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

Leblanc, A., Sprowl, J., Alberti, P., Chiorazzi, A., Arnold, W., Gibson, A., et al. (2018). OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity. THE JOURNAL OF CLINICAL INVESTIGATION, 128(2), 816-825 [10.1172/JCI96160].

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Alberti, Paola;Chiorazzi, Alessia;Cavaletti, Guido;
2018

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
Articolo in rivista - Articolo scientifico
paclitaxel neurotoxicity, OATP1B2 deficiency, animal models
English
2018
128
2
816
825
reserved
Leblanc, A., Sprowl, J., Alberti, P., Chiorazzi, A., Arnold, W., Gibson, A., et al. (2018). OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity. THE JOURNAL OF CLINICAL INVESTIGATION, 128(2), 816-825 [10.1172/JCI96160].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/180374
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