Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 27; pp. 11199 - 11204
• Main Authors: Sprowl, Jason A., Ciarimboli, Giuliano, Lancaster, Cynthia S., Giovinazzo, Hugh, Gibson, Alice A., Du, Guoqing, Janke, Laura J., Cavaletti, Guido, Shields, Anthony F., Sparreboom, Alex
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.07.2013; National Acad Sciences
• Subjects: Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - toxicity; ATP binding cassette transporters; Biological Sciences; Cancer therapies; Cytotoxicity; Deoxyribonucleic acid; DNA; Dosage; Drug carriers; Female; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Gene loci; Genetics; HEK293 cells; Humans; Male; Male animals; Mice; Mice, Knockout; Neurotoxicity; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - genetics; Neurotoxicity Syndromes - metabolism; Octamer Transcription Factor-1 - deficiency; Octamer Transcription Factor-1 - genetics; Octamer Transcription Factor-1 - physiology; Organic Cation Transport Proteins - deficiency; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - physiology; Organic Cation Transporter 2; Organoplatinum Compounds - pharmacokinetics; Organoplatinum Compounds - toxicity; Pharmacology; Platinum; Solutes; Spinal ganglia; neuropathy; chemotherapy; solute carriers
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1305321110

Oxaliplatin is an integral component of colorectal cancer therapy, but its clinical use is associated with a dose-limiting peripheral neurotoxicity. We found that the organic cation transporter 2 (OCT2) is expressed on dorsal root ganglia cells within the nervous system where oxaliplatin is known to accumulate. Cellular uptake of oxaliplatin was increased by 16- to 35-fold in cells overexpressing mouse Oct2 or human OCT2, and this process was associated with increased DNA platination and oxaliplatin-induced cytotoxicity. Furthermore, genetic or pharmacologic knockout of Oct2 protected mice from hypersensitivity to cold or mechanical-induced allodynia, which are established tests to assess acute oxaliplatin-induced neurotoxicity. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity.