Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
Int J Radiat Oncol Biol Phys. 2021 Jul 15;110(4):1210-1221. doi: 10.1016/j.ijrobp.2021.01.046. Epub 2021 Feb 3.
Radiation-induced gastrointestinal syndrome (RIGS) is currently the main cause of death for people exposed to a high dose of irradiation during nuclear incidents, and there is currently no approved effective therapy. Here, we found that CBP/P300 inhibitors, with high efficacy and low toxicity, might be promising radiation mitigators that can cure RIGS.
Ex vivo 3D organoid cultures derived from mouse jejunum and human ileum and colon were used to examine the radio-mitigative effects of CBP/P300 inhibitors. The radio-mitigative effect was evaluated by quantifying the survival rate and size of organoids after radiation. SGC-CBP30 (50 mg/kg body weight), an inhibitor of CBP/P300, was intraperitoneally injected into C57B/6J mice 24 hours after subtotal-body irradiation or whole-body irradiation. The regenerated crypts and animal survival were determined by microcolony assay and the Kaplan-Meier method, respectively. Lgr5-lacZ mice were used to evaluate the survival of intestinal stem cells after treatments.
We found that CBP/P300 inhibitors were effective mitigators that could be used to treat RIGS. CBP/P300 inhibition promoted the regeneration of intestinal organoids in vitro and of crypts in vivo. Remarkably, the administration of CBP/P300 inhibitors to mice 24 hours after lethal irradiation promoted Lgr5 intestinal stem cell and crypt recovery, resulting in improved mouse survival. Moreover, our data show that CBP/P300 inhibitors rescued irradiated mice from RIGS by delaying intestinal epithelial cell cycle progression after radiation.
These data demonstrate that CBP/P300 inhibitors are effective medical countermeasures to mitigate gastrointestinal toxicity from radiation.
辐射诱导的胃肠道综合征（RIGS）是目前核事故中高剂量照射人群死亡的主要原因，目前尚无有效的治疗方法。在这里，我们发现 CBP/P300 抑制剂具有高效低毒的特点，可能是一种有前途的辐射缓解剂，可以治疗 RIGS。
我们使用源自小鼠空肠和人回肠和结肠的体外 3D 类器官培养物来研究 CBP/P300 抑制剂的放射缓解作用。通过辐射后类器官的存活率和大小来评估放射缓解作用。SGC-CBP30（50mg/kg 体重）是一种 CBP/P300 抑制剂，在亚全身体照射或全身照射后 24 小时内通过腹腔注射到 C57B/6J 小鼠体内。通过微集落测定和 Kaplan-Meier 法分别确定再生隐窝和动物存活率。使用 Lgr5-lacZ 小鼠来评估处理后肠干细胞的存活情况。
我们发现 CBP/P300 抑制剂是治疗 RIGS 的有效缓解剂。CBP/P300 抑制促进了体外肠类器官和体内隐窝的再生。值得注意的是，在致死性照射后 24 小时给予 CBP/P300 抑制剂可促进 Lgr5 肠干细胞和隐窝的恢复，从而提高了小鼠的存活率。此外，我们的数据表明，CBP/P300 抑制剂通过延迟辐射后肠上皮细胞周期进程，从 RIGS 中拯救了受照射的小鼠。
这些数据表明，CBP/P300 抑制剂是缓解辐射引起的胃肠道毒性的有效医疗对策。
