Miller Alexandra C, Cohen Stuart, Stewart Michael, Rivas Rafael, Lison Paul
Scientific Research Department, Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University, Bethesda, MD 20889-5603, USA.
Radiat Environ Biophys. 2011 Nov;50(4):585-96. doi: 10.1007/s00411-011-0384-7. Epub 2011 Sep 3.
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.
组蛋白去乙酰化酶抑制剂（HDAC）苯丁酸钠（PB）是一种新型抗肿瘤药物。研究表明，HDAC抑制剂可抑制皮肤辐射综合征并刺激造血。本研究的目的是在DBA/2小鼠模型中测试PB治疗对急性γ射线辐射致死的防护能力。采用为期30天的辐射致死性研究来评估PB的辐射防护能力。通过蛋白质免疫印迹法、流式细胞术和单细胞凝胶电泳试验评估作用机制。蛋白质免疫印迹研究表明，PB治疗可使体内组蛋白乙酰化。在辐射防护研究中，预防性给予PB（辐射前24小时；1 - 50毫克/千克）可对γ射线辐射（8 - 9.5戈瑞）提供辐射防护，PB的剂量率因子为1.31（P = 0.001；95%置信区间：1.27, 1.36）。当在辐射后（4小时）给予PB（10毫克/千克）时，在8.0戈瑞辐射下也提供了显著的辐射防护（P = 0.022）。辐射前给予PB治疗与辐射后中性粒细胞和血小板显著升高有关。外周血白细胞单细胞凝胶电泳结果表明，辐射前给予PB治疗可减轻DNA损伤并抑制辐射诱导的细胞凋亡。这些结果表明，像PB这样的HDAC抑制剂有作为辐射防护剂的潜力，其作用机制包括减轻DNA损伤和抑制细胞凋亡。
