Elemene and cisplatin synergistically induce apoptosis in chemoresistant ovarian carcinoma cells
Xiping Li, Cynthia Cunningham, Gangduo Wang, Jinshun Zhao, Hong Ding, Daniel C. Flynn, Eddie Reed, Qingdi Q. Li. West Virginia University Health Sciences Center, MBR Cancer Center, Morgantown, WV.
Human ovarian cancer is the leading cause of death from gynecologic malignancies in the United States. Drug resistance to platinum-based chemotherapy remains a significant problem in the clinic; thus, overcoming drug resistance is the key to successful treatment of ovarian cancer.
Alpha-Elemene is a novel anticancer drug, isolated from the Chinese medicinal herb Rhizoma zedoariae, that has been demonstrated to exhibit marked antineoplastic activities in vivo and in vitro; it is currently pending approval for the treatment of human tumors in China and is now in application for clinical studies in the United States.
Our recent studies have shown that alpha-elemene increases cisplatin cytotoxicity and enhances cisplatin sensitivity in resistant human ovarian carcinoma cells.
However, the mechanism underlying this effect of alpha-elemene is not understood. In the current study, we asked whether â-elemene augments cisplatin activity in ovarian tumor cells through induction of apoptosis.
Here we show that alpha-elemene triggered apoptotic cell death in cisplatin-resistant human ovarian cancer A2780/CP cells in a time- and dose-dependent manner, as accessed by five different apoptosis assays.
In addition, we demonstrated that alpha-elemene exerted a stronger action in inducing apoptosis in the resistant ovarian carcinoma cells as compared to cisplatin, and a synergistic effect in induction of cell death was seen when cells were treated with both agents.
Furthermore, we showed that alpha-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 cell line. alpha-Elemene also reduced the mitochondrial transmembrane potential (m), and increased the release of cytochrome c into the cytoplasm from mitochondria.
Altogether, these data indicate that alpha-elemene sensitizes chemoresistant ovarian carcinoma cells to apoptosis induced by cisplatin, and that the augmenting effect of â-elemene on cisplatin cytotoxicity in these cells is through a mitochondrial release of cytochrome c-mediated intrinsic cell death pathway.
This study was supported by NIH/NCRR grant P20 RR16440.
Abstract #1742 AACR 2005
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