibited by the selective CB1 receptor antagonist SR 141716A. Cell proliferation was arrested by a prolactin mAb and enhanced by exogenous human prolactin, whose mitogenic action was reverted by very low (0.1–0.5 μM) doses of anandamide. Anandamide suppressed the levels of the long form of the prolactin receptor in both EFM-19 and MCF-7 cells, as well as a typical prolactin-induced response, i.e., the expression of the breast cancer cell susceptibility gene brca1. These data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor




http://www.ncbi.nlm.nih.gov/pubmed/20859676

http://www.ncbi.nlm.nih.gov/pubmed/18025276

http://www.ncbi.nlm.nih.gov/pubmed/21915267

http://jpet.aspetjournals.org/content/e ... l.pdf+html

http://www.molecular-cancer.com/content/9/1/196

http://www.ncbi.nlm.nih.gov/pubmed/22776349

http://www.pnas.org/content/95/14/8375.full.pdf+html



Cancer de pulmon

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1.
Ramer R, Bublitz K, Freimuth N, Merkord J, Rohde H, Haustein M, Borchert P, Schmuhl E, Linnebacher M, Hinz B.
Source

Institute of Toxicology and Pharmacology, Department of General Surgery, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany.
Abstract

Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.




Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis.
Preet A, Qamri Z, Nasser MW, Prasad A, Shilo K, Zou X, Groopman JE, Ganju RK.
Source

Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide; however, only limited therapeutic treatments are available. Hence, we investigated the role of cannabinoid receptors, CB1 and CB2, as novel therapeutic targets against NSCLC. We observed expression of CB1 (24%) and CB2 (55%) in NSCLC patients. Furthermore, we have shown that the treatment of NSCLC cell lines (A549 and SW-1573) with CB1/CB2- and CB2-specific agonists Win55,212-2 and JWH-015, respectively, significantly attenuated random as well as growth factor-directed in vitro chemotaxis and chemoinvasion in these cells. We also observed significant reduction in focal adhesion complex, which plays an important role in migration, upon treatment with both JWH-015 and Win55,212-2. In addition, pretreatment with CB1/CB2 selective antagonists, AM251 and AM630, prior to JWH-015 and Win55,212-2 treatments, attenuated the agonist-mediated inhibition of in vitro chemotaxis and chemoinvasion. In addition, both CB1 and CB2 agonists Win55,212-2 and JWH-133, respectively, significantly inhibited in vivo tumor growth and lung metastasis (∼50%). These effects were receptor mediated, as pretreatment with CB1/CB2 antagonists abrogated CB1/CB2 agonist-mediated effects on tumor growth and metastasis. Reduced proliferation and vascularization, along with increased apoptosis, were observed in tumors obtained from animals treated with JWH-133 and Win55,212-2. Upon further elucidation into the molecular mechanism, we observed that both CB1 and CB2 agonists inhibited phosphorylation of AKT, a key signaling molecule controlling cell survival, migration, and apoptosis, and reduced matrix metalloproteinase 9 expression and activity. These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.




Δ9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo

A Preet1, R K Ganju1,2 and J E Groopman1,2

1Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Correspondence: Drs JE Groopman or RK Ganju, Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine Building, 4 Blackfan Circle, Boston, MA 02115, USA. E-mail: jgroopma@bidmc.harvard.edu or rganju@bidmc.harvard.edu

2JEG and RKG share the senior and corresponding authorship.

Received 21 January 2007; Revised 29 May 2007; Accepted 1 June 2007; Published online 9 July 2007.
Top of page
Abstract

Δ9-Tetrahydrocannabinol (THC) is the primary cannabinoid of marijuana and has been shown to either potentiate or inhibit tumor growth, depending on the type of cancer and its pathogenesis. Little is known about the activity of cannabinoids like THC on epidermal growth factor receptor-overexpressing lung cancers, which are often highly aggressive and resistant to chemotherapy. In this study, we characterized the effects of THC on the EGF-induced growth and metastasis of human non-small cell lung cancer using the cell lines A549 and SW-1573 as in vitro models. We found that these cells express the cannabinoid receptors CB1 and CB2, known targets for THC action, and that THC inhibited EGF-induced growth, chemotaxis and chemoinvasion. Moreover, signaling studies indicated that THC may act by inhibiting the EGF-induced phosphorylation of ERK1/2, JNK1/2 and AKT. THC also induced the phosphorylation of focal adhesion kinase at tyrosine 397. Additionally, in in vivo studies in severe combined immunodeficient mice, there was significant inhibition of the subcutaneous tumor growth and lung metastasis of A549 cells in THC-treated animals as compared to vehicle-treated controls. Tumor samples from THC-treated animals revealed antiproliferative and antiangiogenic effects of THC. Our study suggests that cannabinoids like THC should be explored as novel therapeutic molecules in controlling the growth and metastasis of certain lung cancers.




http://www.ncbi.nlm.nih.gov/pubmed/2219 ... t=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/2109 ... t=Abstract

http://www.nature.com/onc/journal/v27/n ... 0641a.html


Cancer de próstata

Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production.
Mimeault M, Pommery N, Wattez N, Bailly C, Hénichart JP.
Source

Institut de Chimie Pharmaceutique Albert Lespagnol, 3 Rue du Professeur Laguesse, BP83, Lille, France.
Abstract
BACKGROUND:

Anandamide (ANA) is an endogenous lipid which acts as a cannabinoid receptor ligand and with potent anticarcinogenic activity in several cancer cell types.
METHODS:

The inhibitory effect of ANA on the epidermal growth factor receptor (EGFR) levels expressed on the EGF-stimulated prostatic cancer cells LNCaP, DU145, and PC3 was estimated by ELISA tests. The anti-proliferative and cytotoxic effects of ANA were also evaluated on these human prostatic cancer cell lines by growth tests, flow cytometric analyses, trypan blue dye exclusion assays combined with the Papanicolaou cytological staining method.
RESULTS:

ANA induced a decrease of EGFR levels on LNCaP, DU145, and PC3 prostatic cancer cells by acting through cannabinoid CB(1) receptor subtype and this leaded to an inhibition of the EGF-stimulated growth of these cells. Moreover, the G(1) arrest of metastatic DU145 and PC3 growth was accompanied by a massive cell death by apoptosis and/or necrosis while LNCaP cells were less sensitive to cytotoxic effects of ANA. The apoptotic/necrotic responses induced by ANA on these prostatic cancer cells were also potentiated by the acidic ceramidase inhibitor, N-oleoylethanolamine and partially inhibited by the specific ceramide synthetase inhibitor, fumonisin B1 indicating that these cytotoxic actions of ANA might be induced via the cellular ceramide production.
CONCLUSIONS:

The potent anti-proliferative and cytotoxic effects of ANA on metastatic prostatic cancer cells might provide basis for the design of new therapeutic agents for effective treatment of recurrent and invasive prostatic cancers.



The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications
Juan A. Ramos and Fernando J. Bianco1
Author information ► Copyright and License information ►
Go to:
Abstract

Prostate cancer is a global public health problem, and it is the most common cancer in American men and the second cause for cancer-related death. Experimental evidence shows that prostate tissue possesses cannabinoid receptors and their stimulation results in anti-androgenic effects. To review currently relevant findings related to effects of cannabinoid receptors in prostate cancer. PubMed search utilizing the terms “cannabis,” “cannabinoids,” “prostate cancer,” and “cancer pain management,” giving preference to most recent publications was done. Articles identified were screened for their relevance to the field of prostate cancer and interest to both urologist and pain specialists. Prostate cancer cells possess increased expression of both cannabinoid 1 and 2 receptors, and stimulation of these results in decrease in cell viability, increased apoptosis, and decreased androgen receptor expression and prostate-specific antigen excretion. It would be of interest to conduct clinical studies utilizing cannabinoids for patients with metastatic prostate cancer, taking advantage not only of its beneficial effects on prostate cancer but also of their analgesic properties for bone metastatic cancer pain.




Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms.
De Petrocellis L, Ligresti A, Schiano Moriello A, Iappelli M, Verde R, Stott CG, Cristino L, Orlando P, Di Marzo V.
Source

Istituto di Cibernetica, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy. l.depetrocellis@cib.na.cnr.it
Abstract
BACKGROUND AND PURPOSE:

Cannabinoid receptor activation induces prostate carcinoma cell (PCC) apoptosis, but cannabinoids other than Δ(9) -tetrahydrocannabinol (THC), which lack potency at cannabinoid receptors, have not been investigated. Some of these compounds antagonize transient receptor potential melastatin type-8 (TRPM8) channels, the expression of which is necessary for androgen receptor (AR)-dependent PCC survival.
EXPERIMENTAL APPROACH:

We tested pure cannabinoids and extracts from Cannabis strains enriched in particular cannabinoids (BDS), on AR-positive (LNCaP and 22RV1) and -negative (DU-145 and PC-3) cells, by evaluating cell viability (MTT test), cell cycle arrest and apoptosis induction, by FACS scans, caspase 3/7 assays, DNA fragmentation and TUNEL, and size of xenograft tumours induced by LNCaP and DU-145 cells.
KEY RESULTS:

Cannabidiol (CBD) significantly inhibited cell viability. Other compounds became effective in cells deprived of serum for 24 h. Several BDS were more potent than the pure compounds in the presence of serum. CBD-BDS (i.p.) potentiated the effects of bicalutamide and docetaxel against LNCaP and DU-145 xenograft tumours and, given alone, reduced LNCaP xenograft size. CBD (1-10 µM) induced apoptosis and induced markers of intrinsic apoptotic pathways (PUMA and CHOP expression and intracellular Ca(2+)). In LNCaP cells, the pro-apoptotic effect of CBD was only partly due to TRPM8 antagonism and was accompanied by down-regulation of AR, p53 activation and elevation of reactive oxygen species. LNCaP cells differentiated to androgen-insensitive neuroendocrine-like cells were more sensitive to CBD-induced apoptosis.
CONCLUSIONS AND IMPLICATIONS:

These data support the clinical testing of CBD against prostate carcinoma.




http://www.ncbi.nlm.nih.gov/pubmed/1274 ... t=Abstract

http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22594963



Cancer de colon

J Mol Med (Berl). 2012 Aug;90(8):925-34. doi: 10.1007/s00109-011-0856-x. Epub 2012 Jan 10.
Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer.
Aviello G, Romano B, Borrelli F, Capasso R, Gallo L, Piscitelli F, Di Marzo V, Izzo AA.
Source

Department of Experimental Pharmacology, Endocannabinoid Research Group, University of Naples Federico II, Naples, Italy.
Abstract

Colon cancer affects millions of individuals in Western countries. Cannabidiol, a safe and non-psychotropic ingredient of Cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis. Thus, we investigated its possible chemopreventive effect in the model of colon cancer induced by azoxymethane (AOM) in mice. AOM treatment was associated with aberrant crypt foci (ACF, preneoplastic lesions), polyps, and tumour formation, up-regulation of phospho-Akt, iNOS and COX-2 and down-regulation of caspase-3. Cannabidiol-reduced ACF, polyps and tumours and counteracted AOM-induced phospho-Akt and caspase-3 changes. In colorectal carcinoma cell lines, cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels and reduced cell proliferation in a CB(1)-, TRPV1- and PPARγ-antagonists sensitive manner. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms.




http://www.ncbi.nlm.nih.gov/pubmed/22231745

tracto oral

Cannabinoids inhibit cellular respiration of human oral cancer cells.

The primary cannabinoids, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and Delta(8)-tetrahydrocannabinol (Delta(8)-THC) are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted us to investigate their effects on the mitochondrial O(2) consumption in human oral cancer cells (Tu183). This epithelial cell line overexpresses bcl-2 and is highly resistant to anticancer drugs.
EXPERIMENTAL APPROACH:

A phosphorescence analyzer that measures the time-dependence of O(2) concentration in cellular or mitochondrial suspensions was used for this purpose.
KEY RESULTS:

A rapid decline in the rate of respiration was observed when Delta(9)-THC or Delta(8)-THC was added to the cells. The inhibition was concentration-dependent, and Delta(9)-THC was the more potent of the two compounds. Anandamide (an endocannabinoid) was ineffective; suggesting the effects of Delta(9)-THC and Delta(8)-THC were not mediated by the cannabinoidreceptors. Inhibition of O(2) consumption by cyanide confirmed the oxidations occurred in the mitochondrial respiratory chain. Delta(9)-THC inhibited the respiration of isolated mitochondria from beef heart.
CONCLUSIONS AND IMPLICATIONS:

These results show the cannabinoids are potent inhibitors of Tu183 cellular respiration and are toxic to this highly malignant tumor.




http://www.ncbi.nlm.nih.gov/pubmed/20516734

Cancer de ovarios

Cannabinoid receptors as a target for therapy of ovarian cancer
Farrukh Afaq, Sami Sarfaraz, Deeba N. Syed, Naghma Khan, Arshi Malik, Howard H. Bailey and Hasan Mukhtar

University of Wisconsin, Madison, WI

Ovarian cancer represents one of the leading cause of cancer-related deaths for women and is the most common gynecologic malignancy. In spite of relative low morbidity, ovarian cancer has a high fatality ratio, with overall 5-year survival of less than 30%. At present, there are inadequate treatment options for the management of advanced ovarian cancer, and therefore development of novel approaches for treatment of this disease are needed. Cannabinoids, the active components of Cannabis sativa linnaeous and their derivatives have received considerable attention in recent years due to their diverse pharmacological activities such as cell growth inhibition and tumor regression. To date, two different cannabinoid receptors have been characterized and cloned from mammalian tissues: the "central" CB1 receptor and the "peripheral" CB2 receptor. We found that compared to normal Chinese hamster ovarian (CHO) cells, the expression levels of both cannabinoid receptors CB1 and CB2 were significantly higher in human ovarian cancer cells OVCAR-3 and SKOV-3. We then determined expression levels of the cannabinoid receptors in different grades of human ovarian cancer specimens and employing western blot analysis found that both CB1 and CB2 receptors were expressed. To evaluate the cell growth response of WIN-55,212-2 (a mixed CB1/CB2 agonist) on CHO, OVCAR-3 and SKOV-3 cells, we employed MTT assay. Of interest, our results demonstrated that treatment of CHO cells with WIN-55,212-2 (5-20 µM; 48 h), did not affect cell viability. In sharp contrast, treatment of OVCAR-3 and SKOV-3 cells with WIN-55,212-2 under similar conditions significantly decreased the viability of cells. The decrease in cell viability in OVCAR-3 and SKOV-3 cells suggests the involvement of either or both CB1 and CB2 receptors in the antiproliferative action of cannabinoids. To evaluate the possible implication of CB1 and CB2 receptors in WIN-55,212-2-mediated decrease in cell viability, the effect of selective receptor antagonists was studied. Blocking of both receptors by their antagonists SR141716 (CB1) and SR144528 (CB2) significantly prevented this growth inhibitory effect. Further, WIN-55,212-2 treatment of both OVCAR-3 and SKOV-3 cells resulted in G1 arrest in cell cycle progression, which was associated with a marked decrease in the protein expression of cyclin D1, D2, and E and their activating partner cdk2, 4 and 6. In addition WIN-55,212-2 treatment of both OVCAR-3 and SKOV-3 cells was found to result in induction of apoptosis as determined by PARP cleavage and flow cytometry. We also found that treatment of both OVCAR-3 and SKOV-3 cells with WIN-55,212-2 resulted in down-regulation of the expression of PCNA and VEGF. These results support a new therapeutic approach for the treatment of ovarian cancer. It is also conceivable that with available cannabinoids as lead compounds, non-habit forming agents that have higher biological effects could be developed.



http://www.aacrmeetingabstracts.org/cgi ... 006/1/1084


Hematológicos

Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease.
McKallip RJ, Lombard C, Fisher M, Martin BR, Ryu S, Grant S, Nagarkatti PS, Nagarkatti M.
Source

Department of Microbiology and Immunology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
Abstract

