DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug

Bingxue Yang; Xinran Xie; Zhaoyu Wu; Dazhao Lv; Jiajun Hu; Yuyun Chen; Jiaxing Li; Shuyue Luo; Jiacheng Li; Jie Luo; Shiyi Zhang

doi:10.1016/j.gendis.2022.10.004

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DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug

Full-length article | 更新时间：2024-02-04

- DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug
- Genes & Diseases Vol. 1, Issue 6, Pages: 2557-2571(2023)
- 作者机构：
  
  1. School of Pharmacy, Shanghai Jiao Tong University,Shanghai,China,200240
  2. School of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University,Shanghai,China,200240
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2022.10.004
  CLC：
- Published：2023，
  
  Published Online：1 November 2023，
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Bingxue Yang, Xinran Xie, Zhaoyu Wu, et al. DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug. [J]. Genes & Diseases 1(6):2557-2571(2023)
DOI：

Bingxue Yang, Xinran Xie, Zhaoyu Wu, et al. DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug. [J]. Genes & Diseases 1(6):2557-2571(2023) DOI： 10.1016/j.gendis.2022.10.004.

摘要

Abstract

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.

关键词

Keywords

Cellular senescencecGAS-STINGCutaneous toxicityDNA damageFluoropyrimidineHand-foot syndromeKeratinocytesThymidine prodrug

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