title: Radioprotection by the histone deacetylase inhibitor phenylbutyrate.
abstract: 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.
authors: Scientific Research Department, Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University, Bethesda, MD 20889-5603, USA. millera@afrri.usuhs.mil
authors: Alexandra C
authors: AC
authors: Miller
authors: Stuart
authors: S
authors: Cohen
authors: Michael
authors: M
authors: Stewart
authors: Rafael
authors: R
authors: Rivas
authors: Paul
authors: P
authors: Lison
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006655:Histone Deacetylases / Q000378:metabolism*; D008297:Male; D051379:Mice; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000633:toxicity; D011837:Radiation-Protective Agents / Q000494:pharmacology* / Q000633:toxicity; D015996:Survival Rate; D023382:Toxicity Tests, Acute
chemical_list: D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; D011837:Radiation-Protective Agents; D006655:Histone Deacetylases