In the current study, we examined whether ligation of CB2 receptors would lead to induction of apoptosis in tumors of immune origin and whether CB2 agonist could be used to treat such cancers. Exposure of murine tumors EL-4, LSA, and P815 to delta-9-tetrahydrocannabinol (THC) in vitro led to a significant reduction in cell viability and an increase in apoptosis. Exposure of EL-4 tumor cells to the synthetic cannabinoid HU-210 and the endogenous cannabinoid anandamide led to significant induction of apoptosis, whereas exposure to WIN55212 was not effective. Treatment of EL-4 tumor-bearing mice with THC in vivo led to a significant reduction in tumor load, increase in tumor-cell apoptosis, and increase in survival of tumor-bearing mice. Examination of a number of human leukemia and lymphoma cell lines, including Jurkat, Molt-4, and Sup-T1, revealed that they expressed CB2 receptors but not CB1. These human tumor cells were also susceptible to apoptosis induced by THC, HU-210, anandamide, and the CB2-selective agonist JWH-015. This effect was mediated at least in part through the CB2 receptors because pretreatment with the CB2 antagonist SR144528 partially reversed the THC-induced apoptosis. Culture of primary acute lymphoblastic leukemia cells with THC in vitro reduced cell viability and induced apoptosis. Together, the current data demonstrate that CB2 cannabinoid receptors expressed on malignancies of the immune system may serve as potential targets for the induction of apoptosis. Also, because CB2 agonists lack psychotropic effects, they may serve as novel anticancer agents to selectively target and kill tumors of immune origin.




Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of Bad to mitochondria.
Jia W, Hegde VL, Singh NP, Sisco D, Grant S, Nagarkatti M, Nagarkatti PS.
Source

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, USA.
Abstract

Plant-derived cannabinoids, including Delta9-tetrahydrocannabinol (THC), induce apoptosis in leukemic cells, although the precise mechanism remains unclear. In the current study, we investigated the effect of THC on the upstream and downstream events that modulate the extracellular signal-regulated kinase (ERK) module of mitogen-activated protein kinase pathways primarily in human Jurkat leukemia T cells. The data showed that THC down-regulated Raf-1/mitogen-activated protein kinase/ERK kinase (MEK)/ERK/RSK pathway leading to translocation of Bad to mitochondria. THC also decreased the phosphorylation of Akt. However, no significant association of Bad translocation with phosphatidylinositol 3-kinase/Akt and protein kinase A signaling pathways was noted when treated cells were examined in relation to phosphorylation status of Bad by Western blot and localization of Bad to mitochondria by confocal analysis. Furthermore, THC treatment decreased the Bad phosphorylation at Ser(112) but failed to alter the level of phospho-Bad on site Ser(136) that has been reported to be associated with phosphatidylinositol 3-kinase/Akt signal pathway. Jurkat cells expressing a constitutively active MEK construct were found to be resistant to THC-mediated apoptosis and failed to exhibit decreased phospho-Bad on Ser(112) as well as Bad translocation to mitochondria. Finally, use of Bad small interfering RNA reduced the expression of Bad in Jurkat cells leading to increased resistance to THC-mediated apoptosis. Together, these data suggested that Raf-1/MEK/ERK/RSK-mediated Bad translocation played a critical role in THC-induced apoptosis in Jurkat cells.





Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: Growth inhibition by receptor activation

Endogenous and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL). In this study, we evaluated the expression of cannabinoid receptors type 1 and type 2 (CB1 and CB2) in non-Hodgkin lymphomas of B cell type (n = 62). A majority of the lymphomas expressed higher mRNA levels of CB1 and/or CB2 as compared to reactive lymphoid tissue. With the exception of MCL, which uniformly overexpresses both CB1 and CB2, the levels of cannabinoid receptors within other lymphoma entities were highly variable, ranging from 0.1 to 224 times the expression in reactive lymph nodes. Low levels of the splice variant CB1a, previously shown to have a different affinity for cannabinoids than CB1, were detected in 44% of the lymphomas, while CB1b expression was not detected. In functional studies using MCL, Burkitt lymphoma (BL), chronic lymphatic leukemia (CLL) and plasma cell leukemia cell lines, the stable anandamide analog R(+)-methanandamide (R(+)-MA) induced cell death only in MCL and CLL cells, which overexpressed both cannabinoid receptors, but not in BL. In vivo treatment with R(+)-MA caused a significant reduction of tumor size and mitotic index in mice xenografted with human MCL. Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing CB1 and CB2. © 2008 Wiley-Liss, Inc.



Cannabinoid Receptor-Mediated Apoptosis Induced by R(+)-Methanandamide and Win55,212-2 Is Associated with Ceramide Accumulation and p38 Activation in Mantle Cell Lymphoma

Kristin Gustafsson,
Birger Christensson,
Birgitta Sander and
Jenny Flygare

+ Author Affiliations

Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital Huddinge, Stockholm, Sweden

Address correspondence to:
Birgitta Sander, Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital Huddinge, F-46, SE-14186 Stockholm, Sweden. E-mail: birgitta.sander@ki.se

Abstract

We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB1 and CB2). In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated. Induction of apoptosis after treatment with the synthetic agonists R(+)-methanandamide [R(+)-MA] and Win55,212-2 (Win55; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone) was dependent on both cannabinoid receptors, because pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) and N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) (SR144528), specific antagonists to CB1 and CB2, respectively, abrogated caspase-3 activity. Preincubation with the inhibitors 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB202190) showed that phosphorylation of MAPK p38 was implicated in the signal transduction leading to apoptosis. Treatment with R(+)-MA and Win55 was associated with accumulation of ceramide, and pharmacological inhibition of ceramide synthesis de novo prevented both p38 activation and mitochondria depolarization assessed by binding of 3,3′-dihexyloxacarbocyanine iodide (DiOC6). In contrast, the pancaspase inhibitor z-Val-Ala-Asp(Ome)-CH2F (z-VAD-FMK) did not protect the mitochondrial integrity. Taken together, these results suggest that concurrent ligation of CB1 and CB2 with either R(+)-MA or Win55 induces apoptosis via a sequence of events in MCL cells: accumulation of ceramide, phosphorylation of p38, depolarization of the mitochondrial membrane, and caspase activation. Although induction of apoptosis was observed in both MCL cell lines and primary MCL, normal B cells remained unaffected. The present data suggest that targeting CB1/CB2 may have therapeutic potential for the treatment of mantle cell lymphoma.




http://www.ncbi.nlm.nih.gov/pubmed/12091357

http://www.ncbi.nlm.nih.gov/pubmed/16908594

http://onlinelibrary.wiley.com/doi/10.1 ... 4/abstract

http://molpharm.aspetjournals.org/conte ... 2.abstract


Cancer de piel

Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors.
Casanova ML, Blázquez C, Martínez-Palacio J, Villanueva C, Fernández-Aceñero MJ, Huffman JW, Jorcano JL, Guzmán M.
Source

Project on Cellular and Molecular Biology and Gene Therapy, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain.
Abstract

Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB(1) and CB(2)), we studied the potential utility of these compounds in anti-skin tumor therapy. Here we show that the CB(1) and the CB(2) receptor are expressed in normal skin and skin tumors of mice and humans. In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB(1)/CB(2) agonist WIN-55,212-2 or the selective CB(2) agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumo
rs.



http://www.ncbi.nlm.nih.gov/pubmed/12511587

Cancer Hepático

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy.
Vara D, Salazar M, Olea-Herrero N, Guzmán M, Velasco G, Díaz-Laviada I.
Source

Department of Biochemistry and Molecular Biology, School of Medicine, Alcalá University, Madrid, Spain.
Erratum in

Cell Death Differ. 2011 Jul;18(7):1237.

