Radiation protective effects of baclofen predicted by a computational drug repurposing strategy.
Exposure to ionizing radiation causes damage to living tissues; however, only a small number of agents have been approved for use in radiation injuries. Radioprotector is the primary countermeasure to radiation injury and none radioprotector has indeed reached the drug development stage. Repurposing the long list of approved, non-radioprotective drugs is an attractive strategy to find new radioprotective agents. Here, we applied a computational approach to discover new radioprotectors in silico by comparing publicly available gene expression data of ionizing radiation-treated samples from the Gene Expression Omnibus (GEO) database with gene expression signatures of more than 1309 small-molecule compounds from the Connectivity Map (cmap) dataset. Among the best compounds predicted to be therapeutic for ionizing radiation damage by this approach were some previously reported radioprotectors and baclofen (P<0.01), a chemical that was not previously used as radioprotector. Validation using a cell-based model and a rodent in vivo model demonstrated that treatment with baclofen reduced radiation-induced cytotoxicity in vitro (P<0.01), attenuated bone marrow damage and increased survival in vivo (P<0.05). These findings suggest that baclofen might serve as a radioprotector. The drug repurposing strategy by connecting the GEO data and cmap can be used to identify known drugs as potential radioprotective agents.
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China; Hospital Attached to Aeromedicine Institute of PLA, Beijing 100089, P.R. China.
Lei
L
Ren
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China.
Dafei
D
Xie
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China.
Peng
P
Li
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China.
Xinyan
X
Qu
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China.
Xiujuan
X
Zhang
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China.
Yaling
Y
Xing
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China.
Pingkun
P
Zhou
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China. Electronic address: boxc@bmi.ac.cn.
Xiaochen
X
Bo
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China. Electronic address: zhouzhe@bmi.ac.cn.
Zhe
Z
Zhou
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China. Electronic address: sqwang@bmi.ac.cn.
Shengqi
S
Wang
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects; D058492:Drug Repositioning / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects
D011837:Radiation-Protective Agents; D001418:Baclofen
Baclofen; Radiation protector; Repurposing