| Colorectal cancer is the second most common cancer in both incidence and mortality in developed countries. Dietary factors play important roles in colorectal carcinogenesis; the identification of dietary constituents that prevent this cancer and the elucidation of mechanisms of action are important areas of research. The objectives of this study were (1) to determine inhibitory activities of the two main constituents in green tea, EGCG and caffeine, against intestinal tumorigenesis in Apc Min mice, a recognized mouse model for human colorectal cancer, (2) to elucidate possible mechanisms involved in the inhibitory action of EGCG, and (3) to evaluate the combined efficacy of EGCG with other agents: voluntary exercise, curcumin, or leukotriene A4 hydrolase inhibitor, on the inhibition of intestinal tumorigenesis in the Apc Min mice. Oral administration of EGCG in drinking fluid at the range of 0.02% to 0.32% dose-dependently inhibited small intestinal tumorigenesis in ApcMin mice, whereas caffeine at the dose of 0.044% did not exert any inhibitory effect. Oral administration of EGCG resulted in increased E-cadherin and nuclear p53 levels and decreased nuclear beta-catenin, c-Myc, phospho-Akt, and phospho-Erk1/2 levels in small intestinal tumors. Treatment of HT29 human colon cancer cells with EGCG (12.5 or 20 muM for different times) also increased protein levels of E-cadherin, induced the translocation of beta-catenin from nucleus to cytoplasm and the plasma membrane, and decreased levels of c-Myc, cyclin D1, and phosphorylation of Akt (20 muM EGCG for 24 hours). The combination of EGCG with voluntary exercise, curcumin, or leukotriene A4 hydrolase inhibitor did not significantly enhance the inhibitory activity against intestinal tumorigenesis in Apc Min mice. Together, these findings indicate that EGCG effectively inhibited intestinal tumorigenesis in the ApcMin mice, partially through the attenuation of the carcinogenic events, which include the aberrant nuclear beta-catenin levels, activated Akt and Erk signaling, and impaired p53 signaling. The information obtained from the present study will be useful for the development of EGCG as an effective chemopreventive agent for human intestinal cancer. |
