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Inhibition of Prostate Cancer Growth by Muscadine Grape Skin Extract and Resveratrol through Distinct Mechanisms

¹ Laboratory of Cellular Regulation and Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland; ² College of Pharmacy, Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia; ³ Division of Nutritional Sciences, University of Texas, Austin, Texas; ⁴ Phytonutrients Laboratory, Beltsville Human Nutrition Research Center, U.S. Department of Agriculture, Beltsville, Maryland; and ⁵ Department of Epidemiology and Biostatistics, The George Washington University School of Public Health and Health Services, Washington, District of Columbia

Requests for reprints: Jeffrey Green, Laboratory of Cellular Regulation and Carcinogenesis, National Cancer Institute, NIH, Building 41, Room C619, Bethesda, MD 20892. Phone: 301-435-5193; Fax: 301-496-8395; E-mail: jegreen{at}mail.nih.gov.

The phytochemical resveratrol contained in red grapes has been shown to inhibit prostate cancer cell growth, in part, through its antioxidant activity. Muscadine grapes contain unique phytochemical constituents compared with other grapes and are potentially a source for novel compounds with antitumor activities. We compared the antitumor activities of muscadine grape skin extract (MSKE), which we show contains no resveratrol, with that of resveratrol using primary cultures of normal prostate epithelial cells (PrEC) and the prostate cancer cell lines RWPE-1, WPE1-NA22, WPE1-NB14, and WPE1-NB26, representing different stages of prostate cancer progression. MSKE significantly inhibited tumor cell growth in all transformed prostate cancer cell lines but not PrEC cells. Prostate tumor cell lines, but not PrEC cells, exhibited high rates of apoptosis in response to MSKE through targeting of the phosphatidylinositol 3-kinase–Akt and mitogen-activated protein kinase survival pathways. The reduction in Akt activity by MSKE is mediated through a reduction in Akt transcription, enhanced proteosome degradation of Akt, and altered levels of DJ-1, a known regulator of PTEN. In contrast to MSKE, resveratrol did not induce apoptosis in this model but arrested cells at the G₁-S phase transition of the cell cycle associated with increased expression of p21 and decreased expression of cyclin D1 and cyclin-dependent kinase 4 proteins. These results show that MSKE and resveratrol target distinct pathways to inhibit prostate cancer cell growth in this system and that the unique properties of MSKE suggest that it may be an important source for further development of chemopreventive or therapeutic agents against prostate cancer. [Cancer Res 2007;67(17):8396–405]

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