title: Sequential treatment with aurora B inhibitors enhances cisplatin-mediated apoptosis via c-Myc.
abstract: Platinum compound such as cisplatin is the first-line chemotherapy of choice in most patients with ovarian carcinoma. However, patients with inherent or acquired cisplatin resistance often experience relapse. Therefore, novel therapies are urgently required to treat drug-resistant ovarian carcinoma. Here, we showed that compared to the non-functional traditional simultaneous treatment, sequential combination of Aurora B inhibitors followed by cisplatin synergistically enhanced apoptotic response in cisplatin-resistant OVCAR-8 cells. This effect was accompanied by the induction of polyploidy in a c-Myc-dependent manner, as c-Myc knockdown reduced the efficacy of the combination by suppressing the expression of Aurora B and impairing cellular response to Aurora B inhibitor, as indicated by the decreased polyploidy and hyperphosphorylation of histone H1. In c-Myc-deficient SKOV3 cells, c-Myc overexpression restored Aurora B expression, induced polyploidy after inhibition of Aurora B, and sensitized cells to this combination therapy. Thus, our report reveals for the first time that sequential treatment of Aurora B inhibitors and cisplatin is essential to inhibit ovarian carcinoma by inducing polyploidy and downregulating c-Myc and that c-Myc is identified as a predictive biomarker to select cells responsive to chemotherapeutical combinations targeting Aurora B. Collectively, these studies provide novel approaches to overcoming cisplatin chemotherapy resistance in ovarian cancer.
  
  
  CONCLUSIONS
  Pretreatment of Aurora B inhibitors augment apoptotic effects of cisplatin. The synergy of Aurora B inhibitor with cisplatin is dependent on c-Myc expression. c-Myc-dependent induction of polyploidy sensitizes cells to cisplatin.
authors.affiliation: Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Ma
authors.forename: Handi
authors.initials: H
authors.lastname: Cao
authors.forename: Siyue
authors.initials: S
authors.lastname: Lou
authors.forename: Xuejing
authors.initials: X
authors.lastname: Shao
authors.forename: Wen
authors.initials: W
authors.lastname: Lv
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Qi
authors.forename: Yujia
authors.initials: Y
authors.lastname: Liu
authors.forename: Meidan
authors.initials: M
authors.lastname: Ying
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D006801:Humans; D010755:Organophosphates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000970:Antineoplastic Agents; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011799:Quinazolines; C576921:AURKB protein, human; D064107:Aurora Kinase B; D002945:Cisplatin