title: Sequential combination therapy of ovarian cancer with cisplatin and γ-secretase inhibitor MK-0752.
abstract: OBJECTIVE
  Ovarian cancer is one of the most lethal of women cancers and lack potent therapeutic options. There have many evidences demonstrate the Notch signaling has deregulation in variety of human malignancies.MK-0752 is a novel potent γ-secretase inhibitor and now assessed in clinical trial for treatment of several types of cancer, our objective was to investigate the anticancer effects and mechanisms of MK-0752 alone or combined with cisplatin in ovarian cancer.
  
  
  METHODS
  Cell lines used: A2780, OVCAR3, SKOV3, HO8910PM, the effects of MK-0752 and cisplatin on cell proliferation were measured by MTT assay. The effect of combination treatment was examined by isobologram analysis. The distribution of cell cycle and cell apoptosis were analyzed using PI and Annexin V-FITC/PI staining by flow cytometric analysis. The mechanism in biochemistry was analyzed by using Western blot. Mouse xenograft model of A2780 was established to observe the anti-ovarian cancer effects in vivo setting, nude mice were randomized into four groups (n=6 per group) and treated every 4 days with control (solvent) group, MK-0752(25mg/kg) group, cisplatin (2mg/kg)group, combination group (both of MK-0752 and cisplatin).
  
  
  RESULTS
  MK-0752 alone actively induced cell growth inhibition, G2/M phase cell cycle arrest and apoptosis with down-regulation of Notch1 and its downstream effectors including Hes1, XIAP, c-Myc and MDM2 in a dose- and time-dependent manner. Moreover, sequential combination of cisplatin prior to MK-0752 significantly promoted cell apoptosis and inhibited the subcutaneous xenograft growth of ovarian cancer in nude mice.
  
  
  CONCLUSIONS
  Our data supports the sequential combination of cisplatin prior to MK-0752 is a highly promising novel experimental therapeutic strategy against ovarian cancer.
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: XiuXiu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: LiHua
authors.initials: L
authors.lastname: Gong
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: RongYing
authors.initials: R
authors.lastname: Ou
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: ZhenZhen
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: JinYan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: FengFeng
authors.initials: F
authors.lastname: Xie
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: XiaoXiu
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Cell Biology & 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 510632, China.
authors.forename: JianGe
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Cell Biology & 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 510632, China.
authors.forename: WenJi
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology & 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 510632, China.
authors.forename: QiWei
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Cell Biology & 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 510632, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Cell Biology & 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 510632, China. Electronic address: tshizhi@jnu.edu.cn.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: yxjbetter@126.com.
authors.forename: XiaoJian
authors.initials: X
authors.lastname: Yan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000627:therapeutic use*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011422:Propionates / Q000008:administration & dosage / Q000627:therapeutic use*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000627:therapeutic use*; D000072056:Transcription Factor HES-1; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D001555:Benzene Derivatives; D002945:Cisplatin; D018398:Homeodomain Proteins; D011422:Propionates; D051736:Proto-Oncogene Proteins c-mdm2; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D013450:Sulfones; D000072056:Transcription Factor HES-1; D051636:X-Linked Inhibitor of Apoptosis Protein; C554093:3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; C497761:NOTCH1 protein, human; C496866:XIAP protein, human; C078493:HES1 protein, human; C497206:MDM2 protein, human
keywords: Cisplatin; Combination therapy; MK-0752; Ovarian cancer