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A Novel Prodrug of the Green Tea Polyphenol (–)-Epigallocatechin-3-Gallate as a Potential Anticancer Agent

¹ The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan; ² Department of Applied Biology and Chemical Technology and the Institute of Molecular Technology for Drug Discovery and Synthesis, the Hong Kong Polytechnic University, Hong Kong SAR, China; and ³ School of Applied Science, University of Science and Technology Beijing, Beijing, PR China

Requests for reprints: Q. Ping Dou, The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, 640.1 HWCRC, 4100 John R Road, Detroit, MI 48201. Phone: 313-576-8301; Fax: 313-576-8307; E-mail: doup{at}karmanos.org.

The most abundant and biologically active green tea catechin, (–)-epigallocatechin-3-gallate or (–)-EGCG, has been shown to act as a proteasome inhibitor and tumor cell death inducer. However, (–)-EGCG is unstable under physiologic conditions and has poor bioavailability. Previously, in an attempt to increase the stability of (–)-EGCG, we introduced peracetate protections to its reactive hydroxyl groups and showed that this peracetate-protected (–)-EGCG [Pro-EGCG (1); formerly named compound 1] could be converted into (–)-EGCG under cell-free conditions. In the current study, we provide evidence that when cultured human breast cancer MDA-MB-231 cells were treated with Pro-EGCG (1), (–)-EGCG was not only converted but also accumulated, accompanied by enhanced levels of proteasome inhibition, growth suppression, and apoptosis induction, compared with cells treated with natural (–)-EGCG. To investigate the potential use of Pro-EGCG (1) as a novel prodrug that converts to a cellular proteasome inhibitor and anticancer agent in vivo, MDA-MB-231 tumors were induced in nude mice, followed by treatment with Pro-EGCG (1) or (–)-EGCG for 31 days. Results of this in vivo study showed a significant inhibition of breast tumor growth by Pro-EGCG (1), compared with (–)-EGCG, associated with increased proteasome inhibition and apoptosis induction in tumor tissues. In conclusion, we have shown that Pro-EGCG (1) increases the bioavailability, stability, and proteasome-inhibitory and anticancer activities of (–)-EGCG in human breast cancer cells and tumors, suggesting its potential use for cancer prevention and treatment. [Cancer Res 2007;67(9):4303–10]

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