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

Abstract 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]