title: YM155 sensitizes ovarian cancer cells to cisplatin inducing apoptosis and tumor regression.
abstract: OBJECTIVE
  The objective of this study is to chemosensitize ovarian cancer (OVCa) cells to cisplatin (CDDP) using an inhibitor of Survivin, YM155. The efficacy of YM155 in combination with CDDP was determined in vitro, ex vivo and in vivo.
  
  
  METHODS
  Human OVCa cell lines A2780p and their cisplatin-resistant derivative A2780cis, were treated with CDDP, YM155, and the combined treatment (YM155+CDDP), and cell viability, mRNA and protein expression levels, cell-cycle distribution, and DNA damage were then evaluated. Furthermore, the efficacy of YM155 combined with CDDP was further examined in established primary cell cultures and xenograft models.
  
  
  RESULTS
  The combination of YM155 with CDDP induced G2/M cell cycle arrest and apoptosis, increased DNA damage, and decreased Survivin levels, especially in A2780cis CDDP-resistant cells. Additionally, YM155 in combination with CDDP sensitized primary cell cultures to CDDP. Studies in vivo showed how this combination significantly decreased the tumor size of OVCa xenografts.
  
  
  CONCLUSIONS
  Our results demonstrate that in OVCa cells the expression of Survivin did not affect their sensitivity to YM155, suggesting that Survivin was not the only target of YM155. The combination of YM155 with CDDP could be a good option for therapy of CDDP-resistant OVCa, independently of p53 status.
authors.affiliation: Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Mir
authors.affiliation: Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Stanzani
authors.affiliation: Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain; Department of Basic Nursing, School of Nursing of the Health Campus of Bellvitge, Universitat de Barcelona, IDIBELL, Spain.
authors.forename: Fina
authors.initials: F
authors.lastname: Martinez-Soler
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, IDIBELL, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Department of Pathology, Hospital de Bellvitge, Department of Pathology and Experimental Therapeutics, Universitat de Barcelona, IDIBELL, Spain.
authors.forename: August
authors.initials: A
authors.lastname: Vidal
authors.affiliation: Department of Pathology, Hospital de Bellvitge, Department of Pathology and Experimental Therapeutics, Universitat de Barcelona, IDIBELL, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Condom
authors.affiliation: Department of Gynecology, Hospital de Bellvitge, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ponce
authors.affiliation: Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Gil
authors.affiliation: Department of Basic Nursing, School of Nursing of the Health Campus of Bellvitge, Universitat de Barcelona, IDIBELL, Spain. Electronic address: atortosa@ub.edu.
authors.forename: Avelina
authors.initials: A
authors.lastname: Tortosa
authors.affiliation: Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain. Electronic address: pgimenez@ub.edu.
authors.forename: Pepita
authors.initials: P
authors.lastname: Giménez-Bonafé
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D018450:Disease Progression; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D009285:Naphthoquinones / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; D002945:Cisplatin; C523798:sepantronium
keywords: AnV; Annexin V; Apoptosis; CDDP; CI; Chemoresistance; Cisplatin; DSB; EOC; FBS; IAP; IP; LASC; MLPA; OVCa; Ovarian cancer; PBS; Propidium iodide; QVD; RT-PCR; Real time polymerase chain reaction; Survivin; YM155; ascites; caspase inhibitor Q-VD-Oph; cisplatin; combination index; double-strand breaks; epithelial ovarian cancer; fetal bovine serum; h; hour; inhibitor of apoptosis protein; multiplex ligation-dependent probe amplification; ovarian cancer; phosphate-buffered saline