AbstractWe provide evidence for the first time, that two natural compounds ginsenoside Rh2 (G‐Rh2) and betulinic acid (Bet A) synergistically induce apoptosis in human cervical adenocarcinoma (HeLa), human lung cancer A549, and human hepatoma HepG2 cells. G‐Rh2 and Bet A cooperated to induce Bax traslocation to mitochondria and cytochrome c release. Co‐treatment of G‐Rh2 and Bet A resulted in enhanced cleavage of caspase‐8 and Bid. Moreover, specific inhibition of caspase‐8 by siRNA technology effectively reduced caspase‐9 processing, poly (ADP‐ribose) polymerase (PARP) cleavage, caspase‐3 activation, and apoptosis in co‐treated cells, which indicated that the caspase‐8 feedback amplification pathway may have been involved in the apoptosis process. A previous study has shown that G‐Rh2 induces cancer cell apoptosis via a Bcl‐2 and/or Bcl‐xL‐independent mechanism, and Bet A induces apoptosis mainly through a mitochondrial pathway with tumor specificity. Since the antiapoptotic Bcl‐2 and Bcl‐xL are frequently overexpressed in human cancer cells, combined treatment with G‐Rh2 and Bet A may be a novel strategy to enhance efficacy of anticancer therapy. © 2011 Wiley‐Liss, Inc.