SKIN-CANCER CHEMOPREVENTIVE EFFECTS OF A FLAVONOID ANTIOXIDANT SILYMARIN ARE MEDIATED VIA IMPAIRMENT OF RECEPTOR TYROSINE KINASE SIGNALING AND PERTURBATION IN CELL-CYCLE PROGRESSION

Enhanced tyrosine kinase activity due to aberrant or overexpression of receptor and/or non-receptor tyrosine kinases has been implicated in a variety of human malignancies including cutaneous neoplasms. Epiderm al growth factor receptor (EGFR)-mediated tyrosine phosphorylation may be a primary indicator of signal transduction regulating cell growth and proliferation. Recent studies have shown that skin tumor promoters such as phorbol ester and ultraviolet B radiation activate EGrFR in m ouse skin as well as in cell culture, Similarly, oxidative stress, whi ch is implicated in skin tumor promotion, also activates EGFR-mediated cell signaling. Since this signaling pathway has been suggested to be involved in skin tumor promotion, its impairment by antioxidants may lead to an efficient way for skin cancer prevention and therapy. Recen tly, we showed that silymarin, a flavonoid antioxidant, affords except ionally high to complete protection against several skin tumor promote rs caused tumor promotion in mouse skin. Employing human epidermoid ca rcinoma cells A431 that contain overexpressed EGFR, in this study, we assessed whether the anti-skin tumor promoting effects of silymarin ar e due to its inhibitory effect on EGFR activation and down stream sign aling pathway leading to perturbations in cell cycle progression. Trea tment of cells with silymarin resulted in a significant inhibition of ligand-induced activation of EGFR with no change in its protein levels . Silymarin treatment also resulted in a significant decrease in tyros ine phosphorylation of Shc, an immediate downstream target of EG;FR, b ut no change in the protein levels of Shc. The inhibition of EGFR acti vation by silymarin was associated with a highly significant significa nt to complete inhibition of EGFR intrinsic kinase activity. Cells tre ated with silymarin also showed a significant G2-M arrest in cell cycl e progression, and a highly significant inhibition of DNA synthesis an d cell growth in a dose-dependent manner. Taken together, these result s suggest that skin cancer chemopreventive effects of silymarin are me diated via impairment of EG;FR signaling which ultimately leads to per turbation in cell cycle progression resulting in the inhibition of pro liferation and induction of growth arrest. (C) 1998 Academic Press.