Cyclin-dependent kinase inhibitor dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer.
Cyclin-dependent kinase inhibitor dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer.
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细胞周期蛋白依赖性激酶抑制剂 dinaciclib 在卵巢癌临床前模型中与顺铂具有有效协同作用
DOI：
10.18632/oncotarget.3717
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发表时间：
2015-06-20
期刊：
影响因子：
--
通讯作者：
Yan XJ
中科院分区：
文献类型：
--
作者：
Chen XX;Xie FF;Zhu XJ;Lin F;Pan SS;Gong LH;Qiu JG;Zhang WJ;Jiang QW;Mei XL;Xue YQ;Qin WM;Shi Z;Yan XJ
卵巢癌是最致命的女性癌症之一，目前临床治疗效果不理想。Dinaciclib是一种新的CDK1、CDK2、CDK5和CDK9小分子抑制剂，在临床试验中用于治疗几种类型的癌症。在本研究中，我们探讨了地那西尼单用或联合顺铂治疗卵巢癌的抗癌作用及机制。单用Dinaciclib可积极诱导细胞生长抑制、细胞周期阻滞和凋亡，细胞内ROS水平升高，并伴有CDKs、Cyclins、Mcl-1、XIAP、survivin等相关蛋白的明显改变。n -乙酰- l -半胱氨酸预处理可显著阻断ROS的生成，但只能部分挽救地那西利触发的细胞凋亡。此外，地那西布与顺铂联用可协同促进细胞周期阻滞和细胞凋亡，抑制裸鼠卵巢癌皮下异种移植物生长。总之，在卵巢癌的临床前模型中，dinaciclib与顺铂有明显的协同作用，表明这种有益的联合治疗可能是一种很有前景的卵巢癌治疗策略。
Ovarian cancer is one of the most lethal of woman cancers, and its clinical therapeutic outcome currently is unsatisfied. Dinaciclib, a novel small molecule inhibitor of CDK1, CDK2, CDK5 and CDK9, is assessed in clinical trials for the treatment of several types of cancers. In this study, we investigated the anticancer effects and mechanisms of dinaciclib alone or combined with cisplatin in ovarian cancer. Dinaciclib alone actively induced cell growth inhibition, cell cycle arrest and apoptosis with the increased intracellular ROS levels, which were accompanied by obvious alterations of related proteins such as CDKs, Cyclins, Mcl-1, XIAP and survivin. Pretreatment with N-acety-L-cysteine significantly blocked ROS generation but only partially rescued apoptosis triggered by dinaciclib. Moreover, the combination of dinaciclib with cisplatin synergistically promoted cell cycle arrest and apoptosis, and inhibited the subcutaneous xenograft growth of ovarian cancer in nude mice. Altogether, dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer, indicating this beneficial combinational therapy may be a promising strategy for treatment of ovarian cancer.