Octyl Ester of Ginsenoside Rh2 Induces Apoptosis and G1 Cell Cycle Arrest in Human HepG2 Cells by Activating the Extrinsic Apoptotic Pathway and Modulating the Akt/p38 MAPK Signaling Pathway

Ginsenoside Rh2 is a potential active metabolite of ginseng that has antitumor activity against a variety of tumor cells. Previously, we reported that Rh2-O, an octyl ester derivative of ginsenoside Rh2, had a higher anti-cancer activity than Rh2 through activating the intrinsic apoptotic pathway. In this study, we found that the extrinsic apoptotic pathway was also involved in Rh2-O-induced HepG2 cells apoptosis as evidenced by the up-regulation of Fas, FasL, TNFR1 and TNF-α, as well as the cleavage of caspase 8. Moreover, flow cytometric analysis demonstrated that Rh2-O induced G1 cell cycle arrest in HepG2 cells. Rh2-O-induced G1 phase arrest was accompanied by the down-regulation of cyclin D3 and cyclin E and cyclin-dependent kinase (CDK) 4 and 6, and the up-regulation of p21WAF1/CIP1 and p27KIP1. In addition, Rh2-O down-regulated the phosphorylation of Akt, and its inhibitor LY294002 promoted Rh2-O-induced G1 phase arrest. Rh2-O treatment also activated p38 MAPK, JNK and ERK expression. Inhibitors of...