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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wayne State University
Schools of Medicine
United States
Zip Code
Schmitt, Sara M; Neslund-Dudas, Christine; Shen, Min et al. (2016) Involvement of ALAD-20S Proteasome Complexes in Ubiquitination and Acetylation of Proteasomal ?2 Subunits. J Cell Biochem 117:144-51
Arkwright, Richard T; Deshmukh, Rahul; Adapa, Nikhil et al. (2015) Lessons from Nature: Sources and Strategies for Developing AMPK Activators for Cancer Chemotherapeutics. Anticancer Agents Med Chem 15:657-71
Block, Keith I; Gyllenhaal, Charlotte; Lowe, Leroy et al. (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35 Suppl:S276-S304
Farshi, Pershang; Deshmukh, Rahul R; Nwankwo, Joseph O et al. (2015) Deubiquitinases (DUBs) and DUB inhibitors: a patent review. Expert Opin Ther Pat 25:1191-1208
Tomco, Dajena; Schmitt, Sara; Heeg, Mary Jane et al. (2014) Inhibition of the 26S proteasome as a possible mechanism for toxicity of heavy metal species. J Inorg Biochem 132:96-103
Shen, Min; Zhang, Zhen; Ratnam, Manohar et al. (2014) The interplay of AMP-activated protein kinase and androgen receptor in prostate cancer cells. J Cell Physiol 229:688-95
Zhang, Pengfei; Bi, Caifeng; Schmitt, Sara M et al. (2014) Metal-based 2,3-indolinedione derivatives as proteasome inhibitors and inducers of apoptosis in human cancer cells. Int J Mol Med 34:870-9
Nardon, Chiara; Schmitt, Sara M; Yang, Huanjie et al. (2014) Gold(III)-dithiocarbamato peptidomimetics in the forefront of the targeted anticancer therapy: preclinical studies against human breast neoplasia. PLoS One 9:e84248
Zuo, Jian; Bi, Caifeng; Fan, Yuhua et al. (2013) Cellular and computational studies of proteasome inhibition and apoptosis induction in human cancer cells by amino acid Schiff base-copper complexes. J Inorg Biochem 118:83-93
Landis-Piwowar, Kristin; Chen, Di; Foldes, Robert et al. (2013) Novel epigallocatechin gallate analogs as potential anticancer agents: a patent review (2009 - present). Expert Opin Ther Pat 23:189-202

Showing the most recent 10 out of 82 publications