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.

• Authors: Kristin R Landis-Piwowar, Congde Huo, Di Chen, Vesna Milacic, Guoqing Shi, Tak Hang Chan, Q Ping Dou
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 9 Pg. 4303-10 (May 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17483343 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Prodrugs
• Protease Inhibitors
• Catechin
• epigallocatechin gallate
• Chymotrypsin
• Peracetic Acid

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, enzymology, metabolism, pathology)
• Catechin (analogs & derivatives, pharmacokinetics, pharmacology)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Chromatography, High Pressure Liquid
• Chymotrypsin (antagonists & inhibitors, metabolism)
• Female
• Humans
• Mice
• Mice, Nude
• Peracetic Acid (pharmacokinetics, pharmacology)
• Prodrugs (pharmacokinetics, pharmacology)
• Protease Inhibitors (pharmacokinetics, pharmacology)
• Xenograft Model Antitumor Assays