The chemopreventive agent resveratrol: tumor-selective sensitization for anticancer drug-induced apoptosis

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Current attempts to improve the survival of cancer patients largely depend on strategies to target tumor cell resistance. Since most anticancer therapies primarily act by triggering apoptosis in cancer cells, resistance to current treatment protocols may be caused by defects in apoptosis programs. Survivin is a member of the inhibitor of apoptosis proteins (IAPs) that is expressed at high levels in most human cancers and may facilitate evasion from apoptosis and aberrant mitotic progression. Naturally occurring dietary compounds such as resveratrol have gained considerable attention as cancer chemopreventive agents. Here, we report that resveratrol acts as potent sensitizer for anticancer drug-induced apoptosis by inducing cell cycle arrest, which in turn resulted in survivin depletion. Concomitant analysis of cell cycle and apoptosis revealed that pretreatment with resveratrol resulted in cell cycle arrest in S phase and apoptosis induction preferentially out of S phase upon subsequent drug treatment. Likewise, cell cycle arrest in S phase by cell cycle inhibitors enhanced drug-induced apoptosis. Resveratrol-mediated cell cycle arrest sensitized for apoptosis by downregulating survivin expression. Interestingly, resveratrol repressed survivin expression through transcriptional mechanisms by inhibiting survivin promotor activity and also through posttranscriptional mechanisms by enhancing proteasomal degradation of survivin protein. Similarly, downregulation of survivin expression using survivin antisense oligonucleotides sensitized for drug-induced apoptosis. Notably, survivin depletion and enhanced drug-induced apoptosis by resveratrol occurred irrespective of wild-type p53 status. Importantly, resveratrol sensitized various tumor cell lines and also primary tumor cells, but not normal human fibroblasts, for cytotoxic drug-induced apoptosis. These findings indicate some tumor specificity of the resveratrol-mediated sensitization for chemotherapy. Thus, this combined sensitizer (resveratrol)/ inducer (cytotoxic drugs) concept may be a novel strategy to enhance the efficacy of anticancer therapy selectively in tumor cells in a variety of human cancers.