Resveratrol (Rsv), a dietary compound from grapes gained considerable attention as a cancer chemopreventive agent in several preclinical rodent models of prostate carcinogenesis. However, the poor bioavailability of Rsv in human plasma raised reservations about the potential health benefits of dietary Rsv. The objective of the present study was to combine Rsv with other agents, that can be given at non-toxic concentrations, in order to produce strong anticancer effects at low Rsv concentrations. For this purpose, we choose the histone deacetylase inhibitor (HDAC) suberoyl-anilide hydroxamic acid (SAHA), and the demethylating agent, 5-aza-2′-deoxycytidine (5-aza) which we evaluated in PC-3 prostate cancer cells. We found that Rsv at relatively low concentrations (2.5 μM) inhibited only marginally cell growth (<15 %). Similarly, the selected concentration of SAHA (0.5 μM) or 5-aza (0.05 μM) also produced minimal inhibition of cell growth (<17 % and <15 % inhibition respectively). A substantial decrease (> 50 %) in cellular proliferation was evident when Rsv was combined with either one of the chromatin modifying agents. Concomitant analysis of cell proliferation and apoptosis revealed that pre-treatment with SAHA or 5-aza followed by Rsv administration suspended cell growth. Cell cycle arrest was also evident which was associated with p53-indepented up-regulation of p21 and accompanied by an increase in the ratio of Bax/Bcl-2. Treatment with the pan-caspase inhibitor, z-vad.fmk did not restore cell growth, indicating that the mechanism by which these compounds trigger apoptosis is independed of caspase activation. These data suggest that the growth-inhibitory effect is mediated via upregulation of p21, down regulation of key cell cycle activators, and followed by apoptotic cell death. This combined action of Rsv might be the result of transcriptional alterations of specific genes that participate in the apoptotic and survival pathways due to the chromatin remodeling effects of SAHA and 5-aza. Our results show conclusively that, in a highly invasive prostate cancer cell line, the combination of Rsv with an HDAC inhibitor or a demethylaying agent, increases Rsv's anticancer activity. These new insights, in enhancing the anticancer effect of Rsv, may be applied to new and innovative strategies in the treatment or prevention of prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1610A. doi:1538-7445.AM2012-1610A