Cyclin-dependent kinase inhibitor dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer

Abstract

// Xiu-Xiu Chen 1,* , Feng-Feng Xie 1,* , Xiu-Jie Zhu 1 , Feng Lin 1 , Shi-Shi Pan 1 , Li-Hua Gong 1 , Jian-Ge Qiu 2 , Wen-Ji Zhang 2 , Qi-Wei Jiang 2 , Xiao-Long Mei 2 , You-Qiu Xue 2 , Wu-Ming Qin 2 , Zhi Shi 2  and Xiao-Jian Yan 1 1 Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 2 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 * These authors have contributed equally to this work Correspondence to: Zhi Shi, email: // Xiao-Jian Yan, email: // Keywords : ovarian cancer, dinaciclib, cisplatin, combination therapy Received : January 23, 2015 Accepted : March 05, 2015 Published : March 30, 2015 Abstract 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.