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Inhibition of Intestinal Tumorigenesis in Apc^min/+ Mice by (–)-Epigallocatechin-3-Gallate, the Major Catechin in Green Tea

¹ Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey; ² Department of Physiology, Robert Wood Johnson Medical School, Piscataway, New Jersey; ³ Cancer Institute of New Jersey, New Brunswick, New Jersey; and ⁴ Strang Cancer Prevention Center, New York, New York

Requests for reprints: Chung S. Yang, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020. Phone: 732-445-5360; Fax: 732-445-0687; E-mail: csyang{at}rci.rutgers.edu.

The present study was designed to investigate the effects of two main constituents of green tea, (–)-epigallocatechin-3-gallate (EGCG) and caffeine, on intestinal tumorigenesis in Apc^min/+ mice, a recognized mouse model for human intestinal cancer, and to elucidate possible mechanisms involved in the inhibitory action of the active constituent. We found that p.o. administration of EGCG at doses of 0.08% or 0.16% in drinking fluid significantly decreased small intestinal tumor formation by 37% or 47%, respectively, whereas caffeine at a dose of 0.044% in drinking fluid had no inhibitory activity against intestinal tumorigenesis. In another experiment, small intestinal tumorigenesis was inhibited in a dose-dependent manner by p.o. administration of EGCG in a dose range of 0.02% to 0.32%. P.o. administration of EGCG resulted in increased levels of E-cadherin and decreased levels of nuclear ß-catenin, c-Myc, phospho-Akt, and phospho-extracellular signal–regulated kinase 1/2 (ERK1/2) in small intestinal tumors. Treatment of HT29 human colon cancer cells with EGCG (12.5 or 20 µmol/L at different times) also increased protein levels of E-cadherin by 27% to 58%, induced the translocation of ß-catenin from nucleus to cytoplasm and plasma membrane, and decreased c-Myc and cyclin D1 (20 µmol/L EGCG for 24 hours). These results indicate that EGCG effectively inhibited intestinal tumorigenesis in Apc^min/+ mice, possibly through the attenuation of the carcinogenic events, which include aberrant nuclear ß-catenin and activated Akt and ERK signaling.

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