title: Suramin protects from cisplatin-induced acute kidney injury.
abstract: Cisplatin, a commonly used cancer chemotherapeutic, has a dose-limiting side effect of nephrotoxicity. Approximately 30% of patients administered cisplatin suffer from kidney injury, and there are limited treatment options for the treatment of cisplatin-induced kidney injury. Suramin, which is Federal Drug Administration-approved for the treatment of trypanosomiasis, improves kidney function after various forms of kidney injury in rodent models. We hypothesized that suramin would attenuate cisplatin-induced kidney injury. Suramin treatment before cisplatin administration reduced cisplatin-induced decreases in kidney function and injury. Furthermore, suramin attenuated cisplatin-induced expression of inflammatory cytokines and chemokines, endoplasmic reticulum stress, and apoptosis in the kidney cortex. Treatment of mice with suramin 24 h after cisplatin also improved kidney function, suggesting that the mechanism of protection is not by inhibition of tubular cisplatin uptake or its metabolism to nephrotoxic species. If suramin is to be used in the context of cancer, then it cannot prevent cisplatin-induced cytotoxicity of cancer cells. Suramin did not alter the dose-response curve of cisplatin in lung adenocarcinoma cells in vitro. In addition, suramin pretreatment of mice harboring lung adenocarcinomas did not alter the initial cytotoxic effects of cisplatin (DNA damage and apoptosis) on tumor cells. These results provide evidence that suramin has potential as a renoprotective agent for the treatment/prevention of cisplatin-induced acute kidney injury and justify future long-term preclinical studies using cotreatment of suramin and cisplatin in mouse models of cancer.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Tess V
authors.initials: TV
authors.lastname: Dupre
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Mark A
authors.initials: MA
authors.lastname: Doll
authors.affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky;
authors.forename: Parag P
authors.initials: PP
authors.lastname: Shah
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Cierra N
authors.initials: CN
authors.lastname: Sharp
authors.affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky;
authors.forename: Alex
authors.initials: A
authors.lastname: Kiefer
authors.affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky;
authors.forename: Michael T
authors.initials: MT
authors.lastname: Scherzer
authors.affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky;
authors.forename: Kumar
authors.initials: K
authors.lastname: Saurabh
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Doug
authors.initials: D
authors.lastname: Saforo
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Deanna
authors.initials: D
authors.lastname: Siow
authors.affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky;
authors.forename: Lavona
authors.initials: L
authors.lastname: Casson
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Arteel
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky;
authors.forename: Alfred Bennett
authors.initials: AB
authors.lastname: Jenson
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas and Veterans Healthcare System, Little Rock, Arkansas; and.
authors.forename: Judit
authors.initials: J
authors.lastname: Megyesi
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina.
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; Department of Medicine, University of Louisville, Louisville, Kentucky; James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky;
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Beverly
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky; leah.siskind@louisville.edu.
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Siskind
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D002945:Cisplatin; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection; D004249:DNA Damage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020011:Protective Agents / Q000494:pharmacology*; D013498:Suramin / Q000494:pharmacology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D020011:Protective Agents; D013498:Suramin; D002945:Cisplatin
keywords: acute kidney injury; cisplatin; renoprotective strategies; suramin