Genetic and Pharmacological Inhibition of OCT2 Protects Rats against Oxaliplatin‐Induced Peripheral Neuropathy

Abstract

BACKGROUNDColorectal cancer (CRC) is the third leading cause of cancer‐related mortalities in the United States. Oxaliplatin (OXPt) is widely used in the treatment of patients with CRC in both an adjuvant and metastatic setting; however, OXPt induces acute and chronic peripheral neuropathy (PN) in up to 90% of patients, characterized by paresthesia or sensory ataxia in the extremities. Previously, we identified organic cation transporter 2 (OCT2) as a contributor initiating OXPt‐induced PN in mice, and that pre‐treatment with the tyrosine kinase inhibitor, dasatinib, ameliorated acute and chronic forms of PN. Since the rat orthologue of OCT2 shares >90% sequence homology, we hypothesized that OCT2 inhibition can also afford protection in rats against OXPt‐induced PN.METHODSIn vitro transport studies were conducted in stably‐transfected HEK293 overexpressing rat OCT2. In vivo studies were conducted in age‐matched wild‐type and OCT2‐deficient Sprague dawley rats receiving a single dose of OXPt (10mg/kg, i.p.), with or without pre‐treatment with an OCT2 inhibitor (dasatinib, 15 mg/kg, p.o.). Mechanical‐induced allodynia were recorded before and 24 hours after the treatment. Platinum exposure in plasma, dorsal root ganglia cells (DRGs), kidneys, and urinary excretion were analyzed by atomic absorption spectroscopy. Gene expression of OCT‐related transporters in DRGs and kidneys were also analyzed by qPCR. The cytotoxicity of OXPt in the presence of dasatinib was evaluated in the NCI panel of colorectal cancer cells.RESULTSOur in vitro studies showed that OXPt is also a substrate of rat OCT2 and that this transport process is sensitive to pharmacological inhibition by the tyrosine kinase inhibitor, dasatinib (IC50 25.8 nM). Treatment with OXPt significantly increased wild‐type rats to mechanical allodynia sensitivity (40%), whereas OCT2‐deficient rats were completely protected from OXPt‐induced PN (p<0.05). Furthermore, pre‐treatment with dasatinib in wild‐type rats ameliorated OXPt‐induced PN. Platinum accumulation in DRGs was 7.3‐fold higher in wild‐type rats compared to OCT2‐deficient rats, while treatment with dasatinib significantly diminished accumulation in DRGs of wild‐type rats. These results are corroborated by high expression of OCT2 in DRGs. In addition, plasma exposure and urinary excretion of total platinum was not significantly altered both wild‐type and OCT2‐deficient rats, treated with or without dasatinib. Lastly, in vitro screening of the NCI panel of CRCs demonstrated that concomitant treatment with dasatinib did not compromise the antitumor properties of OXPt.CONCLUSIONOur study serves as a model that inhibition of OCT2 provides protection against OXPt‐induced PN. As this debilitating side effect greatly diminishes quality of life, these type of preventative strategies addresses an unmet therapeutic need in colorectal cancer patients receiving oxaliplatin‐based therapy.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.