Resveratrol interferes with N-nitrosodiethylamine-induced hepatocellular carcinoma at early and advanced stages in male Wistar rats

Abstract

Abstract. Resveratrol, a phytochemical compound abundant in red wine and grapes, is known to affect cancer cells both in vitro and in vivo. A great amount of data have indicated the therapeutic benefits of resveratrol against cancer. However, it remains unclear whether these benefits are similar and equally effective in both the early and advanced stages of cancer or carcinogenesis. In this study, we report the effects of resveratrol in the early and advanced stages of hepatocarcinogenesis in a model of N-nitrosodiethylamine (DEN)-induced hepatocellular carcinoma (HCC) of male Wistar rats. For the experiment, rats were divided into different groups and treated with resveratrol either from day 1 of DEN administration for 15 days (pre-HCC), or after the development of HCC, i.e., 15-16 weeks after DEN administration (post-HCC), and compared to untreated HCC-bearing rats. Biochemical analysis of α-fetoprotein, the known serum marker for HCC, and other serum and liver marker enzymes also demonstrated a decreased level upon resveratrol treatment compared to the untreated HCC-bearing rats. H&E staining of tissue sections from the liver showed alteration or transformation of liver parenchymatous tissue in DEN-induced HCC (at 15-16 weeks). Resveratrol treatment during early (on day 1 of DEN-induction) and advanced (weeks 17-18) HCC showed a marked difference in the tissue architecture compared to untreated HCC. Immunoblot analysis revealed that resveratrol intervention at both the early and advanced stages of DEN-induced HCC activated the apoptotic markers, such as PARP cleavage, caspase-3 activation, p53 up-regulation and cytochrome-c release. In addition, semiquantitative RT-PCR and immunoblot analysis demonstrated the up-and downregulation of key apoptotic regulators, such as Bax and Bcl 2 , respectively, in a resveratrol treatment-dependent manner. Our results indicate that the administration of resveratrol either at the early or advanced stages of hepatocarcinogenesis is equally effective and involves the activation of the apoptotic pathway in male Wistar rats.

Natural Polyphenols for Prevention and Treatment of Cancer

“…At low concentration, resveratrol treatment (25–100 μM) inhibited metastasis of HCC cells and decreased expression of urokinase-type plasminogen activator (u-PA), which involved down-regulation of the SP-1 signaling pathway [175]. Besides, in N -nitrosodiethylamine treated rat, the oral administration of resveratrol (20 mg/kg/day) either at early or advanced stages of liver carcinogenesis was equally effective, possibly mediated by apoptosis [176]. In androgen independent prostate cancer cells, resveratrol treatment (25–100 μM) induced autophagy-mediated cell death [177].…”

Resveratrol ameliorates diabetic nephropathy in rats through negative regulation of the p38 MAPK/TGF-β1 pathway

“…Resveratrol (RSV) is a natural polyphenolic compound found in various fruits, such as grapes, nuts and berries, as well as in red wine (16). Previous studies have demonstrated that RSV has diverse beneficial health effects including anti-oxidative (17), anti-inflammatory (18), anti-cancer (19), cardioprotective (20) and neuroprotective (21) activities.…”

Critical review of resveratrol in xenobiotic-induced hepatotoxicity

“…Interestingly, RSV inhibition of NF-kB was also shown to decrease VEGF expression and angiogenesis in both HepG2 cell lines and mice (Yu et al, 2010; Zhang et al, 2014), a process critical for metastasis (Stetler-Stevenson, 1999). That RSV has been shown to be protective at both early and late stages of carcinogenesis (Rajasekaran et al, 2011) underscores the complexity of the effects RSV in HCC.…”