Antitumor effect of β-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death

-Elemene is a novel anticancer drug, which was extracted from the ginger plant. However, the mechanism of action of -elemene in non-small-cell lung cancer (NSCLC) remains unknown. Here we show that -elemene had differential inhibitory effects on cell growth between NSCLC cell lines and lung fibroblast and bronchial epithelial cell lines. In addition, -elemene was found to arrest NSCLC cells at G2-M phase, the arrest being accompanied by decreases in the levels of cyclin B1 and phospho-Cdc2 (Thr-161) and increases in the levels of p27^kip1 and phospho-Cdc2 (Tyr-15). Moreover, -elemene reduced the expression of Cdc25C, which dephosphorylates/activates Cdc2, but enhanced the expression of the checkpoint kinase, Chk2, which phosphorylates/ inactivates Cdc25C. These findings suggest that the effect of -elemene on G2-M arrest in NSCLC cells is mediated partly by a Chk2-dependent mechanism. We also demonstrate that -elemene triggered apoptosis in NSCLC cells. Our results clearly show that -elemene induced caspase-3, –7 and –9 activities, decreased Bcl-2 expression, caused cytochrome c release and increased the levels of cleaved caspase-9 and poly(ADP-ribose) polymerase in NSCLC cells. These data indicate that the effect of -elemene on lung cancer cell death may be through a mitochondrial release of the cytochrome c-mediated apoptotic pathway.Received 12 January 2005; accepted 5 February 2005