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Radioprotection by the histone deacetylase inhibitor phenylbutyrate

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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.

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Abbreviations

PB:

Phenylbutyrate

HDAC:

Histone deacetylase inhibitor

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Acknowledgments

The authors are grateful to Dr. Christopher Lissner and Dr. John Gilstad for their encouragement and support of this work. The assistance of the AFRRI Veterinary Science Department was invaluable to the project. The authors would also like to thank the US Defense Threat Reduction Agency for their continued grant support (G1B2BJ and G1B2EM).

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Authors and Affiliations

  1. Scientific Research Department, Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University, 8901 Wisconsin Ave, Bethesda, MD, 20889-5603, USA

    Alexandra C. Miller, Stuart Cohen, Michael Stewart, Rafael Rivas & Paul Lison

  2. Department of Occupational and Environmental Medicine, University of Paris, 93017, Paris, France

    Paul Lison

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  1. Alexandra C. Miller
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  2. Stuart Cohen
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  4. Rafael Rivas
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Correspondence to Alexandra C. Miller.

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Miller, A.C., Cohen, S., Stewart, M. et al. Radioprotection by the histone deacetylase inhibitor phenylbutyrate. Radiat Environ Biophys 50, 585–596 (2011). https://doi.org/10.1007/s00411-011-0384-7

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  • DOI: https://doi.org/10.1007/s00411-011-0384-7

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