Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice

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Abstract

Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells in oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventive strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.

Authors

Kevin M. Huang, Alix F. Leblanc, Muhammad Erfan Uddin, Ji Young Kim, Mingqing Chen, Eric D. Eisenmann, Alice A. Gibson, Yang Li, Kristen W. Hong, Duncan DiGiacomo, Sherry H. Xia, Paola Alberti, Alessia Chiorazzi, Stephen N. Housley, Timothy C. Cope, Jason A. Sprowl, Jing Wang, Charles L. Loprinzi, Anne Noonan, Maryam B. Lustberg, Guido Cavaletti, Navjot Pabla, Shuiying Hu, Alex Sparreboom