CBP/P300 Inhibitors Mitigate Radiation-Induced GI Syndrome by Promoting Intestinal Stem Cell-Mediated Crypt Regeneration
| Autor: | Long Zhang, Guoqiang Hua, Jianjun Gao, Yi Zhou, Yuanchuang Li, Shaobo Mo, Guoxiang Fu, Xiaoya Xu, Zhen Zhang, Junjie Peng, Xinxin Rao, Peiyuan Tang, Shengzhi Chen, Xiaomeng Li, Sanjun Cai |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Crypt Ileum 030218 nuclear medicine & medical imaging Mice 03 medical and health sciences 0302 clinical medicine medicine Organoid Animals Regeneration p300-CBP Transcription Factors Radiology Nuclear Medicine and imaging Radiation Injuries Survival rate Radiation business.industry Stem Cells Regeneration (biology) LGR5 Epithelium Intestines medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research Stem cell business |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 110:1210-1221 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/j.ijrobp.2021.01.046 |
| Popis: | Purpose 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. Methods and Materials 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. Results 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. Conclusions These data demonstrate that CBP/P300 inhibitors are effective medical countermeasures to mitigate gastrointestinal toxicity from radiation. |
| Databáze: | OpenAIRE |
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