Diosgenin, a naturally occurring furostanol saponin suppresses 3-hydroxy-3-methylglutaryl CoA reductase expression and induces apoptosis in HCT-116 human colon carcinoma cells

A growing body of experimental evidence suggests the therapeutic potential of diosgenin, a furostanol saponin against several cancers. However. precise molecular and cellular mechanisms underlying the modes of action of this compound against colon cancer remain only partially understood. In this study, we investigated if the anticancer mechanism of diosgenin in HCT-116 human colon carcinoma cells involves modulation in the expression of 3-hydroxy-3-methylglutaryl Co-enzyrne A (HMG-CoA) reductase, the rate-limiting enzyme of the cholesterol biosynthetic pathway. Diosgenin treatment resulted in a dose-dependent decrease in the viability and growth of HCT-116 cells. The IC50 cytotoxic dose of diosgenin in HCT-116 was similar to 35 mu M after 24 h, while concentrations of similar to 32 mu M or greater decreased the percent viable cells by 50%. Higher doses of diosgenin (30-40 mu M) effectively inhibited recovery of cells for up to 24 It post-treatments. At sub-cytotoxic doses, diosgenin induced a dose-dependent increase in apoptotic demise. In part, the apoptotic mechanism was through the cleavage of the 116 kDa poly (ADP-ribose) polymerase protein to the 85 kDa fragment. The expression of HMG-CoA reductase at both mRNA and protein levels was significantly lowered by increasing concentrations of diosg,enin. This was accompanied by a concomitant dose-dependent decrease in the expression of p21 ras and beta-catenin. In conclusion, our data demonstrates that the food saponin, diosgenin is a potent inhibitor of HCT-116 human colon carcinoma cells by growth inhibition and induction of apoptosis. Importantly, our result identifies that the growth suppressive or apoptotic activity of diosgenin may involve cholesterol homeostasis. (c) 2007 Elsevier Ireland Ltd. All rights reserved.