Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 27, Pages 11199-11204Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1305321110
Keywords
neuropathy; chemotherapy; solute carriers
Categories
Funding
- American Lebanese Syrian Associated Charities
- US Public Health Service Cancer Center [3P30CA021765]
- National Cancer Institute [5R01CA151633-01]
- Interdisciplinary Center for Clinical Research (IZKF) Munster [Cia2/013/13]
- Network Enabled Drug Design (NEDD) Lombardy Region grant
- National Institutes of Health [5 U42 RR006042]
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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.
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