Yao Yanling, Chen Chen, Cai Zuchao, Liu Guochao, Ding Chenxia, Lim David, Chao Dong, Feng Zhihui
Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
Health services Management, School of Science and Health, Translational Health Research Institute, Western Sydney University, Campbelltown 1797, Australia.
Toxicol Res (Camb). 2022 Jul 22;11(4):662-672. doi: 10.1093/toxres/tfac042. eCollection 2022 Aug.
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.
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.
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.
Our study identified fasudil as a novel radioprotector that exert radioprotective effects on normal cells through regulation of DSB repair by promoting HR repair.
辐射防护剂通过在放射治疗期间保护正常细胞免受辐射损伤来保护暴露于电离辐射（IR）的生物系统。由于目前辐射防护剂的毒性和有限的临床效用，促使我们寻找能够减轻IR诱导的正常组织细胞毒性的新型辐射防护剂。
为了鉴定新的辐射防护剂，我们通过CCK-8测定法和克隆形成存活测定法，在受IR照射的正常人成纤维细胞（HFs）或16HBE细胞中筛选了一个包含253种化合物的化学分子文库。法舒地尔被鉴定为一种潜在有效的辐射防护剂。
结果表明，法舒地尔通过调节双链断裂（DSB）修复，对HFs发挥辐射防护作用，抵抗IR诱导的DNA双链断裂。与未处理的细胞相比，法舒地尔使同源重组（HR）修复增加45.24%，使非同源末端连接（NHEJ）减少63.88%，且不影响细胞周期分布的变化。我们进一步发现，法舒地尔在IR照射后显著促进了HR核心蛋白如Rad51和BRCA1的表达和焦点形成，并在IR照射后24小时降低了NHEJ相关蛋白如DNA-PKcs的表达。
我们的研究鉴定法舒地尔为一种新型辐射防护剂，其通过促进HR修复来调节DSB修复，从而对正常细胞发挥辐射防护作用。
