Hepatocellular carcinoma (HCC) is one of the most common cancers and lethal diseases. In view of the limited treatment and a grave prognosis of liver cancer, preventive control has been emphasized. Resveratrol, a polyphenol found in grape skins, peanuts, berries and red wine, has been shown to possess potent growth inhibitory effects against various human cancer cells. Although resveratrol has been found to exhibit chemopreventive actions in experimentally induced skin, breast, colon and esophagus rodent tumors, chemopreventive potential of this dietary constituent has not been explored well against experimental liver cancer. We evaluated the inhibitory effect of resveratrol using a two-stage model of rat hepatocarcinogenesis in Sprague-Dawley rats. Initiation was performed by a single intraperitoneal injection of diethylnitrosamine (DENA, 200 mg/kg), followed by promotion with phenobarbital (0.05%) in drinking water. The rats had free access to food supplemented with resveratrol equivalent to 50, 100 or 300 mg/kg body weight/day. Resveratrol treatment was started 4 weeks prior to the initiation and continued for 20 weeks. Resveratrol dose-dependently reduced the incidence, total number and multiplicity of visible hepatocyte nodules. Mean nodular volume and nodular volume as percentage of liver volume were also inhibited upon resveratrol treatment. Histopathological examination of liver tissue confirmed the protective effect of resveratrol. Immunohistochemical detection of cell proliferation and assay of apoptosis indicated a decrease in cell proliferation and increase of apoptotic cells in the livers of resveratrol-supplemented rats. Resveratrol also induced the expression of pro-apoptotic protein Bax, reduced anti-apoptotic Bcl-2 expression, with a concurrent increase in Bax/Bcl-2 ratio with respect to DENA control. The present study provides evidence, for the first time, that resveratrol exerts a significant chemopreventive effect on DENA-initiated hepatocarcinogenesis through inhibition of cell proliferation and induction of apoptosis. Resveratrol-induced apoptogenic signal during rat liver carcinogenesis may be mediated through the downregulation of Bcl-2 and upregulation of Bax expression. Due to a favorable toxicity profile, resveratrol can potentially be developed as a chemopreventive drug against human HCC.

El carcinoma hepatocelular (CHC) es uno de los cánceres más comunes entre las enfermedades letales. Teniendo en cuenta el tratamiento limitado que existe y un pronóstico grave de cáncer de hígado, el control preventivo se muestra como indispensable. El resveratrol, un polifenol encontrado en las pieles de uva y en el vino tinto ha demostrado poseer un potente efecto inhibidor del crecimiento en contra de varias células de cáncer humano. Aunque el resveratrol se ha encontrado que presenta acciones quimiopreventivos el potencial quimiopreventivo de este componente de la dieta no se ha explorado bien experimentalmente contra el cáncer de hígado. Para ello se evaluó el efecto inhibitorio del resveratrol mediante un modelo de dos etapas de hepatocarcinogénesis rata en ratas Sprague-Dawley. La iniciación se realizó mediante una única inyección intraperitoneal de dietilnitrosamina (DENA, 200 mg / kg), seguida con fenobarbital (0,05%) en agua potable. Las ratas tuvieron libre acceso a una alimentación suplementada con resveratrol equivalentes a 50, 100 o 300 mg / kg de peso corporal / día. El examen histopatológico del tejido del hígado confirmó el efecto protector del resveratrol. El resveratrol también indujo la expresión de proteínas pro-apoptóticas Bax, la reducción de la expresión de anti-apoptóticas Bcl-2. El presente estudio proporciona una evidencia, por primera vez de que el resveratrol ejerce un efecto significativo sobre los quimiopreventivos. El resveratrol induce la señal apoptotica durante la carcinogénesis de hígado de rata lo cual puede ser mediado a través de la regulación de Bcl-2 y la regulación positiva de la expresión de Bax.