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Title: Inhibition of prostate cancer growth by muscadine grapeskin extract and resveratrol through distinct mechanisms

Author
item HUDSON, TAMARO - NCI/NIH, BETHESDA, MD
item HARTLE, DIANE - UNIV. GEORGIA, ATHENS
item HURSTING, STEPHEN - UNIV. OF TEXAS, AUSTIN
item NUNEZ, NOMELI - UNIV. OF TEXAS, AUSTIN
item Wang, Thomas - Tom
item YOUNG, HEATHER - GW UNIV.,WASHINGTON, DC
item ARANY, PRAVEEN - NCI/NIH, BETHESDA, MD
item GREEN, JEFFREY - NCI/NIH, BETHESDA, MD

Submitted to: Cancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/22/2007
Publication Date: 9/1/2007
Citation: Hudson, T.S., Hartle, D.K., Hursting, S.D., Nunez, N.P., Wang, T.T., Young, H.A., Arany, P., Green, J.E. 2007. Inhibition of prostate cancer growth by muscadine grapeskin extract and resveratrol through distinct mechanisms. Cancer Research. 67(17):8396-8405.

Interpretive Summary: A study was conducted in collaboration with scientist at the National Cancer Insitute and three universities to test the prostate cancer preventive properties of muscadine grape skin extracts (MSKE). Muscadine grapes contain different phytochemical constituents compared to other grapes and are potentially a source for novel compounds with anti-tumor activities. The anti-cancer activities of MSKE were tested in a cell culture model of prostate cancer progression and compared with the candidate prostate cancer preventive agent resveratrol, a phytochemical from red grapes. Markers for cell proliferation, cell cycles, and cell death pathways were use to monitor the effects of MSKE and resveratrol. These pathways are an important regulator of prostate cancer development and progression. We found 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 preventive agents against prostate cancer. This work provides novel information for cancer research scientists regarding interactions and mechanism(s) of action of health promoting phytochemicals from grapes and serves as important basis for future design of cancer preventive strategy.

Technical Abstract: Phytochemicals are naturally occurring compounds with demonstrated anti-tumor activities. The phytochemical resveratrol, contained in red grapes, has been shown to inhibit prostate cancer cell growth, potentially through its anti-oxidant activity. Muscadine grapes contain different phytochemical constituents compared to other grapes and are potentially a source for novel compounds with anti-tumor activities. We compared the anti-tumor activities of muscadine grape skin extracts (MSKE), which we demonstrate contain no resveratrol, with that of resveratrol using normal primary prostate 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 the PrEC cells. Prostate tumor cell lines, but not PrEC cells, exhibited high rates of apoptosis in response to MSKE (as determined by annexin V-FITC, TUNEL, and propidium iodide FACS analyses) through targeting of the PI3K-Akt and MAP kinase survival pathways. The reduction in Akt activity by MSKE is mediated in part 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 system 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 (Cdk4) proteins. These results demonstrate 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.