1. OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity
- Author
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Guido Cavaletti, Jason A. Sprowl, Alix F. Leblanc, Kevin M. Huang, Alice A. Gibson, Alex Sparreboom, Vamsi Chodisetty, Paola Alberti, Alessia Chiorazzi, Peter de Bruijn, Olivia Costa, Shuiying Hu, Tatiana Florea, W. David Arnold, Maryam B. Lustberg, Ron H.J. Mathijssen, Marissa S. Pioso, Mingqing Chen, Kristen W. Hong, Raquel E. Reinbolt, Lara E. Sucheston-Campbell, Leblanc, A, Sprowl, J, Alberti, P, Chiorazzi, A, Arnold, W, Gibson, A, Hong, K, Pioso, M, Chen, M, Huang, K, Chodisetty, V, Costa, O, Florea, T, de Bruijn, P, Mathijssen, R, Reinbolt, R, Lustberg, M, Sucheston-Campbell, L, Cavaletti, G, Sparreboom, A, Hu, S, and Medical Oncology
- Subjects
0301 basic medicine ,Genotype ,Paclitaxel ,medicine.drug_class ,Organic Anion Transporters ,Antineoplastic Agents ,Mice, Transgenic ,Pharmacology ,Tyrosine-kinase inhibitor ,Inhibitory Concentration 50 ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Mediator ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Mice, Knockout ,Liver-Specific Organic Anion Transporter 1 ,Chemistry ,paclitaxel neurotoxicity, OATP1B2 deficiency, animal models ,Neurotoxicity ,Peripheral Nervous System Diseases ,General Medicine ,medicine.disease ,Solute carrier family ,HEK293 Cells ,Phenotype ,Pyrimidines ,030104 developmental biology ,Allodynia ,Nilotinib ,Hyperalgesia ,Mice, Inbred DBA ,030220 oncology & carcinogenesis ,MCF-7 Cells ,medicine.symptom ,Biomarkers ,Function (biology) ,Research Article ,medicine.drug - Abstract
Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion-transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.
- Published
- 2018