CBP/P300 Inhibitors Mitigate Radiation-Induced GI Syndrome by Promoting Intestinal Stem Cell-Mediated Crypt Regeneration.

Animals Intestines / cytology Mice Radiation Injuries / drug therapy Regeneration / drug effects Stem Cells / cytology p300-CBP Transcription Factors / antagonists & inhibitors

Journal

International journal of radiation oncology, biology, physics
ISSN: 1879-355X
Titre abrégé: Int J Radiat Oncol Biol Phys
Pays: United States
ID NLM: 7603616

Informations de publication

Date de publication:
15 07 2021
Historique:
received: 23 06 2020
revised: 08 01 2021
accepted: 23 01 2021
pubmed: 6 2 2021
medline: 25 9 2021
entrez: 5 2 2021
Statut: ppublish

Résumé

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 These data demonstrate that CBP/P300 inhibitors are effective medical countermeasures to mitigate gastrointestinal toxicity from radiation.

Identifiants

DOI: 10.1016/j.ijrobp.2021.01.046 PMID: 33545304
pubmed: 33545304
pii: S0360-3016(21)00120-6
doi: 10.1016/j.ijrobp.2021.01.046
pii:
doi:

Substances chimiques

p300-CBP Transcription Factors EC 2.3.1.48

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1210-1221

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

Auteurs

Xinxin Rao (X)

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Peiyuan Tang (P)

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Yuanchuang Li (Y)

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Guoxiang Fu (G)

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Shengzhi Chen (S)

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Xiaoya Xu (X)

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Yi Zhou (Y)

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Xiaomeng Li (X)

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Long Zhang (L)

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.

Shaobo Mo (S)

Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Sanjun Cai (S)

Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Junjie Peng (J)

Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Zhen Zhang (Z)

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.

Jianjun Gao (J)

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Guoqiang Hua (G)

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China; Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. Electronic address: guoqianghua@fudan.edu.cn.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › CBP/P300 Inhibitors Mitigate Radiation-Induced...
questionsmedicales.fr › Système digestif › Tube digestif › Intestins › CBP/P300 Inhibitors Mitigate Radiation-Induced...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › CBP/P300 Inhibitors Mitigate Radiation-Induced...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Hygiène radiologique › Effets des rayonnements › Lésions radiques › CBP/P300 Inhibitors Mitigate Radiation-Induced...
questionsmedicales.fr › Phénomènes biologiques › Régénération › CBP/P300 Inhibitors Mitigate Radiation-Induced...
questionsmedicales.fr › Cellules › Cellules souches › CBP/P300 Inhibitors Mitigate Radiation-Induced...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription CBP-p300 › CBP/P300 Inhibitors Mitigate Radiation-Induced...