Chen Xiu-Xiu, Xie Feng-Feng, Zhu Xiu-Jie, Lin Feng, Pan Shi-Shi, Gong Li-Hua, Qiu Jian-Ge, Zhang Wen-Ji, Jiang Qi-Wei, Mei Xiao-Long, Xue You-Qiu, Qin Wu-Ming, Shi Zhi, Yan Xiao-Jian
Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China.
Oncotarget. 2015 Jun 20;6(17):14926-39. doi: 10.18632/oncotarget.3717.
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.
卵巢癌是最致命的女性癌症之一,目前其临床治疗效果并不理想。地西他滨,一种新型的CDK1、CDK2、CDK5和CDK9小分子抑制剂,正在进行治疗几种癌症的临床试验评估。在本研究中,我们研究了地西他滨单独或与顺铂联合应用于卵巢癌的抗癌作用及机制。单独使用地西他滨可通过增加细胞内ROS水平,积极诱导细胞生长抑制、细胞周期阻滞和细胞凋亡,同时伴随着相关蛋白如CDKs、细胞周期蛋白、Mcl-1、XIAP和survivin的明显变化。用N-乙酰-L-半胱氨酸预处理可显著阻断ROS生成,但仅部分挽救地西他滨触发的细胞凋亡。此外,地西他滨与顺铂联合应用可协同促进细胞周期阻滞和细胞凋亡,并抑制裸鼠卵巢癌皮下异种移植物的生长。总之,在地西他滨在卵巢癌的临床前模型中与顺铂有强大的协同作用,表明这种有益的联合治疗可能是治疗卵巢癌的一种有前景的策略。