title: Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions.
abstract: The use of the effective antineoplastic agent cisplatin is limited by its serious side effects, such as oto- and nephrotoxicity. Ototoxicity is a problem of special importance in children, because deafness hampers their language and psychosocial development. Recently, organic cation transporters (OCTs) were identified in vitro as cellular uptake mechanisms for cisplatin. In the present study, we investigated in an in vivo model the role of OCTs in the development of cisplatin oto- and nephrotoxicity. The functional effects of cisplatin treatment on kidney (24 hours excretion of glucose, water, and protein) and hearing (auditory brainstem response) were studied in wild-type and OCT1/2 double-knockout (KO) mice. No sign of ototoxicity and only mild nephrotoxicity were observed after cisplatin treatment of knockout mice. Comedication of wild-type mice with cisplatin and the organic cation cimetidine protected from ototoxicity and partly from nephrotoxicity. For the first time we showed that OCT2 is expressed in hair cells of the cochlea. Furthermore, cisplatin-sensitive cell lines from pediatric tumors showed no expression of mRNA for OCTs, indicating the feasibility of therapeutic approaches aimed to reduce cisplatin toxicities by competing OCT2-mediated cisplatin uptake in renal proximal tubular and cochlear hair cells. These findings are very important to establish chemotherapeutical protocols aimed to maximize the antineoplastic effect of cisplatin while reducing the risk of toxicities.
authors.affiliation: Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Domagkstr. 3a, 48149 Münster, Germany. gciari@uni-muenster.de
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ciarimboli
authors.forename: Dirk
authors.initials: D
authors.lastname: Deuster
authors.forename: Arne
authors.initials: A
authors.lastname: Knief
authors.forename: Michael
authors.initials: M
authors.lastname: Sperling
authors.forename: Michael
authors.initials: M
authors.lastname: Holtkamp
authors.forename: Bayram
authors.initials: B
authors.lastname: Edemir
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanvers-Kaminsky
authors.forename: Antoinette
authors.initials: A
authors.lastname: am Zehnhoff-Dinnesen
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.forename: Heribert
authors.initials: H
authors.lastname: Jürgens
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schlatter
mesh_terms: D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000079923:Copper Transporter 1; D004427:Ear Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D010984:Platinum / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D013316:Stria Vascularis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D020011:Protective Agents; C491012:Slc22a2 protein, mouse; C490077:Slc31a1 protein, mouse; D010984:Platinum; D005947:Glucose; D002945:Cisplatin