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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA112625-02
Application #
6952307
Study Section
Special Emphasis Panel (ZCA1-SRRB-Q (O1))
Program Officer
Steele, Vernon E
Project Start
2004-09-30
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$75,500
Indirect Cost
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Yang, Huanjie; Wang, Ying; Cheryan, Vino T et al. (2012) Withaferin A inhibits the proteasome activity in mesothelioma in vitro and in vivo. PLoS One 7:e41214
Barrea, Raul A; Chen, Di; Irving, Thomas C et al. (2009) Synchrotron X-ray imaging reveals a correlation of tumor copper speciation with Clioquinol's anticancer activity. J Cell Biochem 108:96-105
Dou, Q Ping (2009) Molecular mechanisms of green tea polyphenols. Nutr Cancer 61:827-35
Yang, Huanjie; Zonder, Jeffrey A; Dou, Q Ping (2009) Clinical development of novel proteasome inhibitors for cancer treatment. Expert Opin Investig Drugs 18:957-71
Milacic, Vesna; Banerjee, Sanjeev; Landis-Piwowar, Kristin R et al. (2008) Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo. Cancer Res 68:7283-92
Landis-Piwowar, K R; Dou, Q P (2008) Polyphenols: biological activities, molecular targets, and the effect of methylation. Curr Mol Pharmacol 1:233-43
Dou, Q P; Landis-Piwowar, K R; Chen, D et al. (2008) Green tea polyphenols as a natural tumour cell proteasome inhibitor. Inflammopharmacology 16:208-12
Huo, C; Wan, S B; Lam, W H et al. (2008) The challenge of developing green tea polyphenols as therapeutic agents. Inflammopharmacology 16:248-52
Yang, H; Landis-Piwowar, K R; Chen, D et al. (2008) Natural compounds with proteasome inhibitory activity for cancer prevention and treatment. Curr Protein Pept Sci 9:227-39
Landis-Piwowar, Kristin R; Milacic, Vesna; Dou, Q Ping (2008) Relationship between the methylation status of dietary flavonoids and their growth-inhibitory and apoptosis-inducing activities in human cancer cells. J Cell Biochem 105:514-23

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