Synergistic effects of (-)-epigallocatechin gallate with sulindac against colon carcinogenesis of rats treated with azoxymethane

(-)-Epigallocatechin gallate (EGCG), a major constituent of green tea, has been shown to exhibit anti-cancer activity. Sulindac is also well known as a cancer-preventive agent against colon cancer, but its usage is restricted because of its adverse effects, as exemplified by gastrointestinal bleeding. In the present study, we examined whether a combination of EGCG and sulindac shows synergistic effects for cancer-preventive activity for rat colon carcinogenesis induced by azoxymethane (AOM); we examined the number of aberrant crypt foci (ACF) representing preneoplastic lesions, the argyrophilic nucleolar organizer region (AgNOR) as an indicator of cell proliferation, and the incidence of apoptosis. The AOM treatment induced an average of 46.2 +/- 4.9 ACF/colon, and sulindac and EGCG significantly reduced the incidence of ACF/colon to 21.4 +/- 3.4 and 19.5 +/- 5.8, respectively (P < 0.01). The co-treatment with EGCG and sulindac resulted in significantly reduced ACF formation (10.0 +/- 3.2; P < 0.01). The results of the AgNOR analysis indicated that the treatment with EGCG and/or sulindac suppressed AOM-induced cell proliferation. The present results also revealed that the combination of EGCG and sulindac synergistically enhanced apoptosis significantly (P < 0.01). Thus, our findings suggest that EGCG with sulindac synergistically suppresses ACF formation by enhancing apoptosis and, therefore, that EGCG is a suitable candidate for use in combination with cancer-preventive agents, such as sulindac, to reduce their adverse effects. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.