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Identification of OAT1/OAT3 as Contributors to Cisplatin Toxicity.
Hu, S; Leblanc, A F; Gibson, A A; Hong, K W; Kim, J Y; Janke, L J; Li, L; Vasilyeva, A; Finkelstein, D B; Sprowl, J A; Sweet, D H; Schlatter, E; Ciarimboli, G; Schellens, Jhm; Baker, S D; Pabla, N; Sparreboom, A.
Afiliación
  • Hu S; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
  • Leblanc AF; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
  • Gibson AA; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
  • Hong KW; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
  • Kim JY; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
  • Janke LJ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • Li L; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • Vasilyeva A; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • Finkelstein DB; Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • Sprowl JA; Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D'Youville College, Buffalo, New York, USA.
  • Sweet DH; Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA.
  • Schlatter E; Medical Clinic D, Experimental Nephrology, Münster Medical Faculty, Münster, Germany.
  • Ciarimboli G; Medical Clinic D, Experimental Nephrology, Münster Medical Faculty, Münster, Germany.
  • Schellens J; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Baker SD; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
  • Pabla N; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
  • Sparreboom A; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
Clin Transl Sci ; 10(5): 412-420, 2017 Sep.
Article en En | MEDLINE | ID: mdl-28689374
Cisplatin is among the most widely used anticancer drugs and known to cause a dose-limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2-independent pathway of cisplatin-induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter-deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin. The function of these two transport systems can be simultaneously inhibited by the tyrosine kinase inhibitor nilotinib through noncompetitive mechanisms, without compromising the anticancer properties of cisplatin. Collectively, our findings reveal a novel pathway that explains the fundamental basis of cisplatin-induced nephrotoxicity, with potential implications for its therapeutic management.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cisplatino / Transportadores de Anión Orgánico Sodio-Independiente / Proteína 1 de Transporte de Anión Orgánico Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Clin Transl Sci Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cisplatino / Transportadores de Anión Orgánico Sodio-Independiente / Proteína 1 de Transporte de Anión Orgánico Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Clin Transl Sci Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos