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Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

Chemotherapy‐induced peripheral neuropathy (CIPN) is a dose‐limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the cur...

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Autores principales: Xiong, Chenling, Chua, Katherina C., Stage, Tore B., Priotti, Josefina, Kim, Jeffrey, Altman‐Merino, Anne, Chan, Daniel, Saraf, Krishna, Canato Ferracini, Amanda, Fattahi, Faranak, Kroetz, Deanna L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993321/
https://www.ncbi.nlm.nih.gov/pubmed/33340242
http://dx.doi.org/10.1111/cts.12912
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author Xiong, Chenling
Chua, Katherina C.
Stage, Tore B.
Priotti, Josefina
Kim, Jeffrey
Altman‐Merino, Anne
Chan, Daniel
Saraf, Krishna
Canato Ferracini, Amanda
Fattahi, Faranak
Kroetz, Deanna L.
author_facet Xiong, Chenling
Chua, Katherina C.
Stage, Tore B.
Priotti, Josefina
Kim, Jeffrey
Altman‐Merino, Anne
Chan, Daniel
Saraf, Krishna
Canato Ferracini, Amanda
Fattahi, Faranak
Kroetz, Deanna L.
author_sort Xiong, Chenling
collection PubMed
description Chemotherapy‐induced peripheral neuropathy (CIPN) is a dose‐limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the current study, a human induced pluripotent stem cell–derived sensory neuron (iPSC‐SN) model was developed for the study of chemotherapy‐induced neurotoxicity. The iPSC‐SNs express proteins characteristic of nociceptor, mechanoreceptor, and proprioceptor sensory neurons and show Ca(2+) influx in response to capsaicin, α,β‐meATP, and glutamate. The iPSC‐SNs are relatively resistant to the cytotoxic effects of paclitaxel, with half‐maximal inhibitory concentration (IC(50)) values of 38.1 µM (95% confidence interval (CI) 22.9–70.9 µM) for 48‐hour exposure and 9.3 µM (95% CI 5.7–16.5 µM) for 72‐hour treatment. Paclitaxel causes dose‐dependent and time‐dependent changes in neurite network complexity detected by βIII‐tubulin staining and high content imaging. The IC(50) for paclitaxel reduction of neurite area was 1.4 µM (95% CI 0.3–16.9 µM) for 48‐hour exposure and 0.6 µM (95% CI 0.09–9.9 µM) for 72‐hour exposure. Decreased mitochondrial membrane potential, slower movement of mitochondria down the neurites, and changes in glutamate‐induced neuronal excitability were also observed with paclitaxel exposure. The iPSC‐SNs were also sensitive to docetaxel, vincristine, and bortezomib. Collectively, these data support the use of iPSC‐SNs for detailed mechanistic investigations of genes and pathways implicated in chemotherapy‐induced neurotoxicity and the identification of novel therapeutic approaches for its prevention and treatment.
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spelling pubmed-79933212021-03-29 Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel Xiong, Chenling Chua, Katherina C. Stage, Tore B. Priotti, Josefina Kim, Jeffrey Altman‐Merino, Anne Chan, Daniel Saraf, Krishna Canato Ferracini, Amanda Fattahi, Faranak Kroetz, Deanna L. Clin Transl Sci Research Chemotherapy‐induced peripheral neuropathy (CIPN) is a dose‐limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the current study, a human induced pluripotent stem cell–derived sensory neuron (iPSC‐SN) model was developed for the study of chemotherapy‐induced neurotoxicity. The iPSC‐SNs express proteins characteristic of nociceptor, mechanoreceptor, and proprioceptor sensory neurons and show Ca(2+) influx in response to capsaicin, α,β‐meATP, and glutamate. The iPSC‐SNs are relatively resistant to the cytotoxic effects of paclitaxel, with half‐maximal inhibitory concentration (IC(50)) values of 38.1 µM (95% confidence interval (CI) 22.9–70.9 µM) for 48‐hour exposure and 9.3 µM (95% CI 5.7–16.5 µM) for 72‐hour treatment. Paclitaxel causes dose‐dependent and time‐dependent changes in neurite network complexity detected by βIII‐tubulin staining and high content imaging. The IC(50) for paclitaxel reduction of neurite area was 1.4 µM (95% CI 0.3–16.9 µM) for 48‐hour exposure and 0.6 µM (95% CI 0.09–9.9 µM) for 72‐hour exposure. Decreased mitochondrial membrane potential, slower movement of mitochondria down the neurites, and changes in glutamate‐induced neuronal excitability were also observed with paclitaxel exposure. The iPSC‐SNs were also sensitive to docetaxel, vincristine, and bortezomib. Collectively, these data support the use of iPSC‐SNs for detailed mechanistic investigations of genes and pathways implicated in chemotherapy‐induced neurotoxicity and the identification of novel therapeutic approaches for its prevention and treatment. John Wiley and Sons Inc. 2020-12-19 2021-03 /pmc/articles/PMC7993321/ /pubmed/33340242 http://dx.doi.org/10.1111/cts.12912 Text en © 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Xiong, Chenling
Chua, Katherina C.
Stage, Tore B.
Priotti, Josefina
Kim, Jeffrey
Altman‐Merino, Anne
Chan, Daniel
Saraf, Krishna
Canato Ferracini, Amanda
Fattahi, Faranak
Kroetz, Deanna L.
Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel
title Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel
title_full Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel
title_fullStr Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel
title_full_unstemmed Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel
title_short Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel
title_sort human induced pluripotent stem cell derived sensory neurons are sensitive to the neurotoxic effects of paclitaxel
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993321/
https://www.ncbi.nlm.nih.gov/pubmed/33340242
http://dx.doi.org/10.1111/cts.12912
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