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Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation
Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanism...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736304/ https://www.ncbi.nlm.nih.gov/pubmed/33318563 http://dx.doi.org/10.1038/s41598-020-78896-w |
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author | Cetinkaya-Fisgin, Aysel Luan, Xinghua Reed, Nicole Jeong, Ye Eun Oh, Byoung Chol Hoke, Ahmet |
author_facet | Cetinkaya-Fisgin, Aysel Luan, Xinghua Reed, Nicole Jeong, Ye Eun Oh, Byoung Chol Hoke, Ahmet |
author_sort | Cetinkaya-Fisgin, Aysel |
collection | PubMed |
description | Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy. |
format | Online Article Text |
id | pubmed-7736304 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-77363042020-12-15 Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation Cetinkaya-Fisgin, Aysel Luan, Xinghua Reed, Nicole Jeong, Ye Eun Oh, Byoung Chol Hoke, Ahmet Sci Rep Article Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy. Nature Publishing Group UK 2020-12-14 /pmc/articles/PMC7736304/ /pubmed/33318563 http://dx.doi.org/10.1038/s41598-020-78896-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Cetinkaya-Fisgin, Aysel Luan, Xinghua Reed, Nicole Jeong, Ye Eun Oh, Byoung Chol Hoke, Ahmet Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation |
title | Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation |
title_full | Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation |
title_fullStr | Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation |
title_full_unstemmed | Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation |
title_short | Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation |
title_sort | cisplatin induced neurotoxicity is mediated by sarm1 and calpain activation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736304/ https://www.ncbi.nlm.nih.gov/pubmed/33318563 http://dx.doi.org/10.1038/s41598-020-78896-w |
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