title: LY2109761 enhances cisplatin antitumor activity in ovarian cancer cells.
abstract: OBJECTIVE
  Ovarian cancer is among the most lethal of all malignancies in women. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. Because transforming growth factor-beta (TGF-β) could increase survival of ovarian cancer cells in the presence of cisplatin, we conducted a preclinical study of the antitumor effects of the TGF-β type I (TβRI) and type II (TβRII) kinase inhibitor LY2109761 in combination with cisplatin.
  
  
  METHODS
  SKOV3, OV-90 and SKOV3(DDP) cells were treated with LY2109761, and/or cisplatin, and cell viability, apoptosis mRNA and protein expression levels were then evaluated. Furthermore, the efficacy of LY2109761 combined with cisplatin was further examined in established xenograft models.
  
  
  RESULTS
  LY2109761 was sufficient to induce spontaneous apoptosis of ovarian cancer cells. Combination with LY2109761 significantly augmented the cytotoxicity of cisplatin in both parental and cisplatin resistant ovarian cancer cells. LY2109761 significantly increased apoptotic cell death in cisplatin-resistant cells. Combination treatment of LY2109761 and cisplatin showed antiproliferative effects and induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression in established parental and cisplatin resistant ovarian cancer xenograft models.
  
  
  CONCLUSIONS
  Chemotherapeutic approaches using LY2109761 might enhance the treatment benefit of the cisplatin in the treatment of ovarian cancer patients.
authors.affiliation: Department of Diagnostic Ultrasound, The Affiliated Hospital of Qingdao University Qingdao, China.
authors.forename: Yuxiu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Obstetrics, People's Hospital of Rizhao Rizhao, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Shan
authors.affiliation: Department of Diagnostic Ultrasound, The Affiliated Hospital of Qingdao University Qingdao, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Diagnostic Ultrasound, The Affiliated Hospital of Qingdao University Qingdao, China.
authors.forename: Yunhai
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Diagnostic Ultrasound, The Affiliated Hospital of Qingdao University Qingdao, China.
authors.forename: Fuliang
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Clinical Laboratory, The Affiliated Hospital of Weifang Medical Colloge Weifang, China.
authors.forename: Jiacun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Clinical Laboratory, The Affiliated Hospital of Weifang Medical Colloge Weifang, China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Clinical Laboratory, The Affiliated Hospital of Weifang Medical Colloge Weifang, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Diagnostic Ultrasound, The Affiliated Hospital of Qingdao University Qingdao, China.
authors.forename: Zhengjun
authors.initials: Z
authors.lastname: Yi
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C530108:LY2109761; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011758:Pyrroles; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D002945:Cisplatin
keywords: LY2109761; Ovarian cancer; chemotherapy; transforming growth factor-beta