Research has supported proteasome inhibitors as potential novel anticancer drugs and green tea polyphenols (GTPs) as a cancer-preventative agent. We have reported that GTPs, e.g. (-)-epigallocatechin- 3-gallate or EGCG, are potent and specific inhibitors of proteasomal chymotrypsin-like activity (mediated by b5 subunit). Methylation of GTPs, a major biotransformation reaction limiting their cancer-preventative activities in vivo, is mediated by human polymorphic catechol-O-methyltransferase (COMT). The point- mutated COMT, found in -25% of US population, has 3-4-fold decreased enzymatic activity (COMT-LL). It was reported that women tea-drinkers with at least one low activity COMT allele (but not COMT-HH) showed a significantly reduced risk of breast cancer compared with non-tea drinkers, suggesting less protection by methylated polyphenols. To study the responsible mechanism, we hypothesize that O-methylation of GTPs by COMT in breast cancer cells decreases their proteasome-inhibitory and consequently biological activities. This hypothesis is supported by our preliminary results. To further this study, we propose 5 specific Aims. (1) Synthesize O-methylated GTP analogs (by replacing -OH with -OCH3), the deoxy compounds (without the catechol diol), and polyphenol homologs (replacing -OH with -CH2OH) and determine their binding affinity to the proteasomal b5 subunit by employing computational modeling. (2) Evaluate potencies of these synthetic compounds to inhibit the proteasome activity using purified 20S proteasome, breast cancer cell extracts, and intact breast cancer cells. (3) Evaluate the apoptosis-inducing potencies of these synthetic compounds in human breast cancer cells. (4) Determine the effects of over- and under-expression of COMT gene in cultured human breast cancer cells on methylation of GTPs and their proteasome-inhibitory and apoptosis-inducing activities. (5) Determine whether methylation of GTPs is a mechanism to inactivate their biological functions in vivo using nude mice bearing human breast tumor xenografts. These studies should help develop a fundamental understanding about how the polymorphic COMT regulates the biological functions of GTPs in breast cancer cells and the impact of GTP methylation by COMT on the cancer- preventative effects of tea consumption as well as generate important information for designing future cancer prevention clinical trials using GTPs alone or in combination with a COMT inhibitor. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120009-02
Application #
7221981
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Crowell, James A
Project Start
2006-04-12
Project End
2011-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$233,544
Indirect Cost
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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