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.
Keywords:
chemotherapy; neuropathy; solute carriers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / toxicity
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Female
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / metabolism
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Humans
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Male
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Mice
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Mice, Knockout
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Neurotoxicity Syndromes / etiology*
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Neurotoxicity Syndromes / genetics
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Neurotoxicity Syndromes / metabolism*
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Octamer Transcription Factor-1 / deficiency
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Octamer Transcription Factor-1 / genetics
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Octamer Transcription Factor-1 / physiology
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Organic Cation Transport Proteins / deficiency
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Organic Cation Transport Proteins / genetics
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Organic Cation Transport Proteins / physiology*
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Organic Cation Transporter 2
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Organoplatinum Compounds / pharmacokinetics
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Organoplatinum Compounds / toxicity*
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Oxaliplatin
Substances
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Antineoplastic Agents
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Octamer Transcription Factor-1
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Organic Cation Transport Proteins
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Organic Cation Transporter 2
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Organoplatinum Compounds
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Pou2f1 protein, mouse
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SLC22A2 protein, human
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Slc22a2 protein, mouse
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Oxaliplatin