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...
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| Format: | Article |
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KeAi Communications Co., Ltd.
2023-11-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304222002677 |
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| author | Bingxue Yang Xinran Xie Zhaoyu Wu Dazhao Lv Jiajun Hu Yuyun Chen Jiaxing Li Shuyue Luo Jiacheng Li Jie Luo Shiyi Zhang |
| author_facet | Bingxue Yang Xinran Xie Zhaoyu Wu Dazhao Lv Jiajun Hu Yuyun Chen Jiaxing Li Shuyue Luo Jiacheng Li Jie Luo Shiyi Zhang |
| author_sort | Bingxue Yang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T19:32:51Z |
| format | Article |
| id | doaj.art-b9bf1fb4ca2745d5a4676de23f8b27ea |
| institution | Directory Open Access Journal |
| issn | 2352-3042 |
| language | English |
| last_indexed | 2024-03-12T19:32:51Z |
| publishDate | 2023-11-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Genes and Diseases |
| spelling | doaj.art-b9bf1fb4ca2745d5a4676de23f8b27ea2023-08-02T04:24:27ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422023-11-0110625572571DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrugBingxue Yang0Xinran Xie1Zhaoyu Wu2Dazhao Lv3Jiajun Hu4Yuyun Chen5Jiaxing Li6Shuyue Luo7Jiacheng Li8Jie Luo9Shiyi Zhang10School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaSchool of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaSchool of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaSchool of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaSchool of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaSchool of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaSchool of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaSchool of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaSchool of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaSchool of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; Corresponding author.School of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2352304222002677Cellular senescencecGAS-STINGCutaneous toxicityDNA damageFluoropyrimidineHand-foot syndrome |
| spellingShingle | Bingxue Yang Xinran Xie Zhaoyu Wu Dazhao Lv Jiajun Hu Yuyun Chen Jiaxing Li Shuyue Luo Jiacheng Li Jie Luo Shiyi Zhang DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug Genes and Diseases Cellular senescence cGAS-STING Cutaneous toxicity DNA damage Fluoropyrimidine Hand-foot syndrome |
| 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 | Cellular senescence cGAS-STING Cutaneous toxicity DNA damage Fluoropyrimidine Hand-foot syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2352304222002677 |
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