Abstract

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. When these tumors are in advanced stages, few therapeutic options are available. Therefore, it is essential to search for new treatments to fight this disease. In this study, we investigated the effects of cannabinoids--a novel family of potential anticancer agents--on the growth of HCC. We found that Δ(9)-tetrahydrocannabinol (Δ(9)-THC, the main active component of Cannabis sativa) and JWH-015 (a cannabinoid receptor 2 (CB(2)) cannabinoid receptor-selective agonist) reduced the viability of the human HCC cell lines HepG2 (human hepatocellular liver carcinoma cell line) and HuH-7 (hepatocellular carcinoma cells), an effect that relied on the stimulation of CB(2) receptor. We also found that Δ(9)-THC- and JWH-015-induced autophagy relies on tribbles homolog 3 (TRB3) upregulation, and subsequent inhibition of the serine-threonine kinase Akt/mammalian target of rapamycin C1 axis and adenosine monophosphate-activated kinase (AMPK) stimulation. Pharmacological and genetic inhibition of AMPK upstream kinases supported that calmodulin-activated kinase kinase β was responsible for cannabinoid-induced AMPK activation and autophagy. In vivo studies revealed that Δ(9)-THC and JWH-015 reduced the growth of HCC subcutaneous xenografts, an effect that was not evident when autophagy was genetically of pharmacologically inhibited in those tumors. Moreover, cannabinoids were also able to inhibit tumor growth and ascites in an orthotopic model of HCC xenograft. Our findings may contribute to the design of new therapeutic strategies for the management of HCC.



http://www.ncbi.nlm.nih.gov/pubmed/21475304


Cancer de Vejiga

http://www.medscape.com/viewarticle/803983


link sobre elaboración de aceite de cannabis

http://lamariaguanaca.org/2013/05/22/ac ... -cannabis/
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 5275
Registrado: Dom, 01 Sep 2013, 14:18

Re: Nutrición contra el cancer

Notapor Fisio » Lun, 08 Sep 2014, 08:43

Withania somnifera (ashwaganda)

Imagen


PLoS One. 2011;6(8):e23354. doi: 10.1371/journal.pone.0023354. Epub 2011 Aug 10.
Withaferin A-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species.
Hahm ER1, Moura MB, Kelley EE, Van Houten B, Shiva S, Singh SV.
Author information
Abstract

Withaferin A (WA), a promising anticancer constituent of Ayurvedic medicinal plant Withania somnifera, inhibits growth of MDA-MB-231 and MCF-7 human breast cancer cells in culture and MDA-MB-231 xenografts in vivo in association with apoptosis induction, but the mechanism of cell death is not fully understood. We now demonstrate, for the first time, that WA-induced apoptosis is mediated by reactive oxygen species (ROS) production due to inhibition of mitochondrial respiration. WA treatment caused ROS production in MDA-MB-231 and MCF-7 cells, but not in a normal human mammary epithelial cell line (HMEC). The HMEC was also resistant to WA-induced apoptosis. WA-mediated ROS production as well as apoptotic histone-associated DNA fragment release into the cytosol was significantly attenuated by ectopic expression of Cu,Zn-superoxide dismutase in both MDA-MB-231 and MCF-7 cells. ROS production resulting from WA exposure was accompanied by inhibition of oxidative phosphorylation and inhibition of complex III activity. Mitochondrial DNA-deficient Rho-0 variants of MDA-MB-231 and MCF-7 cells were resistant to WA-induced ROS production, collapse of mitochondrial membrane potential, and apoptosis compared with respective wild-type cells. WA treatment resulted in activation of Bax and Bak in MDA-MB-231 and MCF-7 cells, and SV40 immortalized embryonic fibroblasts derived from Bax and Bak double knockout mouse were significantly more resistant to WA-induced apoptosis compared with fibroblasts derived from wild-type mouse. In conclusion, the present study provides novel insight into the molecular circuitry of WA-induced apoptosis involving ROS production and activation of Bax/Bak.


http://www.ncbi.nlm.nih.gov/pubmed/21853114

Carcinogenesis. 2011 Nov;32(11):1697-705. doi: 10.1093/carcin/bgr192. Epub 2011 Aug 22.
Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells.
Munagala R1, Kausar H, Munjal C, Gupta RC.
Author information
Abstract

Cervical cancer is caused by human papilloma virus (HPV) expressing E6 and E7 oncoproteins, which are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Repression of HPV oncoproteins would therefore result in reactivation of tumor suppressor pathways and cause apoptosis in cancer cells. Withaferin A (WA), the active component of the medicinal plant Withania Somnifera, has exhibited inhibitory effects against several different cancers. We examined the activity of WA on human cervical cancer cells in vitro and in vivo. WA potently inhibited proliferation of the cervical cancer cells, CaSki (IC(50) 0.45 ± 0.05 μM). Mechanistically, WA was found to (i) downregulate expression of HPV E6 and E7 oncoproteins, (ii) induce accumulation of p53, (iii) increase levels of p21(cip1/waf1) and its interaction with proliferating cell nuclear antigen (PCNA), (iv) cause G(2)/M cell cycle arrest, associated with modulation of cyclin B1, p34(cdc2) and PCNA levels, (v) decrease the levels of STAT3 and its phosphorylation at Tyr(705) and Ser(727) and (vi) alter expression levels of p53-mediated apoptotic markers-Bcl2, Bax, caspase-3 and cleaved PARP. In vivo, WA resulted in reduction of nearly 70% of the tumor volume in athymic nude mice with essentially similar trend in the modulation of molecular markers as in vitro. This is the first demonstration indicating that WA significantly downregulates expression of HPV E6/E7 oncogenes and restores the p53 pathway, resulting in apoptosis of cervical cancer cells. Together, our data suggest that WA can be exploited as a potent therapeutic agent for the treatment and prevention of cervical cancer without deleterious effects.


http://www.ncbi.nlm.nih.gov/pubmed/21859835

Angiogenesis. 2004;7(2):115-22.
Withaferin A is a potent inhibitor of angiogenesis.
Mohan R1, Hammers HJ, Bargagna-Mohan P, Zhan XH, Herbstritt CJ, Ruiz A, Zhang L, Hanson AD, Conner BP, Rougas J, Pribluda VS.
Author information
Abstract

The medicinal plant Withania somnifera is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In Ayurveda , the major Traditional Indian medicine system, extracts from W. somnifera are distinctively employed for the treatment of arthritis and menstrual disorders. Because these conditions involve angiogenic processes we hypothesized that the W. somnifera extracts might contain angiogenesis inhibitors. We employed an endothelial cell-sprouting assay to monitor the purification of substances from W. somnifera root extracts and isolated as the active principle the previously known natural product withaferin A. We show that withaferin A inhibits human umbilical vein endothelial cell (HUVEC) sprouting in three-dimensional collagen-I matrix at doses which are relevant to NF-kappa B-inhibitory activity. Withaferin A inhibits cell proliferation in HUVECs (IC50 =12 nM) at doses that are significantly lower than those required for tumor cell lines through a process associated with inhibition of cyclin D1 expression. We propose that the inhibition of NF-kappa B by withaferin A in HUVECs occurs by interference with the ubiquitin-mediated proteasome pathway as suggested by the increased levels of poly-ubiquitinated proteins. Finally, withaferin A is shown to exert potent anti-angiogenic activity in vivo at doses that are 500-fold lower than those previously reported to exert anti-tumor activity in vivo. In conclusion, our findings identify a novel mode of action of withaferin A, which highlights the potential use of this natural product for cancer treatment or prevention.


http://www.ncbi.nlm.nih.gov/pubmed/15516832

Ajo

Imagen

Breast Cancer Res Treat. 2013 Feb;138(1):69-79. doi: 10.1007/s10549-013-2440-2. Epub 2013 Feb 15.
Critical role for reactive oxygen species in apoptosis induction and cell migration inhibition by diallyl trisulfide, a cancer chemopreventive component of garlic.
Chandra-Kuntal K1, Lee J, Singh SV.
Author information
Abstract

Diallyl trisulfide (DATS) is a structurally simple but biologically active constituent of processed garlic with in vivo activity against chemically induced as well as oncogene-driven cancer in experimental rodents. This study offers novel insights into the mechanisms underlying anticancer effects of DATS using human breast cancer cells as a model. Exposure of human breast cancer cells (MCF-7 and MDA-MB-231) and a cell line derived from spontaneously developing mammary tumor of a transgenic mouse (BRI-JM04) to DATS resulted in a dose-dependent inhibition of cell viability that was accompanied by apoptosis induction. A non-tumorigenic normal human mammary cell line (MCF-10A) was resistant to growth inhibition and apoptosis induction by DATS. The DATS-induced apoptosis in MDA-MB-231, MCF-7, and BRI-JM04 cells was associated with reactive oxygen species (ROS) production as evidenced by fluorescence microscopy and flow cytometry using a chemical probe (MitoSOX Red). Overexpression of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) as well as Mn-SOD conferred significant protection against DATS-induced ROS production and apoptotic cell death in MDA-MB-231 and MCF-7 cells. Activation of Bak, but not Bax, resulting from DATS treatment was markedly suppressed by overexpression of Mn-SOD. The DATS treatment caused ROS generation, but not activation of Bax or Bak, in MCF-10A cells. Furthermore, the DATS-mediated inhibition of cell migration was partially but significantly attenuated by Cu,Zn-SOD and Mn-SOD overexpression in association with changes in levels of proteins involved in epithelial-mesenchymal transition. The DATS-mediated induction of heme oxygenase-1 was partially attenuated by overexpression of Mn-SOD. These results provide novel mechanistic insights indicating a critical role for ROS in anticancer effects of DATS.


