ANTICARCINOGENIC EFFECT OF A FLAVONOID ANTIOXIDANT, SILYMARIN, IN HUMAN BREAST-CANCER CELLS MDA-MB-468 - INDUCTION OF G(1) ARREST THROUGH AN INCREASE IN CIP1 P21 CONCOMITANT WITH A DECREASE IN KINASE-ACTIVITY OF CYCLIN-DEPENDENT KINASES AND ASSOCIATED CYCLINS/

There is an increasing interest in identifying potent cancer preventiv e and therapeutic agents against breast cancer, Silymarin, a flavonoid antioxidant isolated from milk thistle, exerts exceptionally high to complete anticarcinogenic effects in tumorigenesis models of epithelia l origin, In this study, we investigated the anticarcinogenic effect o f silymarin and associated molecular mechanisms, using human breast ca rcinoma cells MDA-MB 468, Silymarin treatment resulted in a significan tly high to complete inhibition of both anchorage-dependent and anchor age-independent cell growth in a dose-and time-dependent manner, The i nhibitory effects of silymarin on cell growth and proliferation were a ssociated with a G(1) arrest in cell cycle progression concomitant wit h an induction of up to 19-fold in the protein expression of cyclin-de pendent kinase (CDK) inhibitor Cip1/p21, Following silymarin treatment of cells, an incremental binding of Cip1/p21 with CDK2 and CDK6 paral leled a significant decrease in CDK2-, CDK6-, cyclin D1-, and cyclin E -associated kinase activity with no change in CDK2 and CDK6 expression but a decrease in G(1) cyclins D1 and E. Taken together, these result s suggest that silymarin may exert a strong anticarcinogenic effect ag ainst breast cancer and that this effect possibly involves an inductio n of Cip1/p21 by silymarin, which inhibits the threshold kinase activi ties of CDKs and associated cyclins, leading to a G(1) arrest in cell cycle progression.