Enhancement of cisplatin-induced apoptosis by β-elemene in resistant human ovarian cancer cells
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β-Elemene is a new anticancer compound extracted from the Chinese medicinal herb Rhizoma zedoariae. We have shown previously that β-elemene increases cisplatin cytotoxicity and enhances cisplatin sensitivity via blocking cell cycle progression at G2/M phase in resistant ovarian tumor cells. In the current study, we asked whether β-elemene-augmented cisplatin activity in ovarian carcinoma cells is mediated through the induction of apoptosis. Here, we show that β-elemene triggered apoptotic cell death in chemoresistant human ovarian cancer A2780/CP and MCAS cells in a dose- and time-dependent fashion, as assessed by six different apoptosis assays. Intriguingly, β-elemene was a stronger inducer of apoptosis than cisplatin in this model system, and a synergistic effect on induction of cell death was observed when the tumor cells were treated with both agents. Furthermore, β-elemene plus cisplatin exposure significantly disrupted the mitochondrial transmembrane potential (ΔΨ m) and increased the release of cytochrome c from mitochondria into the cytoplasm. The combination treatment with both compounds also induced increases in caspase-3/8/9 activities and caspase-9 cleavage, enhanced protein expression of Bax and phosphorylation of Bcl-2 at Ser-70, and reduced the protein levels of Bcl-2 and Bcl-XL in the platinum-resistant ovarian cancer cells. Taken together, these data indicate that β-elemene sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced apoptosis and that the augmented effect of β-elemene on cisplatin cytotoxicity and sensitivity in resistant ovarian tumor cells is mediated through a mitochondria- and caspase-dependent cell death pathway.
KeywordsApoptosis Cisplatin resistance β-Elemene Chinese medicine Ovarian cancer
This publication was made possible by grants from the Natural Science Foundation of Science and Technology Department of Guangxi Province (No. 0991294) and the Guangxi Scientific Research and Technological Development Program (No. 200901059), and by grants from the National Institutes of Health (Nos. P20RR16440-010003, P20RR16440-020003, P20RR16440-030003, P20RR16440-040003) and West Virginia University School of Medicine Research Grant (to Q. Q. Li).
Conflict of interest
The authors declare that they have no conflict of interest.
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