title: Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Sprowl
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ciarimboli
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Lancaster
authors.forename: Hugh
authors.initials: H
authors.lastname: Giovinazzo
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.forename: Guoqing
authors.initials: G
authors.lastname: Du
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Janke
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Shields
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D050811:Octamer Transcription Factor-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D027701:Organic Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D000077150:Oxaliplatin
chemical_list: D000970:Antineoplastic Agents; D050811:Octamer Transcription Factor-1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds; C494166:Pou2f1 protein, mouse; C491013:SLC22A2 protein, human; C491012:Slc22a2 protein, mouse; D000077150:Oxaliplatin
keywords: chemotherapy; neuropathy; solute carriers