Sodium Arsenite ± Hyperthermia Sensitizes p53-Expressing Human Ovarian Cancer Cells to Cisplatin by Modulating Platinum-DNA Damage Responses
| Autor: | Guy N. Brock, C. William Helm, Teresa W.-M. Fan, Clarisse S. Muenyi, Allan R. Pinhas, J. Christopher States |
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| Rok vydání: | 2012 |
| Předmět: |
Hyperthermia
Small interfering RNA Sodium arsenite endocrine system diseases Genetic Toxicology Arsenites Cell Survival DNA damage Antineoplastic Agents Biology Transfection Toxicology chemistry.chemical_compound Cell Line Tumor DNA Repair Protein medicine Humans RNA Small Interfering Ovarian Neoplasms Cisplatin Hyperthermia Induced medicine.disease Sodium Compounds Molecular biology female genital diseases and pregnancy complications DNA-Binding Proteins chemistry Drug Resistance Neoplasm Cell culture Drug Therapy Combination Female Drug Screening Assays Antitumor Tumor Suppressor Protein p53 DNA Damage medicine.drug |
| Zdroj: | Toxicological Sciences. 127:139-149 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfs085 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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