Anti‐proliferative and proapoptotic effects of (−)‐epigallocatechin‐3‐gallate on human melanoma: Possible implications for the chemoprevention of melanoma

Abstract

Melanoma accounts for only about 4% of all skin cancer cases but most of skin cancer‐related deaths. Standard systemic therapies such as interferon (IFN) have not been adequately effective in the management of melanoma. Therefore, novel approaches are needed for prevention and treatment of this disease. Chemoprevention by naturally occurring agents present in food and beverages has shown benefits in certain cancers including nonmelanoma skin cancers. Here, employing 2 human melanoma cell lines (A‐375 amelanotic malignant melanoma and Hs‐294T metastatic melanoma) and normal human epidermal melanocytes (NHEM), we studied the antiproliferative effects of epigallocatechin‐3‐gallate (EGCG), the major polyphenolic antioxidant present in green tea. EGCG treatment was found to result in a dose‐dependent decrease in the viability and growth of both melanoma cell lines. Interestingly, at similar EGCG concentrations, the normal melanocytes were not affected. EGCG treatment of the melanoma cell lines resulted in decreased cell proliferation (as assessed by Ki‐67 and PCNA protein levels) and induction of apoptosis (as assessed cleavage of PARP, TUNEL assay and JC‐1 assay). EGCG also significantly inhibited the colony formation ability of the melanoma cells studied. EGCG treatment of melanoma cells resulted in a downmodulation of anti‐apoptotic protein Bcl2, upregulation of proapoptotic Bax and activation of caspases ‐3, ‐7 and ‐9. Furthermore, our data demonstrated that EGCG treatment resulted in a significant, dose‐dependent decrease in cyclin D1 and cdk2 protein levels and induction of cyclin kinase inhibitors (ckis) p16 INK4a, p21 WAF1/CIP1 and p27 KIP1. Our data suggest that EGCG causes significant induction of cell cycle arrest and apoptosis of melanoma cells that is mediated via modulations in the cki‐cyclin‐cdk network and Bcl2 family proteins. Thus, EGCG, alone or in conjunction with current therapies, could be useful for the management of melanoma. © 2004 Wiley‐Liss, Inc.