Background: Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die from platinum (Pt) - resistant disease. Cisplatin resistance is associated with increased nucleotide excision repair (NER), decreased mismatch repair (MMR) and decreased platinum uptake. The objective of this study is to investigate how a novel combination of sodium arsenite (NaAsO2) and hyperthermia (43°C) affect mechanisms of cisplatin resistance in ovarian cancer. Methods: We established a murine model of metastatic EOC by intraperitoneal injection of A2780/CP70 human ovarian cancer cells into nude mice. We developed a murine hyperthermic intraperitoneal chemotherapy model to treat the mice. Mice with peritoneal metastasis were perfused for 1 h with 3 mg/kg cisplatin 26 mg/kg NaAsO2at 37 or 43°C. Tumors and tissues were collected at 0 and 24 h after treatment. Results: Western blot analysis of p53 and key NER proteins (ERCC1, XPC and XPA) and MMR protein (MSH2) suggested that cisplatin induced p53, XPC and XPA and suppressed MSH2 consistent with resistant phenotype. Hyperthermia suppressed cisplatin-induced XPC and prevented the induction of XPA by cisplatin, but it had no effect on Pt uptake or retention in tumors. NaAsO2prevented XPC induction by cisplatin; it maintained higher levels of MSH2 in tumors and enhanced initial accumulation of Pt in tumors. Combined NaAsO2and hyperthermia decreased cisplatin-induced XPC 24 h after perfusion, maintained higher levels of MSH2 in tumors and significantly increased initial accumulation of Pt in tumors. ERCC1 levels were generally low except for NaAsO 2co-treatment with cisplatin. Systemic Pt and arsenic accumulation for all treatment conditions were in the order: kidney > liver = spleen > heart > brain and liver > kidney = spleen > heart > brain respectively. Metal levels generally decreased in systemic tissues within 24 h after treatment. Conclusion: NaAsO2and/or hyperthermia have the potential to sensitize tumors to cisplatin by inhibiting NER, maintaining functional MMR and enhancing tumor platinum uptake.
|Journal||Journal of Ovarian Research|
|State||Published - 2011|
Bibliographical noteFunding Information:
This work was supported in part by the National Institutes of Health Grant P30ES014443 which supported the collection and analysis of data and the National Science Foundation’s Experimental Program to Stimulate Competitive Research Grant EPS-0447479 which provided the ICP-MS instrumentation and personnel support for the analysis of Pt and As reported in the manuscript. Also, the authors thank Dr. Richard Higashi for technical support with ICP-MS analyses and Dr. Huaiyu Zheng of the Brown Cancer Center Small Animal Imaging Facility for technical assistance with microCT scanning of mice.
- metastatic human ovarian cancer
- platinum accumulation
- sodium arsenite
ASJC Scopus subject areas
- Obstetrics and Gynecology