Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions.
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.
Ciarimboli
Giuliano
G
Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Domagkstr. 3a, 48149 Münster, Germany. gciari@uni-muenster.de
Deuster
Dirk
D
Knief
Arne
A
Sperling
Michael
M
Holtkamp
Michael
M
Edemir
Bayram
B
Pavenstädt
Hermann
H
Lanvers-Kaminsky
Claudia
C
am Zehnhoff-Dinnesen
Antoinette
A
Schinkel
Alfred H
AH
Koepsell
Hermann
H
Jürgens
Heribert
H
Schlatter
Eberhard
E
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
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