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

• Published in: Oncotarget 2015-06, Vol.6 (17), p.14926-14939
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cisplatin - administration & dosage; Cisplatin - pharmacology; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - metabolism; Drug Synergism; Female; HEK293 Cells; Humans; Inhibitory Concentration 50; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Pyridinium Compounds - administration & dosage; Pyridinium Compounds - pharmacology; Reactive Oxygen Species - metabolism; Research Paper; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• 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.