Reactive Oxygen Species; Receptors, GABA-A; Tumor Suppressor Protein p53; Flumazenil; gamma-Aminobutyric Acid; Calcium; Bicuculline; Animals; Bicuculline/pharmacology; Chemoradiotherapy; Flumazenil/pharmacology; Humans; Intestines; Mice; Stem Cells/physiology; United States; gamma-Aminobutyric Acid/pharmacology; Tumor Suppressor Protein p53/genetics; Stem Cells; Immunology and Allergy; Immunology
Abstract :
[en] Lethal intestinal tissue toxicity is a common side effect and a dose-limiting factor in chemoradiotherapy. Chemoradiotherapy can trigger DNA damage and induce P53-dependent apoptosis in LGR5+ intestinal stem cells (ISCs). Gamma-aminobutyric acid (GABA) and its A receptors (GABAAR) are present in the gastrointestinal tract. However, the functioning of the GABAergic system in ISCs is poorly defined. We found that GABAAR α1 (GABRA1) levels increased in the murine intestine after chemoradiotherapy. GABRA1 depletion in LGR5+ ISCs protected the intestine from chemoradiotherapy-induced P53-dependent apoptosis and prolonged animal survival. The administration of bicuculline, a GABAAR antagonist, prevented chemoradiotherapy-induced ISC loss and intestinal damage without reducing the chemoradiosensitivity of tumors. Mechanistically, it was associated with the reduction of reactive oxygen species-induced DNA damage via the L-type voltage-dependent Ca2+ channels. Notably, flumazenil, a GABAAR antagonist approved by the U.S. Food and Drug Administration, rescued human colonic organoids from chemoradiotherapy-induced toxicity. Therefore, flumazenil may be a promising drug for reducing the gastrointestinal side effects of chemoradiotherapy.
Disciplines :
Immunology & infectious disease
Author, co-author :
Zhang, Cuiyu ; Department of Physiology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Zhou, Yuping ; Department of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Zheng, Junjie ; Department of Physiology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Ning, Nannan ; Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Liu, Haining ; Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
Jiang, Wenyang ; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
Yu, Xin ; Department of Biotherapy, State Key laboratory of Biotherapy and cancer center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Mu, Kun ; Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Li, Yan ; Translational Medical Research Center, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
Guo, Wei ; Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Hu, Huili ; Department of Systems Biomedicine and Research Center of Stem Cell and Regenerative Medicine, Shandong University Cheeloo Medical College, School of Basic Medical Sciences, Jinan, China
Li, Jingxin ; Department of Physiology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Chen, Dawei ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale ; Department of Physiology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Taishan Pandeng Scholar Program of Shandong Province
Funders :
NSCF - National Natural Science Foundation of China
Funding text :
This work was supported by grants from the National Natural Science Foundation of China (31971061, 81903087) and Taishan Pandeng Scholar Program of Shandong Province (tspd20210321).
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