Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity

Abstract

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a debilitating side effect that afflicts ~90% of patients that is initiated by OCT2-dependent uptake of oxaliplatin in DRG neurons. The antidepressant drug duloxetine has been used to treat OIPN, although its usefulness in preventing this side effect remains unclear. We hypothesized that duloxetine has OCT2-inhibitory properties and can be used as an adjunct to oxaliplatin-based regimens to prevent OIPN. Transport studies were performed in cells stably transfected with mouse or human OCT2 and in isolated mouse DRG neurons ex vivo. Wild-type and OCT2-deficient mice were used to assess effects of duloxetine on hallmarks of OIPN, endogenous OCT2 biomarkers, and the pharmacokinetics of oxaliplatin, and the translational feasibility of a duloxetine-oxaliplatin combination was evaluated in various models of colorectal cancer. We found that duloxetine potently inhibited the OCT2-mediated transport of several xenobiotic substrates, including oxaliplatin, in a reversible, concentration-dependent manner, and independent of species and cell context. Furthermore, duloxetine restricted access of these substrates to DRG neurons ex vivo and prevented OIPN in wild-type mice to a degree similar to the complete protection observed in OCT2-deficient mice, without affecting the plasma levels of oxaliplatin. Importantly, the uptake and cytotoxicity of oxaliplatin in tumor cell lines in vitro and in vivo were not negatively influenced by duloxetine. The observed OCT2-targeting properties of duloxetine, combined with the potential for clinical translation, provide support for its further exploration as a therapeutic candidate for studies aimed at preventing OIPN in cancer patients requiring treatment with oxaliplatin.

Duloxetine prevents bortezomib and paclitaxel large-fiber chemotherapy-induced peripheral neuropathy (LF-CIPN) in sprague dawley rats

“…Thus, it has been shown that Duloxetine also inhibits Organic Cation Transporter 2 (OCT2), a mechanism that is well-established to facilitate the uptake of Oxaliplatin into Dorsal Root Ganglion (DRG) neurons, thought to prevent Oxaliplatin-induced peripheral neuropathy (OIPN). 35 While this study demonstrated that Duloxetine inhibits the uptake of Oxaliplatin into DRG neurons, Duloxetine has not been studied with reference to inhibiting transporters involved with Paclitaxel- and Bortezomib-induced peripheral neuropathy. While the transporters that facilitate the uptake of Paclitaxel into DRG neurons have been studied in vitro and in rodent models, 36 this does not appear to be mediated by OCT2.…”

DRG Explant Model: Elucidating Mechanisms of Oxaliplatin-Induced Peripheral Neuropathy and Identifying Potential Therapeutic Targets

“…Recent studies in mouse models have shown that the organic cation transporter 2 (OCT2) mediates the uptake of oxaliplatin into SGCs, initiating neuropathy symptoms. Blocking this transporter with an OCT2 inhibitor cimetidine (34) has been previously shown to minimize these symptoms (35, 36). To investigate whether OCT2 inhibition could protect neurite outgrowth in the presence of oxaliplatin, DRG explants were co-cultured with a high dose of oxaliplatin (100 μM) and varying concentrations of cimetidine.…”

Proton Pump Inhibitors Ameliorate Oxaliplatin-induced Peripheral Neuropathy: Retrospective Analysis of Two Real-world Clinical Databases

“…Because PPIs have OCT2 inhibitory effects as off-target effect (22), it is possible that elevated blood levels of L-OHP caused by concomitant PPI use may influence the toxicity and efficacy of L-OHP. However, it has been reported that the plasma concentration of L-OHP is not altered by OCT2 knockout in mice (23). In addition, omeprazole was reported to have no effect on the suppression of tumor growth by L-OHP in tumor-bearing mice (19).…”