Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy.

Autor:	Li Y; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and.; Division of Outcomes and Translational Sciences, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA., Drabison T; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Nepal M; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and.; Division of Outcomes and Translational Sciences, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA., Ho RH; Vanderbilt University Medical Center, Nashville, Tennessee, USA., Leblanc AF; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Gibson AA; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Jin Y; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Yang W; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Huang KM; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Uddin ME; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Chen M; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., DiGiacomo DF; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Chen X; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Razzaq S; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Tonniges JR; Campus Microscopy and Imaging Facility., McTigue DM; The Belford Center for Spinal Cord Injury & Department of Neuroscience, College of Medicine, and., Mims AS; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA., Lustberg MB; The Breast Center at Smilow Cancer Hospital at Yale, New Haven, Connecticut, USA., Wang Y; Department of Chemistry and Biochemistry & Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA., Hummon AB; Department of Chemistry and Biochemistry & Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA., Evans WE; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Baker SD; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Cavaletti G; Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy., Sparreboom A; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and., Hu S; Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, and.; Division of Outcomes and Translational Sciences, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2023 Jul 24; Vol. 8 (14). Date of Electronic Publication: 2023 Jul 24.
DOI:	10.1172/jci.insight.164646
Abstrakt:	Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes a dose-limiting peripheral neurotoxicity. There is no clinically effective preventative treatment for vincristine-induced sensory peripheral neurotoxicity (VIPN), and mechanistic details of this side effect remain poorly understood. We hypothesized that VIPN is dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons. Using a xenobiotic transporter screen, we identified OATP1B3 as a neuronal transporter regulating the uptake of vincristine. In addition, genetic or pharmacological inhibition of the murine orthologue transporter OATP1B2 protected mice from various hallmarks of VIPN - including mechanical allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes and neuronal morphology - without negatively affecting plasma levels or antitumor effects of vincristine. Finally, we identified α-tocopherol from an untargeted metabolomics analysis as a circulating endogenous biomarker of neuronal OATP1B2 function, and it could serve as a companion diagnostic to guide dose selection of OATP1B-type transport modulators given in combination with vincristine to prevent VIPN. Collectively, our findings shed light on the fundamental basis of VIPN and provide a rationale for the clinical development of transporter inhibitors to prevent this debilitating side effect.
Databáze:	MEDLINE
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