Lansoprazole identified as a prophylactic agent for oxaliplatin-induced peripheral neuropathy using integrated in silico, in vitro, and in vivo analyses

Abstract

Oxaliplatin (L-OHP) is a platinum-based anticancer drug used to treat various malignant tumors. However, L-OHP-induced peripheral neuropathy (OIPN) is a major clinical problem that often limits treatment. As OIPN occurs when L-OHP accumulates in the dorsal root ganglion (DRG) via organic cation transporter 2 (OCT2/SLC22A2), drugs with OCT2 inhibitory properties may serve as prophylactic agents for OIPN. This study aimed to explore the potential prophylactic agents for OIPN using integrated model with the quantitative structure-activity relationship screening for human organic cation transporter 2 (hOCT2) inhibitors and two real-world data analyses of the Food and Drug Administration Adverse Event Reporting System and Japanese Adverse Drug Event Report, and subsequently evaluate the protective effects of the identified drugs against OIPN. Our integrated model identified lansoprazole, a proton pump inhibitor, as a potential prophylactic agent. In vitro uptake study using hOCT2-expressing HEK293 cells demonstrated that lansoprazole significantly inhibited the hOCT2-mediated transport of L-OHP. In the OIPN mouse model, concomitant lansoprazole drastically suppressed mechanical allodynia and cold hypersensitivity after repeated L-OHP administration. Moreover, the concentration of L-OHP in the DRG was significantly decreased by the concomitant administration of lansoprazole. In primary cultured mouse DRG neurons, cotreatment with lansoprazole significantly inhibited L-OHP uptake and restored the L-OHP-induced decrease in neurite length. These findings suggest that the concomitant administration of lansoprazole ameliorates OIPN by inhibiting OCT2-mediated L-OHP uptake in the mouse DRG. Our findings provide important insights for the establishment of novel protective approaches against OIPN.

Keywords: Drug repositioning; Lansoprazole; Organic cation transporter 2; Oxaliplatin-induced peripheral neuropathy; Proton pump inhibitors.