Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase.
Elemene is a natural antitumor plant drug. However, the effect of elemene on cell growth in ovarian cancer is unknown. In this study, we show that beta-elemene inhibited the proliferation of cisplatin-resistant human ovarian cancer cells and their parental cells, but had only a marginal effect in human ovary cells, indicating differential inhibitory effects on cell growth between ovarian cancer cells and normal ovary cells. We also demonstrated for the first time that beta-elemene markedly enhanced cisplatin-induced growth inhibition in resistant cells compared to sensitive cells. In addition, cell cycle analysis revealed a synergistic effect of beta-elemene and cisplatin on the induction of cell cycle G2-M arrest in our resistant ovarian carcinoma cells. Furthermore, we showed that treatment of these cells with both drugs downregulated cyclin B1 and Cdc2 expression, but elevated the levels of p53, p21waf1/cip1, p27kip1 and Gadd45. Finally, the combination of beta-elemene and cisplatin was found to increase the phosphorylation of Cdc2 and Cdc25C, which leads to a reduction in Cdc2-cyclin B1 activity. These novel findings suggest that beta-elemene sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced growth suppression partly through modulating the cell cycle G2 checkpoint and inducing cell cycle G2-M arrest, which lead to blockade of cell cycle progression.
Li
X
X
The Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University Health Sciences Center, Morgantown, West Virginia 26506, USA.
Wang
G
G
Zhao
J
J
Ding
H
H
Cunningham
C
C
Chen
F
F
Flynn
D C
DC
Reed
E
E
Li
Q Q
QQ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000097642:GADD45 Proteins
D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D002945:Cisplatin; D019926:Cyclin B; D056744:Cyclin B1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D047908:Intracellular Signaling Peptides and Proteins; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000097642:GADD45 Proteins; C534699:CCNB1 protein, human; C445979:beta-elemene