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DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug
Hand-foot syndrome (HFS) is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes. Even though the cause and pathophysiology of HFS are relatively widely reported, how the toxicity of fluoropyrimidine...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Chongqing Medical University
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10404883/ https://www.ncbi.nlm.nih.gov/pubmed/37554214 http://dx.doi.org/10.1016/j.gendis.2022.10.004 |
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author | Yang, Bingxue Xie, Xinran Wu, Zhaoyu Lv, Dazhao Hu, Jiajun Chen, Yuyun Li, Jiaxing Luo, Shuyue Li, Jiacheng Luo, Jie Zhang, Shiyi |
author_facet | Yang, Bingxue Xie, Xinran Wu, Zhaoyu Lv, Dazhao Hu, Jiajun Chen, Yuyun Li, Jiaxing Luo, Shuyue Li, Jiacheng Luo, Jie Zhang, Shiyi |
author_sort | Yang, Bingxue |
collection | PubMed |
description | Hand-foot syndrome (HFS) is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes. Even though the cause and pathophysiology of HFS are relatively widely reported, how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied. Additionally, prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce. In our study, we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS. Mechanistically, DNA damage, as the primary cytotoxic cause, in keratinocytes induces cell cycle arrest, activates the cGAS-STING signaling pathway, and subsequently mediates cellular senescence, ultimately fueling a robust secondary inflammatory response that results in HFS. More importantly, the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence. These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS. |
format | Online Article Text |
id | pubmed-10404883 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Chongqing Medical University |
record_format | MEDLINE/PubMed |
spelling | pubmed-104048832023-08-08 DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug Yang, Bingxue Xie, Xinran Wu, Zhaoyu Lv, Dazhao Hu, Jiajun Chen, Yuyun Li, Jiaxing Luo, Shuyue Li, Jiacheng Luo, Jie Zhang, Shiyi Genes Dis Full Length Article Hand-foot syndrome (HFS) is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes. Even though the cause and pathophysiology of HFS are relatively widely reported, how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied. Additionally, prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce. In our study, we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS. Mechanistically, DNA damage, as the primary cytotoxic cause, in keratinocytes induces cell cycle arrest, activates the cGAS-STING signaling pathway, and subsequently mediates cellular senescence, ultimately fueling a robust secondary inflammatory response that results in HFS. More importantly, the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence. These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS. Chongqing Medical University 2022-10-18 /pmc/articles/PMC10404883/ /pubmed/37554214 http://dx.doi.org/10.1016/j.gendis.2022.10.004 Text en © 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Full Length Article Yang, Bingxue Xie, Xinran Wu, Zhaoyu Lv, Dazhao Hu, Jiajun Chen, Yuyun Li, Jiaxing Luo, Shuyue Li, Jiacheng Luo, Jie Zhang, Shiyi DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug |
title | DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug |
title_full | DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug |
title_fullStr | DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug |
title_full_unstemmed | DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug |
title_short | DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug |
title_sort | dna damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug |
topic | Full Length Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10404883/ https://www.ncbi.nlm.nih.gov/pubmed/37554214 http://dx.doi.org/10.1016/j.gendis.2022.10.004 |
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