title: Triapine potentiates platinum-based combination therapy by disruption of homologous recombination repair.
abstract: BACKGROUND
  Platinum resistance may be attributable to inherent or acquired proficiency in homologous recombination repair (HRR) in epithelial ovarian cancer (EOC). The objective of this study was to evaluate the efficacy of the small molecule inhibitor triapine to disrupt HRR and sensitise BRCA wild-type EOC cells to platinum-based combination therapy in vitro and in vivo.
  
  
  METHODS
  The sensitivity of BRCA wild-type cancer cells to olaparib, cisplatin, carboplatin, doxorubicin, or etoposide in combination with triapine was evaluated by clonogenic survival assays. The effects of triapine on HRR activity in cells were measured with a DR-GFP reporter assay. The ability of triapine to enhance the effects of the carboplatin-doxil combination on EOC tumour growth delay was determined using a xenograft tumour mouse model.
  
  
  RESULTS
  Platinum resistance is associated with wild-type BRCA status. Triapine inhibits HRR activity and enhances the sensitivity of BRCA wild-type cancer cells to cisplatin, olaparib, and doxorubicin. However, sequential combination of triapine and cisplatin is necessary to achieve synergism. Moreover, triapine potentiates platinum-based combination therapy against BRCA wild-type EOC cells and produces significant delay of EOC tumour growth.
  
  
  CONCLUSIONS
  Triapine promises to augment the clinical efficacy of platinum-based combination regimens for treatment of platinum-resistant EOC with wild-type BRCA and proficient HRR activity.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Elena S
authors.initials: ES
authors.lastname: Ratner
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Yong-Lian
authors.initials: YL
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Penketh
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Berenblum
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Whicker
authors.affiliation: Department of Pathology, New Haven, CT, USA.
authors.forename: Pamela H
authors.initials: PH
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Yashang
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Ishiguro
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Sartorelli
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Z Ping
authors.initials: ZP
authors.lastname: Lin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage; D000077216:Carcinoma, Ovarian Epithelial; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage; D059767:Recombinational DNA Repair / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D010793:Phthalazines; D010879:Piperazines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D016190:Carboplatin; D002945:Cisplatin; C531550:olaparib