Esomeprazole prevents oxaliplatin-induced peripheral neuropathy through inhibiting organic cation transporter 2 in...

Oxaliplatin (L-OHP) is widely used as a key drug for the treatment of various cancers, including colorectal cancer. However, L-OHP accumulates in the dorsal root ganglion (DRG) via organic cation transporter 2 (OCT2/SLC22A2), causing L-OHP-induced peripheral neuropathy (OIPN), a major clinical problem. Although proton pump inhibitors (PPIs) exhibit off-target OCT2 inhibitory effects, it remains unclear whether PPIs other than lansoprazole also inhibit OCT2-mediated L-OHP transport and prevent OIPN. This study aimed to investigate the inhibitory effects of PPIs on human OCT2 (hOCT2)-mediated L-OHP transport and assess their prophylactic effects against OIPN through in vitro and in vivo studies. Among the tested PPIs (lansoprazole, omeprazole, rabeprazole, and esomeprazole), the inhibitory effect of esomeprazole on hOCT2-mediated L-OHP transport was greater than those of other PPIs. In the OIPN mouse model, concomitant esomeprazole drastically ameliorated mechanical allodynia and cold hypersensitivity induced by L-OHP. Furthermore, concomitant esomeprazole administration significantly reduced L-OHP accumulation in the mouse DRG without affecting L-OHP plasma concentration. In primary cultures of mouse DRG neurons, cotreatment with esomeprazole significantly inhibited L-OHP uptake and completely restored L-OHP-induced neurite degeneration. Thus, to the best of our knowledge, our study demonstrates for the first time that concomitant esomeprazole prevents OIPN, at least in part, by inhibiting OCT2-mediated L-OHP transport into the DRG, thus decreasing L-OHP accumulation in the DRG. These findings provide important information for the establishment of novel protective approaches to minimize OIPN.