http://www.ncbi.nlm.nih.gov/pubmed/23412769

Cancer Biol Ther. 2009 Nov;8(22):2175-85. Epub 2009 Nov 22.
Garlic constituent diallyl trisulfide induced apoptosis in MCF7 human breast cancer cells.
Malki A1, El-Saadani M, Sultan AS.
Author information
Abstract

Identification of agents that are nontoxic but can delay onset and/or progression of breast cancer, which is the main leading cause of cancer-related deaths among women, is highly desirable. Garlic-derived organosulfur compounds (OSCs) have highly effective antitumor effects, but the mechanism has yet to be investigated. The aim of the present study was undertaken to examine the effect of diallyl trisulfide (DATS), a promising cancer chemopreventive constituent of garlic, on growth of two cell lines respectively, MCF-7 human breast cancer cells and nontumorigenic MCF-12a mammary epithelial cells. The effects of DATS were examined by MTT assay, clonogenic survival assay, ELISA based apoptotic assay, TUNEL assay, immunofluoresence staining, flow Cytometry, RT-PCR and western blot analysis. Garlic constituent diallyl trisulfide (DATS) suppresses viability of cultured MCF-7 and MCF-12a cells respectively by decreasing the percent of cells in G(2)/M and inducing apoptotic cell death. DATS-induced apoptosis was markedly elevated in MCF-7 cells compared with MCF-12a cells and this was correlated with elevated levels of cyclin B1. The results from semi-quantitative and real-time RT-PCR indicated that DATS-enhanced the expression levels of FAS and cyclin D1, but in contrast, downregulated the expression levels of Akt and Bcl-2. Furthermore, the DATS-induced apoptosis was correlated with induction of pro-apoptotic Bax protein and p53 protein expression was upregulated and translocation to nucleus in MCF-7 cells. Together, the results of the present study show, for the first time, that DATS administration might offer a novel strategy for the treatment of human breast cancer.


http://www.ncbi.nlm.nih.gov/pubmed/19823037

Mol Cancer Ther. 2007 May;6(5):1599-609.
Mitochondria-mediated apoptosis by diallyl trisulfide in human prostate cancer cells is associated with generation of reactive oxygen species and regulated by Bax/Bak.
Kim YA1, Xiao D, Xiao H, Powolny AA, Lew KL, Reilly ML, Zeng Y, Wang Z, Singh SV.
Author information
Abstract

Garlic constituent diallyl trisulfide (DATS) inhibits growth of cancer cells in vitro and in vivo by causing apoptosis, but the sequence of events leading to cell death is not fully understood. We now show that DATS treatment triggers mitochondria-mediated apoptosis program in human prostate cancer cells (LNCaP, LNCaP-C81, LNCaP-C4-2) irrespective of their androgen responsiveness. Interestingly, a normal prostate epithelial cell line (PrEC) is significantly more resistant to apoptosis induction by DATS compared with prostate cancer cells. The DATS-induced apoptosis in LNCaP cells correlated with the collapse of mitochondrial membrane potential, modest increase in protein level of Bak, and down-regulation of Bcl-2 and Bcl-xL protein levels. The DATS-induced apoptosis was significantly attenuated by knockdown of Bax and Bak proteins, but not by ectopic expression of either Bcl-2 or Bcl-xL. The DATS treatment caused generation of reactive oxygen species (ROS) in LNCaP cells, but not in PrEC, which was attenuated by pretreatment with antioxidant N-acetylcysteine. The N-acetylcysteine pretreatment conferred significant protection against DATS-mediated disruption of the mitochondrial membrane potential and apoptosis. In conclusion, the present study reveals that the mitochondria-mediated cell death by DATS is associated with ROS generation and regulated by Bax/Bak but independent of Bcl-2 or Bcl-xL.


http://www.ncbi.nlm.nih.gov/pubmed/17513609


Azafrán

Saffron: A potential candidate for a novel anticancer drug against hepatocellular carcinoma†

Amr Amin1,4,‡,*,
Alaaeldin A. Hamza1,
Khuloud Bajbouj1,
S. Salman Ashraf2 and
Sayel Daoud3


Saffron has been proposed as a promising candidate for cancer chemoprevention. The purpose of this investigation was to investigate the chemopreventive action and the possible mechanisms of saffron against diethylnitrosamine (DEN)-induced liver cancer in rats. Administration of saffron at doses of 75, 150, and 300 mg/kg/day was started 2 weeks prior to the DEN injection and was continued for 22 weeks. Saffron significantly reduced the DEN-induced increase in the number and the incidence of hepatic dyschromatic nodules. Saffron also decreased the number and the area of placental glutathione S-transferase–positive foci in livers of DEN-treated rats. Furthermore, saffron counteracted DEN-induced oxidative stress in rats as assessed by restoration of superoxide dismutase, catalase, and glutathione-S-transferase levels and diminishing of myeloperoxidase activity, malondialdehyde and protein carbonyl formation in liver. The results of immunohistochemical staining of rat liver showed that saffron inhibited the DEN-mediated elevations in numbers of cells positive for Ki-67, cyclooxygenase 2, inducible nitric oxide synthase, nuclear factor-kappa B p-65, and phosphorylated tumor necrosis factor receptor. Saffron also blocked the depletion in the number of cells positive for TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling) and M30 CytoDeath in liver tissues of DEN-treated rats. In vitro experiments carried out using HepG2 cells also confirmed these findings and showed inhibition of nuclear factor-kappa B activation, increased cleavage of caspase-3, as well as DNA damage and cell cycle arrest upon saffron treatment. Conclusion: This study provides evidence that saffron exerts a significant chemopreventive effect against liver cancer through inhibition of cell proliferation and induction of apoptosis. This report also shows some evidence that saffron protects rat liver from cancer via modulating oxidative damage and suppressing inflammatory response. (HEPATOLOGY 2011;)

http://onlinelibrary.wiley.com/doi/10.1 ... 3/abstract
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 5275
Registrado: Dom, 01 Sep 2013, 14:18

Re: Nutrición contra el cancer

Notapor Fisio » Lun, 08 Sep 2014, 08:44

Vitamina C

Rationale

Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues.
Chen Q1, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, Shacter E, Levine M.
Author information
Abstract

Human pharmacokinetics data indicate that i.v. ascorbic acid (ascorbate) in pharmacologic concentrations could have an unanticipated role in cancer treatment. Our goals here were to test whether ascorbate killed cancer cells selectively, and if so, to determine mechanisms, using clinically relevant conditions. Cell death in 10 cancer and 4 normal cell types was measured by using 1-h exposures. Normal cells were unaffected by 20 mM ascorbate, whereas 5 cancer lines had EC(50) values of <4 mM, a concentration easily achievable i.v. Human lymphoma cells were studied in detail because of their sensitivity to ascorbate (EC(50) of 0.5 mM) and suitability for addressing mechanisms. Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis and pyknosis/necrosis. Cell death was independent of metal chelators and absolutely dependent on H(2)O(2) formation. Cell death from H(2)O(2) added to cells was identical to that found when H(2)O(2) was generated by ascorbate treatment. H(2)O(2) generation was dependent on ascorbate concentration, incubation time, and the presence of 0.5-10% serum, and displayed a linear relationship with ascorbate radical formation. Although ascorbate addition to medium generated H(2)O(2), ascorbate addition to blood generated no detectable H(2)O(2) and only trace detectable ascorbate radical. Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H(2)O(2), and that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H(2)O(2) may be beneficial.


http://www.ncbi.nlm.nih.gov/pubmed/16157892


Meta análisis

Vitamin C and survival among women with breast cancer: a meta-analysis.
Harris HR1, Orsini N2, Wolk A2.
Author information

1Unit of Nutritional Epidemiology, Institute for Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden; Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA. Electronic address: holly.harris@ki.se.
2Unit of Nutritional Epidemiology, Institute for Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden.

