Search

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a debilitating side effect that afflicts approximately 90% of patients that is initiated by OCT2-dependent uptake of oxaliplatin in dorsal root ganglion (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 patients with cancer requiring treatment with oxaliplatin. Significance: We found that duloxetine has potent OCT2-inhibitory properties and can diminish excessive accumulation of oxaliplatin into DRG neurons. In addition, pretreatment of mice with duloxetine prevented OIPN without significantly altering the plasma pharmacokinetics and antitumor properties of oxaliplatin. These results suggest that intentional inhibition of OCT2-mediated transport by duloxetine can be employed as a prevention strategy to ameliorate OIPN without compromising the effectiveness of oxaliplatin-based treatment.

Supplementary Table S1. Percentage of OCT2 inhibition by compounds reported to reduce platinum-induced toxicities. Supplementary Table S2. Validation of human, rat, and murine overexpressed cells by evaluating their ability to accumulate known prototypical transport substrates. Supplementary Figure S1. Chemical structure of duloxetine. Supplementary Figure S2. IVIS imaging of tumor bearing mice. Supplementary Figure S3. Metabolites of duloxetine do not inhibit OCT2 function. Supplementary Figure S4. Duloxetine is an OCT2 inhibitor that extensively binds to extracellular membrane. Supplementary Figure S5. Duloxetine does not prevent peripheral neurotoxicity associated with vincristine and paclitaxel. Supplementary Figure S6. Paw withdrawal force measured by VFH instrument before the start of the treatment in wild-type (WT) and OCT1/2(-/-) mice (n=5-10 per group). Supplementary Figure S7. Activity of oxaliplatin in various colorectal cancer cell lines. Supplementary Figure S8. Effect of duloxetine on sciatic and caudal nerve velocity and amplitude.

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a debilitating side effect that afflicts approximately 90% of patients that is initiated by OCT2-dependent uptake of oxaliplatin in dorsal root ganglion (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 patients with cancer requiring treatment with oxaliplatin.Significance:We found that duloxetine has potent OCT2-inhibitory properties and can diminish excessive accumulation of oxaliplatin into DRG neurons. In addition, pretreatment of mice with duloxetine prevented OIPN without significantly altering the plasma pharmacokinetics and antitumor properties of oxaliplatin. These results suggest that intentional inhibition of OCT2-mediated transport by duloxetine can be employed as a prevention strategy to ameliorate OIPN without compromising the effectiveness of oxaliplatin-based treatment.

A convenient fluorometrical test method to identify skin sensitizers