Modulation of mitogen-activated protein kinase activation and cell cycle regulators by the potent skin cancer preventive agent silymarin.

Recently we showed that the skin cancer preventive effect of silymarin involves inhibition of erbB1 activation. Here we assessed the effect of silymarin on cytoplasmic and nuclear signals employing human epidermoid carcinoma A431 cells. Silymarin treatment of cells resulted in a significant inhibition of mitogen-activated protein kinase (MAPK)/ERK1/2 activation only at lower doses, whereas higher doses activated MAPK/JNK1. These differential responses of silymarin were accompanied by its growth inhibitory and apoptotic cell death effects at low and high doses, respectively. Silymarin-caused growth inhibition was via both G2-M and G1 arrests due to a significant decrease in the kinase activity and protein levels of CDKs and cyclins. In other studies, only low doses of silymarin also showed an induction of Cip1/p21 and Kip1/p27. Together, these results identify distinct signaling pathways for the antiproliferative and apoptotic effects of silymarin and form a basis for developing strategies targeted to ERK and JNK pathways for the prevention and intervention of malignancies by silymarin.