Abstract
BACKGROUND:

The association between dietary vitamin C intake and breast cancer survival is inconsistent and few studies have specifically examined vitamin C supplement use among women with breast cancer. The purpose of this study was to summarise results from prospective studies on the association between vitamin C supplement use and dietary vitamin C intake and breast cancer-specific mortality and total mortality.
METHODS:

Studies were identified using the PubMed database through February 6, 2014 and by examining the references of retrieved articles. Prospective studies were included if they reported relative risks (RR) with 95% confidence intervals (95% CIs) for at least two categories or as a continuous exposure. Random-effects models were used to combine study-specific results.
RESULTS:

The ten identified studies examined vitamin C supplement use (n=6) and dietary vitamin C intake (n=7) and included 17,696 breast cancer cases, 2791 total deaths, and 1558 breast cancer-specific deaths. The summary RR (95% CI) for post-diagnosis vitamin C supplement use was 0.81 (95% CI 0.72-0.91) for total mortality and 0.85 (95% CI 0.74-0.99) for breast cancer-specific mortality. The summary RR for a 100mg per day increase in dietary vitamin C intake was 0.73 (95% CI 0.59-0.89) for total mortality and 0.78 (95% CI 0.64-0.94) for breast cancer-specific mortality.
CONCLUSION:

Results from this meta-analysis suggest that post-diagnosis vitamin C supplement use may be associated with a reduced risk of mortality. Dietary vitamin C intake was also statistically significantly associated with a reduced risk of total mortality and breast cancer-specific mortality.

http://www.ncbi.nlm.nih.gov/pubmed/24613622

Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 5275
Registrado: Dom, 01 Sep 2013, 14:18

Re: Nutrición contra el cancer

Notapor Fisio » Lun, 08 Sep 2014, 08:44

Propolis

Imagen


Review of the anticancer activities of bee products.
Premratanachai P1, Chanchao C2.
Author information
Abstract

Bee products have long been used in traditional medicine. The raw materials, crude extracts and purified active compounds from them have been found to exhibit interesting bioactivities, such as antimicrobial, anti-inflammatory and antioxidant activities. In addition, they have been widely used in the treatment of many immune-related diseases, as well as in recent times in the treatment of tumors. Bee product peptides induce apoptotic cell death in vitro in several transformed (cancer) human cell lines, including those derived from renal, lung, liver, prostate, bladder and lymphoid cancers. These bioactive natural products may, therefore, prove to be useful as part of a novel targeted therapy for some types of cancer, such as prostate and breast cancer. This review summarizes the current knowledge regarding the in vivo and in vitro potential of selective bee products against tumor cells.

http://www.ncbi.nlm.nih.gov/pubmed/25182716




Antitumor Activity of Chinese Propolis in Human Breast Cancer MCF-7 and MDA-MB-231 Cells.
Xuan H1, Li Z1, Yan H2, Sang Q1, Wang K3, He Q1, Wang Y1, Hu F3.
Author information
Abstract

Chinese propolis has been reported to possess various biological activities such as antitumor. In present study, anticancer activity of ethanol extract of Chinese propolis (EECP) at 25, 50, 100, and 200  μ g/mL was explored by testing the cytotoxicity in MCF-7 (human breast cancer ER(+)) and MDA-MB-231 (human breast cancer ER(-)) cells. EECP revealed a dose- and time-dependent cytotoxic effect. Furthermore, annexin A7 (ANXA7), p53, nuclear factor- κ B p65 (NF- κ B p65), reactive oxygen species (ROS) levels, and mitochondrial membrane potential were investigated. Our data indicated that treatment of EECP for 24 and 48 h induced both cells apoptosis obviously. Exposure to EECP significantly increased ANXA7 expression and ROS level, and NF- κ B p65 level and mitochondrial membrane potential were depressed by EECP dramatically. The effects of EECP on p53 level were different in MCF-7 and MDA-MB-231 cells, which indicated that EECP exerted its antitumor effects in MCF-7 and MDA-MB-231 cells by inducing apoptosis, regulating the levels of ANXA7, p53, and NF- κ B p65, upregulating intracellular ROS, and decreasing mitochondrial membrane potential. Interestingly, EECP had little or small cytotoxicity on normal human umbilical vein endothelial cells (HUVECs). These results suggest that EECP is a potential alternative agent on breast cancer treatment.

http://www.ncbi.nlm.nih.gov/pubmed/24963320




Polyphenols as key players for the antileukaemic effects of propolis.
Abubakar MB1, Abdullah WZ2, Sulaiman SA3, Ang BS4.
Author information
Abstract

Propolis (a bee product) which has a long history of medicinal use by humans has attracted a great deal of research interest in the recent time; this is due to its widely reported biological activities such as antiviral, antifungal, antibacterial, anti-inflammatory, antioxidant, and anticarcinogenic properties. Crude form of propolis and its phenolic contents have both been reported to exhibit antileukaemic effects in various leukaemia cell lines. The ability of the polyphenols found in propolis to arrest cell cycle and induce apoptosis and differentiation in addition to inhibition of cell growth and proliferation makes them promising antileukaemic agents, and hence, they are believed to be a key to the antileukaemic effects of propolis in different types of leukaemia. This paper reviews the molecular bases of antileukaemic activity of both crude propolis and individual polyphenols on various leukaemia cell lines, and it indicates that propolis has the potential to be used in both treatment and prevention of leukaemia. This however needs further evaluation by in vitro, in vivo, and epidemiological studies as well as clinical trials.

http://www.ncbi.nlm.nih.gov/pubmed/24772179




Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE), Modulate Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action.
Omene C1, Kalac M1, Wu J2, Marchi E3, Frenkel K4, O'Connor OA3.
Author information
Abstract

Alternative remedies for cancer treatment is a multi-billion dollar industry. In particular, breast cancer (BC) patients use alternative and natural remedies more frequently than patients with other malignancies. Propolis is an example of a honeybee-produced naturopathic formulation, contents of which differ by geographic location. It is readily available, affordable, and in use safely since ancient times globally. Caffeic acid phenethyl ester (CAPE) is a major active component in propolis and is thought to be responsible for its varied properties, including antibacterial, antiviral, antifungal, antioxidant, anti-inflammatory and anticancer. CAPE is effective in many models of human cancer, including BC as we have previously shown. CAPE affects genes associated with tumor cell growth and survival, angiogenesis and chemoresistance. We demonstrate that these are related in part to CAPE's role as a histone deacetylase inhibitor, a class of drugs designated as epigenetic agents that modulate the activities of oncogenes and tumor suppressor genes. CAPE and propolis, cause an accumulation of acetylated histone proteins in MCF-7 (ER+) and MDA-MB-231 (ER-/PR-/Her2-) cells with associated decreases in ER and PR in MCF-7 cells, and upregulation of ER and decrease in EGFR in MDA-231 cells. In addition, these products reduced activated phosphorylated Her2 protein in SKBR3 (Her2 +) cells. Interestingly, propolis, when normalized for CAPE content, appears to be more potent than CAPE alone similarly to the greater effects of complete foods than isolated components. These data provide a potential mechanistic basis for one of the oldest naturopathic agents used in medicine and cancer treatment.

http://www.ncbi.nlm.nih.gov/pubmed/24466386




Addition of propolis to irinotecan therapy prolongs survival in ehrlich ascites tumor-bearing mice.
Lisičić D1, Benković V, Ðikić D, Blažević AS, Mihaljević J, Oršolić N, Knežević AH.
Author information
Abstract

