Growth inhibition, cell-cycle dysregulation, and induction of apoptosis bygreen tea constituent (-)-epigallocatechin-3-gallate in androgen-sensitiveand androgen-insensitive human prostate carcinoma cells

Prostate cancer (PCA) is the most prevalent cancer diagnosed and the second leading cause of cancer-related deaths among men in the United States. Des criptive epidemiological data suggest that androgens and environmental expo sures play a key role in prostatic carcinogenesis. Since androgen action is intimately associated with proliferation and differentiation, at the time of clinical diagnosis in humans most PCA represent themselves as a mixture of androgen-sensitive and androgen-insensitive cells. Androgen-sensitive ce lls undergo rapid apoptosis upon androgen withdrawal. On the other hand, th e androgen-insensitive cells do not undergo apoptosis upon androgen blockin g, but maintain the molecular machinery of apoptosis. Thus, agents capable of inhibiting growth and/or inducing apoptosis in both androgen-sensitive a nd androgen-insensitive cells will be useful for the management of PCA. In the present study, we show that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, imparts antiproliferat ive effects against both androgen-sensitive and androgen-insensitive human PCA cells, and this effect is mediated by deregulation in cell cycle and in duction of apoptosis. EGCG treatment,vas found to result in a dose-dependen t inhibition of cell growth in both androgen-insensitive DU145 and androgen -sensitive LNCaP cells. In both the cell types, EGCG treatment also resulte d in a dose-dependent G(0)/G(1)-phase arrest of the cell cycle as observed by DNA cell-cycle analysis. As evident by DNA ladder assay, confocal micros copy, and flow cytometry, the treatment of both DU145 and LNCaP cells with EGCG resulted in a dose-dependent apoptosis. Western blot analysis revealed that EGCG treatment resulted in (i) a dose-dependent increase of p53 in LN CaP cells (carrying wild-type p53), but not in DU145 cells (carrying mutant p53), and (ii) induction of cyclin kinase inhibitor WAF1/p21 in both cell types. These results suggest that EGCG negatively modulates PCA cell growth , by affecting mitogenesis as web as inducing apoptosis, in cell-type-speci fic manner which may be mediated by WAF1/p21-caused G(0)/G(1)-phase cell-cy cle arrest, irrespective of the androgen association or p53 status of the c ells. (C) 2000 Academic Press.