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: Jason A Sprowl, Giuliano Ciarimboli, Cynthia S Lancaster, Hugh Giovinazzo, Alice A Gibson, Guoqing Du, Laura J Janke, Guido Cavaletti, Anthony F Shields, Alex Sparreboom
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 27 Pg. 11199-204 (Jul 02 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23776246 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Octamer Transcription Factor-1
• Organic Cation Transport Proteins
• Organic Cation Transporter 2
• Organoplatinum Compounds
• Pou2f1 protein, mouse
• SLC22A2 protein, human
• Slc22a2 protein, mouse
• Oxaliplatin

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, toxicity)
• Female
• Ganglia, Spinal (drug effects, metabolism)
• Humans
• Male
• Mice
• Mice, Knockout
• Neurotoxicity Syndromes (etiology, genetics, metabolism)
• Octamer Transcription Factor-1 (deficiency, genetics, physiology)
• Organic Cation Transport Proteins (deficiency, genetics, physiology)
• Organic Cation Transporter 2
• Organoplatinum Compounds (pharmacokinetics, toxicity)
• Oxaliplatin