Background: Ionizing radiation often causes severe injuries to radiosensitive tissues, especially haematopoietic system. Novel radioprotective drugs with low toxicity and high effectiveness are required. Prolyl hydroxylases domain (PHD) inhibitors have been reported to protect against radiation-induced gastrointestinal toxicity. In this study, we demonstrated the protective effects of a PHD inhibitor, roxadustat (FG-4592), against radiation-induced haematopoietic injuries in vitro and in vivo.
Methods: Tissue injuries were evaluated by Haematoxilin-Eosin (HE) staining assay. HSCs were determined by flow cytometry with the Lin- Sca-1+ c-Kit+ (LSK) phenotype. Cell apoptosis was determined by Annexin V/PI staining assay. Immunofluorescence was performed to measure radiation-induced DNA damage. A western blot assay was used to detect the changes of proteins related to apoptosis.
Results: We found that FG-4592 pretreatment increased survival rate of irradiated mice and protected bone marrow and spleen from damages. Number of bone marrow cells (BMCs) and LSK cells were also increased both in irradiated mice and recipients after bone marrow transplantation (BMT). FG-4592 also protected cells against radiation-induced apoptosis and double strand break of DNA.
Conclusions: Our data showed that FG-4592 exhibited radioprotective properties in haematopoietic system both in vivo and in vitro through up-regulating HIF-1α, indicating a potential role of FG-4592 as a novel radioprotector.
Keywords: HIF; FG-4592; irradiation; radioprotection.
© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.