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

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

机构地区：[1]School of Pharmacy,Shanghai Jiao Tong University,Shanghai 200240,China [2]School of Pharmacy and School of Biomedical Engineering,Shanghai Jiao Tong University,Shanghai 200240,China

出　　处：《Genes & Diseases》2023年第6期2557-2571,共15页基因与疾病（英文）

基　　金：supported by the Youth Thousand Talents Program of China,start-up grants from the Shanghai Jiao Tong University(No.WF220408211);supported by grants from the State Key Laboratory of Oncogenes and Related Genes(No.90-17-02)at Shanghai Jiao Tong University;from the Interdisciplinary Program of Shanghai Jiao Tong University(China)(No.YG2017MS18).

摘　　要：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：Cellular senescence cGAS-STING Cutaneous toxicity DNA damage FLUOROPYRIMIDINE Hand-foot syndrome KERATINOCYTES Thymidine prodrug 

分 类 号：R73[医药卫生—肿瘤]