Radiation protection and mitigation potential of phenylbutyrate: delivered via oral administration

Abstract

Purpose: Phenylbutyrate (PB), a histone deacetylase inhibitor (HDACi) has demonstrated radiation protection in both in vitro and in vivo models. Studies previously demonstrated that PB and other HDAC inhibitors could inhibit radiation lethality in vivo by subcutaneous (s.c) injection. The objective of this study was to test the ability of oral PB treatment to protect against or to mitigate acute gamma radiation-induced lethality in vivo.

Materials and methods: Human osteoblasts cells were used to evaluate radiation survival when PB was delivered pre- or post-radiation. A 30-day radiation lethality study was used to assess the radioprotective (pre-radiation) and radiomitigative (post-radiation) capability of PB. Possible mechanisms evaluated were antioxidant activity effects, HDAC inhibition, DNA damage, and hematological recovery.

Results: Treatment of HOS cells with PB 50 μM either before or after radiation increased radiation resistance as assessed by clonogenic survival. Western blot studies showed that PB treatment acetylated histones in vivo and ameliorated the radiation-induced reduction in acetylated histone-4 (H4). Pre-radiation oral administration of PB (10 mg/kg) provided radioprotection against gamma radiation (7–11.5 Gy) with a dose reduction factor of 1.25 (p = 0.001). PB oral administration post-radiation provided moderate radiation mitigation against gamma radiation (7–11.5 Gy) and demonstrated a dose reduction factor of 1.18 (p = 0.05). PB pre-radiation and post-radiation treatment was associated with significant elevations in neutrophils and platelets and attenuation of DNA damage.

Conclusions: These results indicate that oral PB has potential as a radiation protector and a radiation mitigator and that potential mechanisms of action include attenuation of DNA damage, antioxidant activity, and bone marrow protection.

Keywords:

• Radiation protection
• mitigation
• phenylbutyrate
• survival

Acknowledgements

The authors are grateful to Dr Mark Whitnall and Dr Christopher Lissner for their encouragement and support of this work. The assistance of the AFRRI Veterinary Science Department and the USUHS Graphics office was invaluable to the project. The technical assistance of Rene Albert is greatly appreciated.

Disclosure statement

No potential conflict of interest was reported by the authors.

Disclaimer

This work is the opinion of the authors and is not the opinion of the U.S. Government, Department of Defense, the Uniformed Services University, or the Armed Forces Radiobiology Research Institute.

Funding

The authors would also like to thank the US Defense Threat Reduction Agency for their continued grant support (G1B2BJ, G1B2EM, and G2B2EM).

Notes on contributors

Alexandra C. Miller, PhD, is a principal investigator at the Armed Forces Radiobiology Research Institute, an adjunct associate professor in the Department of Radiology and Radiological Science at the Uniformed Services University of the Health Sciences, and an adjunct senior scientist at Columbia University Center for Radiological Research.

Rafael Rivas, MS, is a technical specialist in animal science at the Armed Forces Radiobiology Research Institute, at the Uniformed Services University of the Health Sciences.

Robert McMahon, MAJ, USA, MS, is a nuclear engineer at the Armed Forces Radiobiology Research Institute, at the Uniformed Services University of the Health Sciences.

Karvelisse Miller is a technical specialist in animal science at the Armed Forces Radiobiology Research Institute, at the Uniformed Services University of the Health Sciences.

Leonard Tesoro is a laboratory manager and a technical specialist in radiation science at the Armed Forces Radiobiology Research Institute, at the Uniformed Services University of the Health Sciences.

Vilmar Villa is a technical specialist in cell culture and animal models at the Armed Forces Radiobiology Research Institute, at the Uniformed Services University of the Health Sciences.

Daminik Yanushkevich is a technical specialist in clinical laboratory science at the Armed Forces Radiobiology Research Institute, at the Uniformed Services University of the Health Sciences.

Paul Lison, MD, PhD, is a clinician and radiation oncologist at the Uniformed Services University of the Health Sciences.