Screen identifies fasudil as a radioprotector on human fibroblasts

Yanling Yao; Chen Chen; Zuchao Cai; Guochao Liu; Chenxia Ding; David Lim; Dong Chao; Zhihui Feng

doi:10.1093/toxres/tfac042

Screen identifies fasudil as a radioprotector on human fibroblasts

Toxicol Res (Camb). 2022 Jul 22;11(4):662-672. doi: 10.1093/toxres/tfac042. eCollection 2022 Aug.

Authors

Yanling Yao¹, Chen Chen¹, Zuchao Cai¹, Guochao Liu¹, Chenxia Ding¹, David Lim^{2

3}, Dong Chao¹, Zhihui Feng¹

Affiliations

¹ Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
² Health services Management, School of Science and Health, Translational Health Research Institute, Western Sydney University, Campbelltown 1797, Australia.
³ College of Medicine and Public Health, Flinders University, Bedford Park 5042, Australia.

Abstract

Background: Radioprotectors safeguard biological system exposed to ionizing radiation (IR) by protecting normal cells from radiation damage during radiotherapy. Due to the toxicity and limited clinical utility of the present radioprotectors, it prompts us to identify novel radioprotectors that could alleviate IR-induced cytotoxicity of normal tissues.

Aims and methods: To identify new radioprotectors, we screened a chemical molecular library comprising 253 compounds in normal human fibroblasts (HFs) or 16HBE cells upon IR by CCK-8 assays and clonogenic survival assays. Fasudil was identified as a potential effective radioprotector.

Results: The results indicated that Fasudil exerts radioprotective effects on HFs against IR-induced DNA double-strand breaks (DSBs) through the regulation of DSB repair. Fasudil increased homologous recombination (HR) repair by 45.24% and decreased non-homologous end-joining (NHEJ) by 63.88% compared with untreated cells, without affecting changes to cell cycle profile. We further found that fasudil significantly facilitated the expression and foci formation of HR core proteins such as Rad51 and BRCA1 upon IR, and decreased the expression of NHEJ-associated proteins such as DNA-PKcs at 24 h post-IR.

Conclusion: Our study identified fasudil as a novel radioprotector that exert radioprotective effects on normal cells through regulation of DSB repair by promoting HR repair.

Keywords: DNA double-strand breaks; fasudil; homologous recombination; human fibroblasts; non-homologous end-joining; radioprotective effects.