title: Circumvention of cisplatin resistance in ovarian cancer by combination of cyclosporin A and low-intensity ultrasound.
abstract: Cisplatin resistance is a challenge in the treatment of ovarian cancer. The aim of this study was to explore if ultrasound can overcome chemoresistance and enhance chemosensitization due to cyclosporin A. Ultrasound and/or cyclosporin A were employed to overcome cisplatin resistance in human ovarian cancer cell line COC1/DDP. Mechanisms were explored from the perspective of: DNA damage, intracellular platinum level, detoxification, and genes related to drug efflux and DNA repair. In vivo therapeutic efficacy was validated in a short-term model (subrenal cell-clot transplantation) in mice and the survival benefit was investigated in an orthotopic cancer model in mice using HO-8910PM cells. The findings were: (i) ultrasound enhanced the effect of cisplatin leading to a lower cell-survival rate (IC50 decreased from 3.19 to 0.35 μg/ml); (ii) ultrasound enhanced cisplatin via direct (increasing the intercellular level of active platinum) and indirect (decreasing the glutathione level, and expression of LRP and ERCC1 genes) mechanisms that intensified cisplatin-induced DNA damage, thus enhancing cell apoptosis and necrosis; (iii) cisplatin followed by ultrasound led to small tumor sizes in the short-term model without exacerbation of the systemic toxicity, and prolonged the survival times in the orthotopic model; and (iv) ultrasound synergized the sensitization due to cyclosporin A in vitro and in vivo. These data demonstrated that ultrasound combined with cyclosporin A overcame cisplatin resistance in ovarian cancer.
authors: Key Medical Laboratory of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: yutinghe@hotmail.com.
authors: Tinghe
authors: T
authors: Yu
authors: Key Medical Laboratory of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors: Yan
authors: Y
authors: Yang
authors: Key Medical Laboratory of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors: Jiao
authors: J
authors: Zhang
authors: Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, Chengdu, China.
authors: Haining
authors: H
authors: He
authors: Chongqing Institute for Food and Drug Control, Chongqing, China.
authors: Xueyi
authors: X
authors: Ren
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D001692:Biological Transport / Q000187:drug effects / Q000528:radiation effects; D001711:Biotransformation / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm / Q000528:radiation effects*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy; D011897:Random Allocation; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D014464:Ultrasonic Therapy; D000069453:Ultrasonic Waves; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D002945:Cisplatin
keywords: Chemosensitization; Cisplatin resistance; Cyclosporin A; Ovarian cancer; Survival; Ultrasound