Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
Cancer Lett. 2021 Mar 31;501:20-30. doi: 10.1016/j.canlet.2020.12.034. Epub 2020 Dec 24.
High-dose radiation exposure induces gastrointestinal (GI) stem cell death, resulting in denudation of the intestinal mucosa and lethality from GI syndrome, for which there is currently no effective therapy. Studying an intestinal organoid-based functional model, we found that Sirtuin1(SIRT1) inhibition through genetic knockout or pharmacologic inhibition significantly improved mouse and human intestinal organoid survival after irradiation. Remarkably, mice administered with two doseages of SIRT1 inhibitors at 24 and 96 h after lethal irradiation promoted Lgr5+ intestinal stem cell and crypt recovery, with improved mouse survival (88.89% of mice in the treated group vs. 0% of mice in the control group). Moreover, our data revealed that SIRT1 inhibition increased p53 acetylation, resulting in the stabilization of p53 and likely contributing to the survival of intestinal epithelial cells post-radiation. These results demonstrate that SIRT1 inhibitors are effective clinical countermeasures to mitigate GI toxicity from potentially lethal radiation exposure.
大剂量辐射会导致胃肠道（GI）干细胞死亡，从而导致肠道黏膜剥脱和 GI 综合征致死，目前尚无有效的治疗方法。通过研究基于肠类器官的功能性模型，我们发现通过基因敲除或药物抑制 Sirtuin1（SIRT1）可显著提高照射后小鼠和人类肠类器官的存活率。值得注意的是，在致死性照射后 24 和 96 小时给予两种剂量 SIRT1 抑制剂的小鼠促进了 Lgr5+肠道干细胞和隐窝的恢复，提高了小鼠的存活率（治疗组中有 88.89%的小鼠存活，而对照组中没有小鼠存活）。此外，我们的数据表明，SIRT1 抑制增加了 p53 的乙酰化，导致 p53 的稳定，可能有助于辐射后肠道上皮细胞的存活。这些结果表明，SIRT1 抑制剂是减轻潜在致死性辐射暴露引起的 GI 毒性的有效临床对策。
