Antiproliferative effect of β-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase

Abstract

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.

In vitro combination characterization of the new anticancer plant drug β-elemene with taxanes against human lung carcinoma

“…We also showed that the antitumor effect of ß-elemene in non-small-cell lung cancer cells is mediated through induction of cell cycle arrest and apoptotic cell death (18). Furthermore, we demonstrated for the first time that ß-elemene markedly enhanced cisplatin-induced cytotoxicity in chemoresistant ovarian carcinoma cells (19). The effect and mechanism of ß-elemene in combination with other chemotherapeutic agents for malignancies are not elucidated, however, investigations have revealed differences in cell toxicity in vitro and side effects in vivo between ß-elemene and taxanes that suggest they may be suitable for use in combination.…”

β-elemene Induces Caspase-dependent Apoptosis in Human Glioma Cells in vitro through the Upregulation of Bax and Fas/FasL and Downregulation of Bcl-2

“…The antitumor effect of β-elemene has been shown in some types of tumor, but the mechanism remains unclear. It has been reported that beta-elemene arrests chemoresistant ovarian carcinoma at the G2-M phase and inhibits the proliferation of cells (Li et al, 2005). Other reported that β-elemene could induce apoptosis in prostate cancer cells and lung tumor cells (Li et al, 2009;.…”

“…β-elemene is the active component (molecular formula C15H24, molecular weight 204.34), which has strong anti-tumor effects in vitro and in vivo (Wang et al, 2005;Yu et al, 2011;Li et al, 2011). The antitumor capability of β-elemene has been shown to display various types of cancers, such as glioma, breast carcinoma, liver cancer, leukemia, laryngeal cancer and ovarian cancer .…”

ß-Elemene inhibits proliferation of human glioblastoma cells and causes cell-cycle G0/G1 arrest via mutually compensatory activation of MKK3 and MKK6

“…As the major active antitumor component, ß-elemene has been isolated as a monomeric drug and found to strongly induce apoptosis and antiproliferation in tumors or cells in vitro and in vivo (6)(7)(8)(9). The antitumor effect of ß-elemene has been demonstrated in the treatment of various tumors, such as glioma, liver cancer, breast carcinoma, leukemia, laryngeal cancer and ovarian cancer (7,(10)(11)(12).…”