Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice
Radiation-induced intestinal injury (RIII) occurs after high doses of radiation exposure. RIII restricts the therapeutic efficacy of radiotherapy in cancer and increases morbidity and mortality in nuclear disasters. Currently, there is no approved agent for the prevention or treatment of RIII. Here,...
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| Format: | Article |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.852669/full |
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| author | Qingwen Yuan Renjun Peng Huijie Yu Sinian Wang Zhongmin Chen Suhe Dong Wei Li Bo Cheng Qisheng Jiang Yuwen Cong Fengsheng Li Changzheng Li |
| author_facet | Qingwen Yuan Renjun Peng Huijie Yu Sinian Wang Zhongmin Chen Suhe Dong Wei Li Bo Cheng Qisheng Jiang Yuwen Cong Fengsheng Li Changzheng Li |
| author_sort | Qingwen Yuan |
| collection | DOAJ |
| description | Radiation-induced intestinal injury (RIII) occurs after high doses of radiation exposure. RIII restricts the therapeutic efficacy of radiotherapy in cancer and increases morbidity and mortality in nuclear disasters. Currently, there is no approved agent for the prevention or treatment of RIII. Here, we reported that the disulfiram, an FDA-approved alcohol deterrent, prolonged the survival in mice after lethal irradiation. Pretreatment with disulfiram inhibited proliferation within 24 h after irradiation, but improved crypt regeneration at 3.5 days post-irradiation. Mechanistically, disulfiram promoted Lgr5+ intestinal stem cells (ISCs) survival and maintained their ability to regenerate intestinal epithelium after radiation. Moreover, disulfiram suppresses DNA damage accumulation, thus inhibits aberrant mitosis after radiation. Unexpectedly, disulfiram treatment did not inhibit crypt cell apoptosis 4 h after radiation and the regeneration of crypts from PUMA-deficient mice after irradiation was also promoted by disulfiram. In conclusion, our findings demonstrate that disulfiram regulates the DNA damage response and survival of ISCs through affecting the cell cycle. Given its radioprotective efficacy and decades of application in humans, disulfiram is a promising candidate to prevent RIII in cancer therapy and nuclear accident. |
| first_indexed | 2024-04-13T06:51:44Z |
| format | Article |
| id | doaj.art-cee7677784b44d84b0ba3da77178b34a |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T06:51:44Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-cee7677784b44d84b0ba3da77178b34a2022-12-22T02:57:23ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-04-011310.3389/fphar.2022.852669852669Disulfiram Protects Against Radiation-Induced Intestinal Injury in MiceQingwen Yuan0Renjun Peng1Huijie Yu2Sinian Wang3Zhongmin Chen4Suhe Dong5Wei Li6Bo Cheng7Qisheng Jiang8Yuwen Cong9Fengsheng Li10Changzheng Li11The Postgraduate Training Base of Jinzhou Medical University, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Nuclear Radiation Injury and Monitoring, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Nuclear Radiation Injury and Monitoring, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Nuclear Radiation Injury and Monitoring, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Nuclear Radiation Injury and Monitoring, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Nuclear Radiation Injury and Monitoring, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Nuclear Radiation Injury and Monitoring, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Pathology, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Nuclear Radiation Injury and Monitoring, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology (BKLRB), Beijing, ChinaDepartment of Nuclear Radiation Injury and Monitoring, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaDepartment of Gastroenterology, The PLA Rocket Force Characteristic Medical Center, Beijing, ChinaRadiation-induced intestinal injury (RIII) occurs after high doses of radiation exposure. RIII restricts the therapeutic efficacy of radiotherapy in cancer and increases morbidity and mortality in nuclear disasters. Currently, there is no approved agent for the prevention or treatment of RIII. Here, we reported that the disulfiram, an FDA-approved alcohol deterrent, prolonged the survival in mice after lethal irradiation. Pretreatment with disulfiram inhibited proliferation within 24 h after irradiation, but improved crypt regeneration at 3.5 days post-irradiation. Mechanistically, disulfiram promoted Lgr5+ intestinal stem cells (ISCs) survival and maintained their ability to regenerate intestinal epithelium after radiation. Moreover, disulfiram suppresses DNA damage accumulation, thus inhibits aberrant mitosis after radiation. Unexpectedly, disulfiram treatment did not inhibit crypt cell apoptosis 4 h after radiation and the regeneration of crypts from PUMA-deficient mice after irradiation was also promoted by disulfiram. In conclusion, our findings demonstrate that disulfiram regulates the DNA damage response and survival of ISCs through affecting the cell cycle. Given its radioprotective efficacy and decades of application in humans, disulfiram is a promising candidate to prevent RIII in cancer therapy and nuclear accident.https://www.frontiersin.org/articles/10.3389/fphar.2022.852669/fulldisulfiramradioprotectorradiation-induced intestinal injuryLgr5+ stem cellDNA damage |
| spellingShingle | Qingwen Yuan Renjun Peng Huijie Yu Sinian Wang Zhongmin Chen Suhe Dong Wei Li Bo Cheng Qisheng Jiang Yuwen Cong Fengsheng Li Changzheng Li Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice Frontiers in Pharmacology disulfiram radioprotector radiation-induced intestinal injury Lgr5+ stem cell DNA damage |
| title | Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice |
| title_full | Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice |
| title_fullStr | Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice |
| title_full_unstemmed | Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice |
| title_short | Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice |
| title_sort | disulfiram protects against radiation induced intestinal injury in mice |
| topic | disulfiram radioprotector radiation-induced intestinal injury Lgr5+ stem cell DNA damage |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.852669/full |
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