Abstract A61: Mechanisms of resveratrol-mediated chemoprevention of hepatocellular carcinogenesis: Suppression of oxidative stress and inflammation
Authors: Bishayee Anupam , Waghray Abhijeet , Barnes Kendra F. , Lotey Rajiv , Darvesh Altaf S. , Bhatia Deepak , Carroll Richard T. 
Published: May 2012

Abstract
Hepatocellular carcinoma (HCC), one of the most common and deadliest malignancies in the world, has been increasing steadily in Japan, Europe as well as the United States. HCC develops most frequently in the background of oxidative stress and chronic unresolved hepatic inflammation due to viral infection, alcoholic cirrhosis as well as exposure to several environmental carcinogens. In the absence of proven effective systemic therapy for HCC, novel chemopreventive strategies are urgently needed to lower the current morbidity and mortality associated with HCC. Previously, we have reported that the phytoalexin resveratrol, present in grapes, berries, peanuts and red wine, significantly prevents diethylnitrosamine (DENA)-initiated liver tumorigenesis in rats though the chemopreventive mechanisms have not been completely elucidated. In the present study, we have investigated the underlying mechanisms of resveratrol chemoprevention of hepatocarcinogenesis by examining the effects of resveratrol on oxidative damage and inflammatory response during DENA-mediated rat liver carcinogenesis. Rats were exposed to dietary resveratrol (equivalent to 50, 100 or 300 mg/kg body weight/day), starting the treatment 4 weeks before initiation with DENA and continued 16 weeks thereafter. At the end of the study (20 weeks), there was an 11-fold increase in hepatic lipid peroxidation (P&lt;0.05) as measured by estimating thiobarbituric acid-reactive substances and 3-fold increase in protein oxidation (P&lt;0.01) based on protein carbonyl content in liver measured by slot-immonoblot technique in DENA control animals compared to their normal counterparts. Dietary resveratrol dose-dependently inhibited oxidative damage during DENA hepatocarcinogenesis as evidenced from its ability to prevent DENA-induced hepatic lipid peroxidation in rats. A statistically significant (P&lt;0.05) result was achieved with resveratrol at dose of 100 or 300 mg/kg. Treatment with resveratrol also elicited a reduction in DENA-induced increment in protein carbonyl content in a dose-responsive fashion. Resveratrol at a dose of 100 or 300 mg/kg produced a statistically significant (P&lt;0.01) result. Immunohistochemical and Western blot analysis revealed a marked elevation in the protein expression of inducible nitric oxide synthase (iNOS), 3-nitrotyrosine (3-NT), cyclooxygenase (COX-2) and nuclear factor- B (NF-κB) p65 in DENA-exposed rat livers. Treatment with resveratrol reversed the elevated hepatic expressions of iNOS, 3-NT, COX-2 and NF-κB p65 in a dose-responsive fashion in rats challenged with DENA. Results of the present study provide convincing evidence, for the first time, that attenuation of oxidative and nitrasative stress as well as suppression of the inflammatory process through modulation of NF-κB signaling pathway could be implicated, at least in part, in the chemopreventive effects of this dietary polyphenol against chemically-induced hepatocellular carcinogenesis in rats. The outcome of this study highlights the potential role of resveratrol in the prevention and treatment of human HCC that accounts for more than half a million deaths each year.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A61.