Cargando…
Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice
Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447787/ https://www.ncbi.nlm.nih.gov/pubmed/32843706 http://dx.doi.org/10.1038/s41598-020-71042-6 |
_version_ | 1783574368322846720 |
---|---|
author | Acklin, Scarlett Zhang, Manchao Du, Wuying Zhao, Xin Plotkin, Matthew Chang, Jianhui Campisi, Judith Zhou, Daohong Xia, Fen |
author_facet | Acklin, Scarlett Zhang, Manchao Du, Wuying Zhao, Xin Plotkin, Matthew Chang, Jianhui Campisi, Judith Zhou, Daohong Xia, Fen |
author_sort | Acklin, Scarlett |
collection | PubMed |
description | Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is available. Senescence induced during cancer treatment has been shown to promote the adverse effects. Here, we show that cisplatin induces senescent-like neuronal cells in primary culture and in mouse dorsal root ganglia (DRG), as determined by the characteristic senescence markers including senescence-associated beta-galactosidase, accumulation of cytosolic p16(INK4A) and HMGB1, as well as increased expression of p16Ink4a, p21, and MMP-9. The accumulation of senescent-like neuronal cells in DRG is associated with cisplatin-induced peripheral neuropathy (CIPN) in mice. To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological ‘senolytic’ agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir (GCV) to selectively kill senescent cells expressing herpes simplex virus 1 thymidine kinase (HSV-TK). We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following platinum-based cancer treatment might be an effective therapy for the debilitating side effect of CIPN. |
format | Online Article Text |
id | pubmed-7447787 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74477872020-08-26 Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice Acklin, Scarlett Zhang, Manchao Du, Wuying Zhao, Xin Plotkin, Matthew Chang, Jianhui Campisi, Judith Zhou, Daohong Xia, Fen Sci Rep Article Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is available. Senescence induced during cancer treatment has been shown to promote the adverse effects. Here, we show that cisplatin induces senescent-like neuronal cells in primary culture and in mouse dorsal root ganglia (DRG), as determined by the characteristic senescence markers including senescence-associated beta-galactosidase, accumulation of cytosolic p16(INK4A) and HMGB1, as well as increased expression of p16Ink4a, p21, and MMP-9. The accumulation of senescent-like neuronal cells in DRG is associated with cisplatin-induced peripheral neuropathy (CIPN) in mice. To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological ‘senolytic’ agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir (GCV) to selectively kill senescent cells expressing herpes simplex virus 1 thymidine kinase (HSV-TK). We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following platinum-based cancer treatment might be an effective therapy for the debilitating side effect of CIPN. Nature Publishing Group UK 2020-08-25 /pmc/articles/PMC7447787/ /pubmed/32843706 http://dx.doi.org/10.1038/s41598-020-71042-6 Text en © The Author(s) 2020 Open AccessThis 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 Acklin, Scarlett Zhang, Manchao Du, Wuying Zhao, Xin Plotkin, Matthew Chang, Jianhui Campisi, Judith Zhou, Daohong Xia, Fen Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice |
title | Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice |
title_full | Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice |
title_fullStr | Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice |
title_full_unstemmed | Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice |
title_short | Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice |
title_sort | depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447787/ https://www.ncbi.nlm.nih.gov/pubmed/32843706 http://dx.doi.org/10.1038/s41598-020-71042-6 |
work_keys_str_mv | AT acklinscarlett depletionofsenescentlikeneuronalcellsalleviatescisplatininducedperipheralneuropathyinmice AT zhangmanchao depletionofsenescentlikeneuronalcellsalleviatescisplatininducedperipheralneuropathyinmice AT duwuying depletionofsenescentlikeneuronalcellsalleviatescisplatininducedperipheralneuropathyinmice AT zhaoxin depletionofsenescentlikeneuronalcellsalleviatescisplatininducedperipheralneuropathyinmice AT plotkinmatthew depletionofsenescentlikeneuronalcellsalleviatescisplatininducedperipheralneuropathyinmice AT changjianhui depletionofsenescentlikeneuronalcellsalleviatescisplatininducedperipheralneuropathyinmice AT campisijudith depletionofsenescentlikeneuronalcellsalleviatescisplatininducedperipheralneuropathyinmice AT zhoudaohong depletionofsenescentlikeneuronalcellsalleviatescisplatininducedperipheralneuropathyinmice AT xiafen depletionofsenescentlikeneuronalcellsalleviatescisplatininducedperipheralneuropathyinmice |