Differential responses of skin cancer-chemopreventive agents silibinin, quercetin, and epigallocatechin 3-gallate on mitogenic signaling and cell cycle regulators in human epidermoid carcinoma A431 cells

Silibinin, quercetin, and epigallocatechin 3-gallate (EGCG) have been shown to be skin cancer-preventive agents, albeit by several different mechanism s. Here, we assessed whether these agents show their cancer-preventive pote ntial by a differential effect on mitogenic signaling molecules and cell cy cle regulators. Treatment of human epidermoid carcinoma A431 cells with the se agents inhibited the activation of the epidermal growth factor receptor and the downstream adapter protein Shc, but only silibinin showed a marked inhibition of mitogen-activated protein kinase-extracellular signal-regulat ed kinase-1 and -2 activation. In terms of cell cycle regulators, silibinin treatment showed an induction of Cip1/p21 and Kip1/p27 together with a sig nificant decrease in cyclin-dependent kinase (CDK)-4, CDK2, and cyclin D1. Quercetin treatment, however, resulted in a moderate increase in Cip1/p21 w ith no change in Kip1/p27 and a decrease in CDK4 and cyclin D1. EGCG treatm ent also led to an induction of Cip1/p21 but no change in Kip1/p27, CDK2, a nd cyclin D1 and a decrease in CDK4 only at low doses. Treatment of cells w ith these agents resulted in a strong dose- and time-dependent cell growth inhibition. A high dose of silibinin and low and high doses of quercetin an d EGCG also led to cell death by apoptosis, suggesting that a lack of their inhibitory effect on mitogen-activated protein kinase-extracellular signal -regulated kinase-1 and -2 activation possibly "turns on" an apoptotic cell death response associated with their cancer preventive and anticarcinogeni c effects. Together, these results suggest that silibinin, quercetin, and E GCG exert their cancer preventive effects by differential responses on mito genic signaling and cell cycle regulators.