Panaxadiol selectively inhibits cyclin A-associated Cdk2 activity by elevating p21WAF1/CIP1 protein levels in mammalian cells

We show that panaxadiol (PD), a ginseng saponin with a dammarane skeleton, selectively interferes with the cell cycle in human cancer cell lines. PD inhibited DNA synthesis in a dose-dependent manner with IC50 values ranging from 0.8 to 1.2 muM in SK-HEP-1 cells and HeLa cells. PD-treated cells were arrested at G(1)/S phase, which coincided well with decreases in Cyclin A-Cdk2 activity, but not in Cyclin E-Cdk2 and Cdc2 activities. The intracellular levels of p21(WAF1/CIP1) were significantly and selectively elevated in a dose- and time-dependent manner in PD-treated HeLa cells. Similarly, levels of the p21(WAF1/CIP1) protein that is associated with the Cyclin A-Cdk2 complex increased, and these increases correlated well with the down-regulation of Cyclin A-Cdk2 activity. Thus, PD selectively elevates p21(WAF1/CIP1) levels and thereby arrests the cell cycle at G(1)/S phase by down-regulating Cyclin A-Cdk2 activity.