Cell cycle dysregulation by green tea polyphenol epigallocatechin-3-gallate

Epidemiological, in vitro cell culture, and in vitro animal studies have sh own that green tea or its constituent polyphenols, particularly its major p olyphenol epigallocatechin-3-gallate (EGCG) may protect against many cancer types. In earlier studies, we showed that green tea polyphenol EGCG causes a G0/G1-phase cell cycle arrest and apoptosis of human epidermoid carcinom a (A431) cells. We also demonstrated that these effects of EGCG may be medi ated through the inhibition of nuclear factor kappa B that has been associa ted with cell cycle regulation and cancer. In this study, employing A431 ce lls, we provide evidence for the involvement of cyclin kinase inhibitor (ck i)-cyclin-cyclin-dependent kinase (cdk) machinery during cell cycle deregul ation by EGCG. As shown by immunoblot analysis, EGCG; treatment of the cell s resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, p16 and p18, (ii) downmodulation of the protein expression of cyclin D1, cdk4 and cdk6, but not of cyclin E and cdk2, (iii) inhibition of the kinase activities associated with cyclin E, cyclin D1, cdk2, cdk4 and cdk6. Taken together, our study suggests that EGCG causes an induction of G1-phase ckis, which inhibit the cyclin-cdk com plexes operative in G0/G1 phase of the cell cycle thereby causing a G0/G1-p hase arrest of the cell cycle, which is an irreversible process ultimately resulting in an apoptotic cell death. We suggest that the naturally occurri ng agents such as green tea polyphenols which may inhibit cell cycle progre ssion could be developed as potent anticancer agents for the management of cancer. (C) 2000 Academic Press.