Department of Medical Biochemistry, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600113, Tamilnadu, India.
Mol Med Rep. 2011 Nov-Dec;4(6):1211-7. doi: 10.3892/mmr.2011.555. Epub 2011 Aug 16.
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 down-regulation of key apoptotic regulators, such as Bax and Bcl2, 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.
白藜芦醇是一种在红酒和葡萄中含量丰富的植物化学物质，已被证实对体外和体内的癌细胞都有影响。大量数据表明，白藜芦醇对癌症具有治疗益处。然而，尚不清楚这些益处在癌症的早期和晚期或癌变过程中是否相似且同样有效。在这项研究中，我们报告了白藜芦醇在 N-亚硝二乙胺（DEN）诱导的雄性 Wistar 大鼠肝癌（HCC）模型中肝癌发生的早期和晚期阶段的作用。在实验中，将大鼠分为不同的组，用白藜芦醇处理，从 DEN 给药的第 1 天开始持续 15 天（肝癌前），或者在 DEN 给药后即 HCC 发生后（DEN 给药后 15-16 周）开始处理（肝癌后），并与未处理的 HCC 荷瘤大鼠进行比较。血清标志物甲胎蛋白（AFP）和其他血清和肝脏标志物酶的生化分析也表明，与未处理的 HCC 荷瘤大鼠相比，白藜芦醇处理后这些标志物的水平降低。对 DEN 诱导的 HCC 肝组织切片进行 H&E 染色显示，DEN 诱导的 HCC 肝实质组织发生改变或转化（在 15-16 周时）。与未处理的 HCC 相比，白藜芦醇在肝癌的早期（DEN 诱导的第 1 天）和晚期（17-18 周）治疗时，组织形态学有明显差异。免疫印迹分析显示，白藜芦醇在 DEN 诱导的 HCC 的早期和晚期阶段的干预均激活了细胞凋亡标志物，如 PARP 切割、caspase-3 激活、p53 上调和细胞色素 c 释放。此外，半定量 RT-PCR 和免疫印迹分析表明，白藜芦醇处理以依赖方式分别上调和下调关键凋亡调节剂，如 Bax 和 Bcl2。我们的结果表明，在肝癌发生的早期或晚期阶段给予白藜芦醇治疗同样有效，并涉及雄性 Wistar 大鼠中凋亡途径的激活。
