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Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity

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...

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Autores principales: Nepal, Mahesh R., Taheri, Hanieh, Li, Yang, Talebi, Zahra, Uddin, Muhammad Erfan, Jin, Yan, DiGiacomo, Duncan F., Gibson, Alice A., Lustberg, Maryam B., Hu, Shuiying, Sparreboom, Alex
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9730833/
https://www.ncbi.nlm.nih.gov/pubmed/36506732
http://dx.doi.org/10.1158/2767-9764.CRC-22-0172
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author Nepal, Mahesh R.
Taheri, Hanieh
Li, Yang
Talebi, Zahra
Uddin, Muhammad Erfan
Jin, Yan
DiGiacomo, Duncan F.
Gibson, Alice A.
Lustberg, Maryam B.
Hu, Shuiying
Sparreboom, Alex
author_facet Nepal, Mahesh R.
Taheri, Hanieh
Li, Yang
Talebi, Zahra
Uddin, Muhammad Erfan
Jin, Yan
DiGiacomo, Duncan F.
Gibson, Alice A.
Lustberg, Maryam B.
Hu, Shuiying
Sparreboom, Alex
author_sort Nepal, Mahesh R.
collection PubMed
description 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.
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spelling pubmed-97308332022-12-12 Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity Nepal, Mahesh R. Taheri, Hanieh Li, Yang Talebi, Zahra Uddin, Muhammad Erfan Jin, Yan DiGiacomo, Duncan F. Gibson, Alice A. Lustberg, Maryam B. Hu, Shuiying Sparreboom, Alex Cancer Res Commun Research Article 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. American Association for Cancer Research 2022-11-03 /pmc/articles/PMC9730833/ /pubmed/36506732 http://dx.doi.org/10.1158/2767-9764.CRC-22-0172 Text en © 2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Research Article
Nepal, Mahesh R.
Taheri, Hanieh
Li, Yang
Talebi, Zahra
Uddin, Muhammad Erfan
Jin, Yan
DiGiacomo, Duncan F.
Gibson, Alice A.
Lustberg, Maryam B.
Hu, Shuiying
Sparreboom, Alex
Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity
title Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity
title_full Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity
title_fullStr Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity
title_full_unstemmed Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity
title_short Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity
title_sort targeting oct2 with duloxetine to prevent oxaliplatin-induced peripheral neurotoxicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9730833/
https://www.ncbi.nlm.nih.gov/pubmed/36506732
http://dx.doi.org/10.1158/2767-9764.CRC-22-0172
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