title: Cyclin-dependent kinase inhibitor dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer.
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.
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiu-Xiu
authors.initials: XX
authors.lastname: Chen
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Feng-Feng
authors.initials: FF
authors.lastname: Xie
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiu-Jie
authors.initials: XJ
authors.lastname: Zhu
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Shi-Shi
authors.initials: SS
authors.lastname: Pan
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Gong
authors.affiliation: 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.
authors.forename: Jian-Ge
authors.initials: JG
authors.lastname: Qiu
authors.affiliation: 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.
authors.forename: Wen-Ji
authors.initials: WJ
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Qi-Wei
authors.initials: QW
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Mei
authors.affiliation: 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.
authors.forename: You-Qiu
authors.initials: YQ
authors.lastname: Xue
authors.affiliation: 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.
authors.forename: Wu-Ming
authors.initials: WM
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Yan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007212:Indolizines; D020128:Inhibitory Concentration 50; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D011726:Pyridinium Compounds; D017382:Reactive Oxygen Species; C553669:dinaciclib; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin
keywords: cisplatin; combination therapy; dinaciclib; ovarian cancer