We investigated possible synergistic action of anticancer drug Irinotecan (IRI) combined with ethanolic (EEP) and water-soluble (WSDP) derivate of propolis on Swiss albino mice injected with Ehrlich ascites tumor (EAT). For survival analysis mice were administered WSDP and EEP (100 mg/kg) daily for 3 consecutive days, beginning on 3rd day after EAT cell (1×10⁶) injection. IRI was administered at a dose of 50 mg/kg on days 1, 13, and 19. We simultaneously studied peripheral white blood cell count, cell types washed from the peritoneal cavity, functional activity of macrophages from peritoneal cavity, and the level of primary DNA damage in leukocytes, kidney, and liver cells using the alkaline comet assay. Three out of 9 mice per group survived the entire duration of the experiment (90 days) in groups treated with IRI combined with WSDP and EEP. All test components increased survival of mice by 7.53% to 231.54%. Combined treatment with IRI and/or WSDP and EEP significantly decreased percentage of tumor cells in the peritoneal cavity as compared to nontreated EAT-injected mice. All treated animals had significantly higher percentage of neutrophils in the peritoneal cavity in comparison to nontreated EAT-injected mice. We observed significantly higher value of DNA damage in leukocytes of mice treated with IRI and combination of IRI and/or WSDP and EEP as compared to nontreated EAT-injected mice, while the same treatment decreased DNA damage in kidney. Our results showed that addition of propolis to IRI treatment enhanced antitumor activity of IRI and prolongs survival in EAT-bearing mice, which definitely deserve further studies to clarify the possible mechanisms of antitumor actions of combined herb-drug treatments.


http://www.ncbi.nlm.nih.gov/pubmed/24383762

Propolis augments apoptosis induced by butyrate via targeting cell survival pathways.
Drago E1, Bordonaro M, Lee S, Atamna W, Lazarova DL.
Author information
Abstract

Diet is one of the major lifestyle factors affecting incidence of colorectal cancer (CC), and despite accumulating evidence that numerous diet-derived compounds modulate CC incidence, definitive dietary recommendations are not available. We propose a strategy that could facilitate the design of dietary supplements with CC-preventive properties. Thus, nutrient combinations that are a source of apoptosis-inducers and inhibitors of compensatory cell proliferation pathways (e.g., AKT signaling) may produce high levels of programmed death in CC cells. Here we report the combined effect of butyrate, an apoptosis inducer that is produced through fermentation of fiber in the colon, and propolis, a honeybee product, on CC cells. We established that propolis increases the apoptosis of CC cells exposed to butyrate through suppression of cell survival pathways such as the AKT signaling. The programmed death of CC cells by combined exposure to butyrate and propolis is further augmented by inhibition of the JNK signaling pathway. Analyses on the contribution of the downstream targets of JNK signaling, c-JUN and JAK/STAT, to the apoptosis of butyrate/propolis-treated CC cells ascertained that JAK/STAT signaling has an anti-apoptotic role; whereas, the role of cJUN might be dependent upon regulatory cell factors. Thus, our studies ascertained that propolis augments apoptosis of butyrate-sensitive CC cells and re-sensitizes butyrate-resistant CC cells to apoptosis by suppressing AKT signaling and downregulating the JAK/STAT pathway. Future in vivo studies should evaluate the CC-preventive potential of a dietary supplement that produces high levels of colonic butyrate, propolis, and diet-derived JAK/STAT inhibitors.


http://www.ncbi.nlm.nih.gov/pubmed/24023824


Anticancer effects of geopropolis produced by stingless bees on canine osteosarcoma cells in vitro.
Cinegaglia NC1, Bersano PR, Araújo MJ, Búfalo MC, Sforcin JM.
Author information
Abstract

Geopropolis is produced by indigenous stingless bees from the resinous material of plants, adding soil or clay. Its biological properties have not been investigated, such as propolis, and herein its cytotoxic action on canine osteosarcoma (OSA) cells was evaluated. OSA is a primary bone neoplasm diagnosed in dogs being an excellent model in vivo to study human OSA. spOS-2 primary cultures were isolated from the tumor of a dog with osteosarcoma and incubated with geopropolis, 70% ethanol (geopropolis solvent), and carboplatin after 6, 24, 48, and 72 hours. Cell viability was analyzed by the crystal violet method. Geopropolis was efficient against canine OSA cells in a dose- and time-dependent way, leading to a distinct morphology compared to control. Geopropolis cytotoxic action was exclusively due to its constituents since 70% ethanol (its solvent) had no effect on cell viability. Carboplatin had no effect on OSA cells. Geopropolis exerted a cytotoxic effect on canine osteosarcoma, and its introduction as a possible therapeutic agent in vivo could be investigated, providing a new contribution to OSA treatment.

http://www.ncbi.nlm.nih.gov/pubmed/23690851




Southern Brazilian autumnal propolis shows anti-angiogenic activity: an in vitro and in vivo study.
Meneghelli C1, Joaquim LS, Félix GL, Somensi A, Tomazzoli M, da Silva DA, Berti FV, Veleirinho MB, Recouvreux Dde O, de Mattos Zeri AC, Dias PF, Maraschin M.
Author information
Abstract

The present study focuses on the effects of a hydro-alcoholic propolis extract collected in autumn (2010) in Santa Catarina State (Southern Brazil), on the angiogenesis, using in vitro and in vivo models. Cultures of human umbilical vein endothelial cells were used to assess the effects of propolis on viability, proliferation, and cell migration, as well as capillary tube formation. The propolis autumnal extracts significantly decreased the cell viability, based on CC50 values, which decreased (56%) from 297 to 130 μg/ml in 24 h and 72 h of treatment, respectively (cytotoxicity assay). The process of cell proliferation was decreased by 81.7 to 48.4% due to exposure (72 h) to 130-180 μg/ml of propolis extract, as compared with control (vehicle). In these same concentrations, the cell migration was also reduced by 39.6 to 12.6%, respectively (versus control). Furthermore, autumnal propolis extract (100-200 μg/ml) inhibited the tube-like structure formation (tubulogenesis) of endothelial cells on Matrigel™ (16.2-69.9% inhibition). The treatments performed in vivo with administration of 450 mg propolis.kg(-1) inhibited both angiogenesis and vasculogenesis by 82.3 and 66.5% in the chorioallantoic and yolk-sac membranes of chick embryos. Furthermore, by means of UV-vis-spectrophotometry, reverse phase-high performance liquid chromatography analysis and 1D and 2D-nuclear magnetic resonance experiments reveal higher contents of flavonoids and total phenolic compounds with predominance of the flavonol quercetin and the phenolic acids, e.g., gallic acid, protocatechuic acid and chlorogenic acid in the propolis hydro-alcoholic extract. Our findings related to the anti-proliferative, anti-migration, and anti-tubulogenic actions on human umbilical vein endothelial cell line agree with the inhibitory effects in the in vivo vessel formation exerted by propolis extract under study. The results also suggest that autumnal propolis extract might be potentially instrumental in providing alternative tools for angiogenic disease therapeutics.

http://www.ncbi.nlm.nih.gov/pubmed/23538317




Caffeic acid phenethyl ester induces E2F-1-mediated growth inhibition and cell-cycle arrest in human cervical cancer cells.
Hsu TH1, Chu CC, Hung MW, Lee HJ, Hsu HJ, Chang TC.
Author information
Abstract

Caffeic acid phenyl ester (CAPE) has been identified as an active component of propolis, a substance that confers diverse activities in cells of various origins. However, the molecular basis of CAPE-mediated cellular activity remains to be clarified. Here, we show that CAPE preferentially induced S- and G2 /M-phase cell-cycle arrests and initiated apoptosis in human cervical cancer lines. The effect was found to be associated with increased expression of E2F-1, as there is no CAPE-mediated induction of E2F-1 in the pre-cancerous cervical Z172 cells. CAPE also up-regulated the E2F-1 target genes cyclin A, cyclin E and apoptotic protease activating of factor 1 (Apaf-1) but down-regulated cyclin B and induced myeloid leukemia cell differentiation protein (Mcl-1). These results suggest the involvement of E2F-1 in CAPE-mediated growth inhibition and cell-cycle arrest. Transient transfection studies with luciferase reporters revealed that CAPE altered the transcriptional activity of the apaf-1 and mcl-1 promoters. Further studies using chromatin immunoprecipitation assays demonstrated that E2F-1 binding to the apaf-1 and cyclin B promoters was increased and decreased, respectively, in CAPE-treated cells. Furthermore, E2F-1 silencing abolished CAPE-mediated effects on cell-cycle arrest, apoptosis and related gene expression. Taken together, these results indicate a crucial role for E2F-1 in CAPE-mediated cellular activities in cervical cancer cells.

