Radioprotection by the histone deacetylase inhibitor phenylbutyrate

• Published in: Radiation and environmental biophysics 2011-11, Vol.50 (4), p.585-596
• Main Authors: Miller, Alexandra C., Cohen, Stuart, Stewart, Michael, Rivas, Rafael, Lison, Paul
• Format: Article
• Language: English
• Subjects: Animals; Biological and Medical Physics; Biophysics; Blood Platelets - drug effects; Blood Platelets - radiation effects; Deoxyribonucleic acid; DNA; DNA Damage; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Ecosystems; Effects of Radiation/Radiation Protection; Electrophoresis; Environmental Physics; Erythrocytes - cytology; Erythrocytes - drug effects; Erythrocytes - radiation effects; Gamma rays; Hematopoiesis - drug effects; Hematopoiesis - radiation effects; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - toxicity; Histone Deacetylases - metabolism; Male; Mice; Monitoring/Environmental Analysis; Original Paper; Phenylbutyrates - pharmacology; Phenylbutyrates - toxicity; Physics; Physics and Astronomy; Radiation; Radiation protection; Radiation-Protective Agents - pharmacology; Radiation-Protective Agents - toxicity; Survival Rate; Toxicity Tests, Acute; Tumors
• ISSN: 0301-634X; 1432-2099
• DOI: 10.1007/s00411-011-0384-7

The histone deacetylase inhibitor (HDAC), phenylbutyrate (PB), is a novel anti-tumor agent. Studies have demonstrated that HDAC inhibitors can suppress cutaneous radiation syndrome and stimulate hematopoiesis. The objective of this study was to test the ability of PB treatment to protect against acute gamma-radiation-induced lethality in the DBA/2 mouse model. A 30-day radiation lethality study was used to assess radioprotective capability of PB. Mechanisms were evaluated using western blots, flow cytometry, and the single-cell gel electrophoresis assay. Western blot studies showed that PB treatment acetylated histones in vivo. For radiation protection studies, prophylactic administration of PB (24 h preradiation; 1–50 mg/kg) provided radioprotection against gamma radiation (8–9.5 Gy) and PB demonstrated a DRF of 1.31 ( P  = 0.001; 95% confidence interval: 1.27, 1.36). When PB (10 mg/kg) was administered post-radiation (4 h), it also provided significant radioprotection at 8.0 Gy radiation ( P  = 0.022). PB treatment before radiation was associated with significant elevations in neutrophils and platelets following radiation. Results from single-cell gel electrophoresis of peripheral blood leukocytes demonstrated that PB treatment before radiation can attenuate DNA damage and inhibit radiation-induced apoptosis. These results indicate that an HDAC inhibitor like PB has potential as a radiation protector and that mechanisms of action include attenuation of DNA damage and inhibition of apoptosis.