title: Sodium arsenite ± hyperthermia sensitizes p53-expressing human ovarian cancer cells to cisplatin by modulating platinum-DNA damage responses.
abstract: Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20μM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40292, USA.
authors.forename: Clarisse S
authors.initials: CS
authors.lastname: Muenyi
authors.forename: Allan R
authors.initials: AR
authors.lastname: Pinhas
authors.forename: Teresa W
authors.initials: TW
authors.lastname: Fan
authors.forename: Guy N
authors.initials: GN
authors.lastname: Brock
authors.forename: C William
authors.initials: CW
authors.lastname: Helm
authors.forename: J Christopher
authors.initials: JC
authors.lastname: States
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018053:Arsenites / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D017670:Sodium Compounds / Q000494:pharmacology*; D014162:Transfection / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018053:Arsenites; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D017670:Sodium Compounds; D016159:Tumor Suppressor Protein p53; C086984:XPC protein, human; C017947:sodium arsenite; D002945:Cisplatin