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.