Antiproliferative effect of β-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase
Antiproliferative effect of β-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase
复制标题
DOI：
10.1007/s00018-005-5027-1
复制
发表时间：
2005-04-01
影响因子：
8
通讯作者：
Li, QQ
中科院分区：
文献类型：
--
作者：
Li, X;Wang, G;Li, QQ
榄香烯是一种天然的抗肿瘤植物药物。然而，榄香烯对卵巢癌细胞生长的影响尚不清楚。在这项研究中，我们发现β-榄香烯可以抑制顺铂耐药的人卵巢癌细胞及其亲本细胞的增殖，但对人卵巢细胞的增殖仅有边际效应，表明对卵巢癌细胞和正常卵巢细胞之间的细胞生长具有不同的抑制作用。我们还首次证明，与敏感细胞相比，β-榄香烯显着增强耐药细胞中顺铂诱导的生长抑制。此外，细胞周期分析表明，β-榄香烯和顺铂对诱导耐药性卵巢癌细胞的细胞周期 G2-M 停滞具有协同作用。此外，我们发现用这两种药物处理这些细胞会下调细胞周期蛋白 B1 和 Cdc2 的表达，但升高 p53、p21(waf1/kip1)、P27(kip1) 和 Gadd45 的水平。最后，发现 β-榄香烯和顺铂的组合会增加 Cdc2 和 Cdc25C 的磷酸化，从而导致 Cdc2-cyclin B1 活性降低。这些新发现表明，β-榄香烯部分通过调节细胞周期 G2 检查点和诱导细胞周期 G2-M 停滞，从而导致细胞周期进展受阻，从而使化疗耐药性卵巢癌细胞对顺铂诱导的生长抑制敏感。
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, p21(waf1/kip1), P27(kip1) 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.