Abstract
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 G(1)-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.
Highlights
Epidemiologic evidence strongly suggests that a diet rich in fruits and vegetables is associated with a reduced risk of developing many types of cancers, including prostate cancer [1]
We show that muscadine grape skin extract (MSKE) does not contain significant amounts of resveratrol and that the major components of MSKE are different from those in muscadine grape seed extract (MSEE), which has been studied for antitumor activities [15]
MSKE-treated cells display condensed nuclei, cell detachment, and irregular shape compared with the control cells after 24 h, consistent with changes occurring during apoptosis
Summary
Epidemiologic evidence strongly suggests that a diet rich in fruits and vegetables is associated with a reduced risk of developing many types of cancers, including prostate cancer [1]. Because such diets are rich sources of phytochemicals, it has been suggested that. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). P. Arany is currently at Biological Sciences in Dental Medicine, Harvard Dental School, Boston, MA 02115. T. Hudson is currently at Howard University Cancer Center, Department of Medicine, Washington, DC 20060
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