http://www.ncbi.nlm.nih.gov/pubmed/23497083




Caffeic acid phenethyl ester as an adjuvant therapy for advanced prostate cancer.
Liu CC1, Hsu JM, Kuo LK, Chuu CP.
Author information
Abstract

Prostate cancer is the second most frequently diagnosed cancer of men. Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, the majority of prostate cancer patients receiving the androgen ablation therapy will ultimately develop recurrent castration-resistant tumors within 3 years. Chemotherapy shows little effect on prolonging survival for patients with metastatic hormone-refractory prostate cancer. More than 80% of prostate tumors acquire mutation or deletion of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signaling. Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells. Combined treatments of CAPE with chemotherapeutic drugs exhibit synergistic suppression effects. Pharmacokinetic studies suggest that intraperitoneal injection of CAPE at concentration of 10mg/kg is not toxic. CAPE treatment sensitizes cancer cells to chemotherapy and radiation treatments. In addition, CAPE treatment protects therapy-associated toxicities in animal models. We therefore propose that administration of CAPE is a potential adjuvant therapy for patients with castration-resistant prostate cancer.

http://www.ncbi.nlm.nih.gov/pubmed/23462369




The anticancer mechanism of caffeic acid phenethyl ester (CAPE): review of melanomas, lung and prostate cancers.
Ozturk G1, Ginis Z, Akyol S, Erden G, Gurel A, Akyol O.
Author information
Abstract
BACKGROUND:

Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, specifically inhibits NF-κB. It exhibits antioxidant, antiinflammatory, antiproliferative, cytostatic, and most importantly, antineoplastic properties.
AIM:

The aim of the present mini-review is to summarize and evaluate the anticancer mechanism of CAPE with examples of several cancer types.
RESULTS:

In view of the mechanisms and findings in our laboratory and those of others in literature, we suggest that CAPE possess anticancer and apoptosis inducing activities.
CONCLUSIONS:

Further researches are needed regarding the anticancer basis of CAPE in all disciplines of medicine. Also, clinical potential toxicities of CAPE should be revealed if it is going to be used as an anticancer agent.

http://www.ncbi.nlm.nih.gov/pubmed/23280020




Caffeic acid phenethyl ester suppresses the proliferation of human prostate cancer cells through inhibition of p70S6K and Akt signaling networks.
Chuu CP1, Lin HP, Ciaccio MF, Kokontis JM, Hause RJ Jr, Hiipakka RA, Liao S, Jones RB.
Author information
Abstract

Caffeic acid phenethyl ester (CAPE) is a bioactive component derived from honeybee hive propolis. CAPE has been shown to have antimitogenic, anticarcinogenic, and other beneficial medicinal properties. Many of its effects have been shown to be mediated through its inhibition of NF-κB signaling pathways. We took a systematic approach to uncover the effects of CAPE from hours to days on the signaling networks in human prostate cancer cells. We observed that CAPE dosage dependently suppressed the proliferation of LNCaP, DU-145, and PC-3 human prostate cancer cells. Administration of CAPE by gavage significantly inhibited the tumor growth of LNCaP xenografts in nude mice. Using LNCaP cells as a model system, we examined the effect of CAPE on gene expression, protein signaling, and transcriptional regulatory networks using micro-Western arrays and PCR arrays. We built a model of the impact of CAPE on cell signaling which suggested that it acted through inhibition of Akt-related protein signaling networks. Overexpression of Akt1 or c-Myc, a downstream target of Akt signaling, significantly blocked the antiproliferative effects of CAPE. In summary, our results suggest that CAPE administration may be useful as an adjuvant therapy for prostate and potentially other types of cancers that are driven by the p70S6K and Akt signaling networks.

http://www.ncbi.nlm.nih.gov/pubmed/22562408




The potential usage of caffeic acid phenethyl ester (CAPE) against chemotherapy-induced and radiotherapy-induced toxicity.
Akyol S1, Ginis Z, Armutcu F, Ozturk G, Yigitoglu MR, Akyol O.
Author information
Abstract

Protection of the patients against the side effects of chemotherapy and radiotherapy regimens has attracted increasing interest of clinicians and practitioners. Caffeic acid phenethyl ester (CAPE), which is extracted from the propolis of honeybee hives as an active component, specifically inhibits nuclear factor κB at micromolar concentrations and show ability to stop 5-lipoxygenase-catalysed oxygenation of linoleic acid and arachidonic acid. CAPE has antiinflammatory, antiproliferative, antioxidant, cytostatic, antiviral, antibacterial, antifungal and antineoplastic properties. The purpose of this review is to summarize in vivo and in vitro usage of CAPE to prevent the chemotherapy-induced and radiotherapy-induced damages and side effects in experimental animals and to develop a new approach for the potential usage of CAPE in clinical trial as a protective agent during chemotherapy and radiotherapy regimens.

http://www.ncbi.nlm.nih.gov/pubmed/22431158




Propolis inhibits the proliferation of human leukaemia HL-60 cells by inducing apoptosis through the mitochondrial pathway.
Eom HS1, Lee EJ, Yoon BS, Yoo BS.
Author information
Abstract

Propolis, a natural product derived from plant resins collected by honeybees, has been reported to exert a wide spectrum of biological functions. This research aimed at investigating the effect of propolis on the proliferation of human leukaemia HL-60 cells and whether propolis might induce apoptosis in HL-60 cells. The results showed dose- and time-dependent decreases in the proliferation of HL-60 cells treated with propolis (above 3 microg mL(-1) of propolis). Further studies revealed that the anti-proliferative effects of propolis were caused by inducing apoptosis. Agarose electrophoresis of genomic DNA of HL-60 cells treated with propolis showed the ladder pattern typical for apoptotic cells. Propolis induced the activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase in HL-60 cells. Propolis also induced the release of cytochrome c from mitochondria to cytosol. Taken together, these findings demonstrate that the inhibitory effect of propolis on HL-60 cell proliferation is caused by inducing apoptosis through the mitochondrial pathway.

http://www.ncbi.nlm.nih.gov/pubmed/20221944




Anti-tumor effects of water-soluble propolis on a mouse sarcoma cell line in vivo and in vitro.
Inoue K1, Saito M, Kanai T, Kawata T, Shigematsu N, Uno T, Isobe K, Liu CH, Ito H.
Author information
Abstract

The honeybee product propolis and its extracts are known to have biological effects such as antibiotic, anti-viral, anti-inflammatory and anti-tumor activities. This study was designed to investigate whether water-soluble propolis (WSP) inhibits tumor growth. The tumor cell line used was mouse sarcoma 180 (S-180), and its growth was determined in vitro and in vivo with exposure to different concentrations of WSP. The effects of WSP on tumor cells in vitro were evaluated by measuring the intracellular uptake of 3H-thymidine. 3H-thymidine uptake was inhibited in accordance with the concentration of WSP. The minimum concentration of WSP necessary for 3H-thymidine uptake inhibition was 1.0 microg/ml and uptake was suppressed to 88% of the level in non-treated cells at this concentration. In an experiment using tumor-bearing mice, oral administration of WSP was begun 24 hours after transplantation of S-180 cells. WSP was administered to the mice 5 times, every other day for 10 days. The doses were 320 mg/kg (10 mg/mouse) or 960 mg/kg (30 mg/mouse) of body weight. All mice were sacrificed 10 days after transplantation, and tumor growth was evaluated. The orally administered WSP significantly inhibited the growth of transplanted tumors (p < 0.05). Furthermore, histological findings revealed a significant reduction in mitotic cells and tumor invasion of the muscular tissue at both dose-levels of WSP.

http://www.ncbi.nlm.nih.gov/pubmed/18543394

Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 5275
Registrado: Dom, 01 Sep 2013, 14:18

Siguiente

Volver a Muscleblog

¿Quién está conectado?

Usuarios navegando por este Foro: No hay usuarios registrados visitando el Foro y 3 invitados
cron