title: Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis.
abstract: Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53's tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.
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 Acupuncture, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Urology, First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, China.
authors.forename: Dayong
authors.initials: D
authors.lastname: Yao
authors.affiliation: Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Cao
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Xinjiang Key Laboratory of Plant Resources and Natural Products Chemistry, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang 830011, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Dou
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: Shan
authors.initials: S
authors.lastname: Guan
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: Huiyuan
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: Yang
authors.initials: Y
authors.lastname: Yu
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: Yongfeng
authors.initials: Y
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: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Roma
authors.initials: R
authors.lastname: Patel
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: Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Sanjeev A
authors.initials: SA
authors.lastname: Vasudevan
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
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jed G
authors.initials: JG
authors.lastname: Nuchtern
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D004151:Dipeptides / Q000008:administration & dosage* / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D004151:Dipeptides; C587624:GSK2830371; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004317:Doxorubicin; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human