Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice

Qingwen Yuan; Renjun Peng; Huijie Yu; Sinian Wang; Zhongmin Chen; Suhe Dong; Wei Li; Bo Cheng; Qisheng Jiang; Yuwen Cong; Fengsheng Li; Changzheng Li

doi:10.3389/fphar.2022.852669

Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice

Front Pharmacol. 2022 Apr 19:13:852669. doi: 10.3389/fphar.2022.852669. eCollection 2022.

Authors

Qingwen Yuan¹, Renjun Peng², Huijie Yu², Sinian Wang², Zhongmin Chen², Suhe Dong², Wei Li², Bo Cheng³, Qisheng Jiang², Yuwen Cong⁴, Fengsheng Li², Changzheng Li⁵

Affiliations

¹ The Postgraduate Training Base of Jinzhou Medical University, The PLA Rocket Force Characteristic Medical Center, Beijing, China.
² Department of Nuclear Radiation Injury and Monitoring, The PLA Rocket Force Characteristic Medical Center, Beijing, China.
³ Department of Pathology, The PLA Rocket Force Characteristic Medical Center, Beijing, China.
⁴ Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory for Radiobiology (BKLRB), Beijing, China.
⁵ Department of Gastroenterology, The PLA Rocket Force Characteristic Medical Center, Beijing, China.

Abstract

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.

Keywords: DNA damage; Lgr5+ stem cell; disulfiram; radiation-induced intestinal injury; radioprotector.