title: Multiple CDK inhibitor dinaciclib suppresses neuroblastoma growth via inhibiting CDK2 and CDK9 activity.
abstract: Neuroblastoma (NB), the most common extracranial solid tumor of childhood, is responsible for approximately 15% of cancer-related mortality in children. Aberrant activation of cyclin-dependent kinases (CDKs) has been shown to contribute to tumor cell progression in many cancers including NB. Therefore, small molecule inhibitors of CDKs comprise a strategic option in cancer therapy. Here we show that a novel multiple-CDK inhibitor, dinaciclib (SCH727965, MK-7965), exhibits potent anti-proliferative effects on a panel of NB cell lines by blocking the activity of CDK2 and CDK9. Dinaciclib also significantly sensitized NB cell lines to the treatment of chemotherapeutic agents such as doxorubicin (Dox) and etoposide (VP-16). Furthermore, dinaciclib revealed in vivo antitumor efficacy in an orthotopic xenograft mouse model of two NB cell lines and blocked tumor development in the TH-MYCN transgenic NB mouse model. Taken together, this study suggests that CDK2 and CDK9 are potential therapeutic targets in NB and that abrogating CDK2 and CDK9 activity by small molecules like dinaciclib is a promising strategy and a treatment option for NB patients.
authors.affiliation: Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China.|Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Zhenghu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Breast Surgery, The second hospital of Jilin University, Changchun, Jilin 130041, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Pang
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|College of Public Health, Xinjiang Medical University, Urumqi 830011, China.
authors.forename: Shayahati
authors.initials: S
authors.lastname: Bieerkehazhi
authors.affiliation: Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China.|Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jiaxiong
authors.initials: J
authors.lastname: Lu
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Hu
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Yi
authors.affiliation: Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China.|Department of Stomatology, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003497:Cyclic N-Oxides; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007212:Indolizines; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011726:Pyridinium Compounds / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; C553669:dinaciclib; D004317:Doxorubicin; C495894:CDK2 protein, human; C467969:CDK9 protein, human; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9