Epidemiological, in vitro cell culture, and in vivo animal studies have shown that
green tea or its constituent
polyphenols, particularly its major
polyphenol 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 carcinoma (A431) cells. We also demonstrated that these effects of EGCG may be mediated through the inhibition of
nuclear factor kappa B that has been associated with cell cycle regulation and
cancer. In this study, employing A431 cells, we provide evidence for the involvement of
cyclin kinase inhibitor (cki)-
cyclin-
cyclin-dependent kinase (cdk) machinery during cell cycle deregulation by EGCG. As shown by immunoblot analysis, EGCG treatment of the cells 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 complexes operative in G0/G1 phase of the cell cycle thereby causing a G0/G1-phase arrest of the cell cycle, which is an irreversible process ultimately resulting in an apoptotic cell death. We suggest that the naturally occurring agents such as
green tea polyphenols which may inhibit cell cycle progression could be developed as potent
anticancer agents for the management of
cancer.