Alternate chemopreventive mechanisms of action of resveratrol and muscadine grape skin extract in prostate cancer

2263

Human prostate cancer is one of the most insidious diseases among men in the Western hemisphere, with few long-term medial treatment options. Identifying methods of preventing clinically significant prostate cancer would, therefore, provide a major advance in public health. Accordingly, there is intense effort to identify naturally-occurring or synthetic agents that may have chemopreventive activity against prostate cancer. Phytochemicals are a class of agents that have been shown to be effective against many different types of cancers. Within this class of agents is resveratrol, a phytoalexin found in grapes, nuts, and wildberries which has been shown to have inhibitory effects against prostate cancer, possibly through anti-oxidant activities. In contrast, muscadine grape seed extract, which also contains phytochemicals, has been shown to inhibit prostate cancer by inducing apoptosis. Despite the biological importance of these phytochemicals, no studies have yet compared the biological potency or mechanisms of action between theses compounds against prostate cancer progression. Human prostate transformed cell lines (RWPE-1, WPE1-NA22, WPE1-NB14, WPE1-NB26) are an excellent model of prostate cancer progression which we have used to compare the biological efficacy of these agents during the multi-step process of prostate carcinogenesis. Therefore, our purpose is to investigate the preventive effects of resveratrol and muscadine grape skin extract (GSE) on prostate tumor progression using a set of human cell lines that mimic prostate progression. We demonstrate that while both agents appear to inhibit prostate tumor cell growth, the mechanisms of action are strikingly different. Our data show that at twenty four hours the compounds induce significant changes in the morphology of all four cell lines that differ between resveratrol and GSE. In addition, propidium iodide and annexin V-FITC FACS analysis indicates that at 24 hours resveratrol arrest the cells in the G1 phase of the cell cycle, whereas GSE induces apoptosis. Furthermore, in situ cell death fluorescence analysis by TUNEL (Terminal deoxynucleotidyl transferase (TDT)) confirms that GSE induces apoptosis in all four cell lines. Consistent with these results is the observation that resveratrol induces overexpression of p21 protein, an inhibitor of cell cycle regulator cyclin E. Thus, these results demonstrate that resveratrol and GSE act on very different pathways to inhibit prostate cancer cell growth. Ongoing studies will further determine whether similar mechanisms are active in vivo, further suggesting that resveratrol and muscadine grape extract may be viable preventive or therapeutic agents against prostate tumor development.