X. Li , G. Wang , J. Zhao , H. Ding , D. C.. Flynn , E. Reed , Q. Q.. Li , West Virginia University, Morgantown, WV

Background: Epithelial ovarian cancer (EOC) is the second most common malignancy of the female genital tract. Resistance to chemotherapeutic drugs is a hallmark of many human cancers including EOC. Therefore, overcoming drug resistance is the key to successful treatment of ovarian cancer. b-elemene, a new antitumor agent, has multiple anticancer properties and was found to inhibit proliferation, stimulate apoptosis, and induce cell cycle arrest in malignant cells. Our recent studies have shown that b-elemene increases cisplatin cytotoxicity and enhances cisplatin sensitivity in resistant human ovarian carcinoma cells. However, the mechanism underlying this effect of b-elemene is not understood.

Methods: Using several ovarian carcinoma cell lines as models for ovarian cancer, we investigated whether b-elemene augments cisplatin activity in ovarian tumor cells through induction of apoptosis by five different apoptosis assays.

Results: Our study showed that b-elemene triggered apoptotic cell death in cisplatin-resistant ovarian cancer A2780/CP cells in a time- and dose-dependent manner. Morever, our results demonstrated that b-elemene exerted a stronger action in inducing apoptosis in the resistant cells as compared to cisplatin, and a synergistic effect in induction of cell death was seen when cells were treated with both agents. Finally, our results indicated that b-elemene induced increases in caspase-9 activity, but down-regulated the protein expression of Bcl-2 and Bcl-XL in the cisplatin-resistant ovarian cancer cells. b-elemene also reduced the mitochondrial transmembrane potential, and increased the release of cytochrome c into the cytoplasm.

Conclusion: These data indicate that b-elemene strongly sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced apoptosis through a mitochondria-dependent intrinsic cell death pathway.