OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity
Alix F. Leblanc, Jason A. Sprowl, Paola Alberti, Alessia Chiorazzi, W. David Arnold, Alice A. Gibson, Kristen W. Hong, Marissa S. Pioso, Mingqing Chen, Kevin M. Huang, Vamsi Chodisetty, Olivia Costa, Tatiana Florea, Peter de Bruijn, Ron H. Mathijssen, Raquel E. Reinbolt, Maryam B. Lustberg, Lara E. Sucheston-Campbell, Guido Cavaletti, Alex Sparreboom, Shuiying Hu
Alix F. Leblanc, Jason A. Sprowl, Paola Alberti, Alessia Chiorazzi, W. David Arnold, Alice A. Gibson, Kristen W. Hong, Marissa S. Pioso, Mingqing Chen, Kevin M. Huang, Vamsi Chodisetty, Olivia Costa, Tatiana Florea, Peter de Bruijn, Ron H. Mathijssen, Raquel E. Reinbolt, Maryam B. Lustberg, Lara E. Sucheston-Campbell, Guido Cavaletti, Alex Sparreboom, Shuiying Hu
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Concise Communication Oncology

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

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.

Authors

Alix F. Leblanc, Jason A. Sprowl, Paola Alberti, Alessia Chiorazzi, W. David Arnold, Alice A. Gibson, Kristen W. Hong, Marissa S. Pioso, Mingqing Chen, Kevin M. Huang, Vamsi Chodisetty, Olivia Costa, Tatiana Florea, Peter de Bruijn, Ron H. Mathijssen, Raquel E. Reinbolt, Maryam B. Lustberg, Lara E. Sucheston-Campbell, Guido Cavaletti, Alex Sparreboom, Shuiying Hu

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Figure 3

Inhibition of OATP1B-type transporters by nilotinib.

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Inhibition of OATP1B-type transporters by nilotinib. Inhibition of OATP1...
Inhibition of OATP1B1 function by tyrosine kinase inhibitors (TKIs) in vitro (10 μM; 15-minute preincubation), using 8-(2-[fluoresceinyl]-aminoethylthio)-adenosine-3′,5′-cyclic monophosphate (8Fc-A) (A) and estradiol-17β-D-glucuronide (E2G) (B) as OATP1B1 substrates in transfected HEK293 cells. (C) Concentration-dependent inhibition of OATP1B1 function by nilotinib using 8Fc-A (2 μM; 15-minute uptake) as a substrate. Inhibition of OATP1B3 (D) and OATP1B2 (E) by nilotinib using 2 different substrates (2 μM; 15-minute uptake). Data (n = 6–9 per group) were normalized to substrate uptake in the absence of nilotinib, and corrected for nonspecific uptake in cells transfected with an empty vector. (F) Plasma concentration-time curves of paclitaxel after paclitaxel administration (10 mg/kg) pretreated with nilotinib (100 mg/kg; p.o.) or vehicle (n = 5 per group). All data represent mean values (bars or symbols) and SD (error bars). *Indicates significant differences from the corresponding vehicle control group (P < 0.05), as evaluated with an unpaired 2-sided Student’s t test with Welch’s correction.