Saikosaponin-d, a calcium mobilizing agent, sensitizes chemoresistant ovarian cancer cells to cisplatin-induced apoptosis by facilitating mitochondrial fission and G2/M arrest.
Saikosaponin-d, a calcium mobilizing agent, sensitizes chemoresistant ovarian cancer cells to cisplatin-induced apoptosis by facilitating mitochondrial fission and G2/M arrest.
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DOI：
10.18632/oncotarget.21076
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发表时间：
2017-11-21
期刊：
影响因子：
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通讯作者：
Tsang BK
中科院分区：
文献类型：
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作者：
Tsuyoshi H;Wong VKW;Han Y;Orisaka M;Yoshida Y;Tsang BK
顺铂(CDDP)及其衍生物是治疗卵巢癌的一线抗癌药物。然而，P53基因突变的高发生率导致化疗耐药，导致临床预后不良。柴胡皂苷-d(SSD)是一种从草本植物提取物中提取的皂苷，已被证明可诱导细胞死亡，并使化疗耐药细胞对化疗药物敏感。在这里，我们证明了SSD增敏化疗耐药的OVCA细胞与P53-wt，-突变和-空的顺铂。SSD的作用可能是通过诱导线粒体断裂和G2/M期阻滞来实现的。SSD通过钙信号、线粒体分裂蛋白Dynamin-Related Protein 1(Drp1)和视神经萎缩1(OPA1)的上调以及线粒体膜电位(Mp)的丧失来介导。此外，在CDDP存在的情况下，SSD还下调蛋白磷酸酶镁依赖的1D(PPM1D)，增加检查点蛋白激酶(Chk)1、细胞分裂周期25c(CDc25c)和细胞周期蛋白依赖的激酶1(CDk1)的磷酸化。我们的研究结果表明，SSD可能通过多个信号通路使OVCA对CDDP增敏，而不依赖于P53状态。他们支持SSD可能是治疗化疗耐药OVCA的一种新的佐剂的观点。
Cisplatin (CDDP) and its derivatives are first line anti-cancer drugs for ovarian cancer (OVCA). However, chemoresistance due to high incidence of p53 mutations leads to poor clinical prognosis. Saikosaponin-d (Ssd), a saponin from a herbal plant extract, has been shown to induce cell death and sensitize chemoresistant cells to chemotherapeutic agents. Here, we demonstrated that Ssd sensitized chemoresistant OVCA cells with either p53-wt, -mutant and -null to CDDP. The action of Ssd appears to be through induction of mitochondrial fragmentation and G2/M arrest. Ssd is mediated via calcium signaling, up-regulation of the mitochondrial fission proteins Dynamin-related protein 1 (Drp1) and optic atrophy 1 (Opa1), and loss in mitochondrial membrane potential (MMP). Moreover, in the presence of CDDP, Ssd also down-regulates protein phosphatase magnesium-dependent 1 D (PPM1D) and increases the phosphorylation of checkpoint protein kinases (Chk) 1, cell division cycle 25c (Cdc25c) and Cyclin dependent kinase 1 (Cdk1). Our findings suggest that Ssd could sensitize OVCA to CDDP independent of the p53 status through multiple signaling pathways. They support the notion that Ssd may be a novel adjuvant for the treatment of chemoresistant OVCA.