Sodium arsenite and hyperthermia modulate cisplatin-DNA damage responses and enhance platinum accumulation in murine metastatic ovarian cancer xenograft after hyperthermic intraperitoneal chemotherapy (HIPEC)

Journal of Ovarian Research

J Christopher States¹  C William Helm²  Teresa W Fan¹  Joshua H Masters³  Vanessa A States³  Clarisse S Muenyi³ 

[1] James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40292, USA;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, St. Louis University School of Medicine, St Louis, MO 63117, USA;Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40292, USA

关键词: platinum accumulation;    MSH2;    XPC;    XPA;    p53;    metastatic human ovarian cancer;    HIPEC;    hyperthermia;    sodium arsenite;    cisplatin;   

Others  :  824525
DOI  :  10.1186/1757-2215-4-9

 received in 2011-05-13, accepted in 2011-06-22,  发布年份 2011

【 摘 要 】

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 NaAsO₂ at 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. NaAsO₂ prevented XPC induction by cisplatin; it maintained higher levels of MSH2 in tumors and enhanced initial accumulation of Pt in tumors. Combined NaAsO₂ and 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 NaAsO₂ co-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

NaAsO₂ and/or hyperthermia have the potential to sensitize tumors to cisplatin by inhibiting NER, maintaining functional MMR and enhancing tumor platinum uptake.

【 授权许可】

   
2011 Muenyi et al; licensee BioMed Central Ltd.

【 图 表 】

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