Diosgenin, a naturally occurring steroid [corrected] 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 steroid [corrected] 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-enzyme 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 IC(50) cytotoxic dose of diosgenin in HCT-116 was approximately 35 microM after 24h, while concentrations of approximately 32 microM or greater decreased the percent viable cells by 50%. Higher doses of diosgenin (30-40 microM) effectively inhibited recovery of cells for up to 24h 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 85kDa fragment. The expression of HMG-CoA reductase at both mRNA and protein levels was significantly lowered by increasing concentrations of diosgenin. 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.
Raju
Jayadev
J
Toxicology Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ont., Canada.
Bird
Ranjana P
RP
D017209:Apoptosis; D002277:Carcinoma / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D004144:Diosgenin / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors; D012503:Saponins / Q000494:pharmacology*; D051176:beta Catenin / Q000037:antagonists & inhibitors
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012503:Saponins; D051176:beta Catenin; D006903:Hydroxymethylglutaryl CoA Reductases; D015689:Oncogene Protein p21(ras); D004144:Diosgenin