The Proteasome as Molecular Target of Grape Polyphenols

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DESCRIPTION (provided by applicant): Our long-term objective is to discover novel potent, specific cancer preventative and anticancer agents with no cytotoxicity. Recent results from in vitro, in vivo and clinical trials have supported the use of proteasome inhibitors as potential novel anticancer drugs. We have found that natural and synthetic green tea polyphenols with an ester bond are potent and specific proteasomal chymotrypsin-like inhibitors, while those without an ester bond are inactive. Most recently, we have reported that grape extract inhibits the proteasomal chymotrypsin-like activity in leukemia Jurkat T cell extract and intact Jurkat T cells, associated with apoptosis induction. Furthermore, grape extract induces the appearance of spherical cells preferentially in prostate cancer PC-3 over normal NIH 3T3 cell line. Our findings suggest that the proteasome is a cancer related molecular target for grape antioxidant components. Based on these results, we hypothesize that inhibition of the proteasome activity by some antioxidant polyphenolic compounds contributes to the prostate cancer-preventative activities of grapes. To address this hypothesis, we propose the following Three Specific Aims. Specific Aim 1 is to evaluate potency and selectivity of several grape polyphenolic compounds to inhibit the proteasome activity using purified 20S proteasome, prostate cancer cell extracts, and intact prostate cancer cells. Specific Aim 2 is to evaluate the apoptosis-inducing potency of these polyphenolic compounds in human prostate cancer and normal cells. Specific Aim 3 is to determine whether the abilities of these grape antioxidant polyphenolic compounds to inhibit the proteasome activity and to induce apoptosis correlate with their cancer-preventative activity in vivo using nude mice bearing human prostate cancer cells. These studies should help develop a fundamental understanding about how consumption of grapes and other fruits and vegetables prevents cancer, and discover potent, specific and stable polyphenol proteasome inhibitors with no or little toxicity for the prevention of prostate and other cancers.