Radioprotection by the histone deacetylase inhibitor phenylbutyrate

Scientific Research Department, Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University, Bethesda, MD 20889-5603, USA.
Biophysik (Impact Factor: 1.53). 09/2011; 50(4):585-96. DOI: 10.1007/s00411-011-0384-7
Source: PubMed

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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    • "4-phenylbutyrate (4-PBA) is a low molecular weight chemical chaperone that is currently approved for clinical use in urea cycle disorders. 4-PBA has 3 main biologic effects: it is an ammonia scavenger [16], a weak histone deacetylase (HDAC) inhibitor [17], and an ER stress inhibitor [18]–[20]. It has been shown to restore glucose homeostasis in obese mice [21], and has been used in clinical trials for treatment of cystic fibrosis [22], sickle cell disease [23], neurodegenerative diseases [24] and certain cancers [25]–[27]. "
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    ABSTRACT: Different forms of acute kidney injury (AKI) have been associated with endoplasmic reticulum (ER) stress; these include AKI caused by acetaminophen, antibiotics, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic known to induce ER stress and is a commonly used inducer of AKI. 4-phenylbutyrate (4-PBA) is an FDA approved substance used in children who suffer from urea cycle disorders. 4-PBA acts as an ER stress inhibitor by aiding in protein folding at the molecular level and preventing misfolded protein aggregation. The main objective of this study was to determine if 4-PBA could protect from AKI induced by ER stress, as typified by the TM-model, and what mechanism(s) of 4-PBA's action were responsible for protection. C57BL/6 mice were treated with saline, TM or TM plus 4-PBA. 4-PBA partially protected the anatomic segment most susceptible to damage, the outer medullary stripe, from TM-induced AKI. In vitro work showed that 4-PBA protected human proximal tubular cells from apoptosis and TM-induced CHOP expression, an ER stress inducible proapoptotic gene. Further, immunofluorescent staining in the animal model found similar protection by 4-PBA from CHOP nuclear translocation in the tubular epithelium of the medulla. This was accompanied by a reduction in apoptosis and GRP78 expression. CHOP(-/-) mice were protected from TM-induced AKI. The protective effects of 4-PBA extended to the ultrastructural integrity of proximal tubule cells in the outer medulla. When taken together, these results indicate that 4-PBA acts as an ER stress inhibitor, to partially protect the kidney from TM-induced AKI through the repression of ER stress-induced CHOP expression.
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    • "Our findings will inform future clinical studies designed to explore how panobinostat might be used in combination with other therapies to improve outcomes in patients with epithelial tumours, for example, through its sequential delivery with other mitosis blocking agents such as taxanes. Given that there is now considerable interest in exploring how epigenetic priming may make cancer cells more sensitive to radiotherapy, there is a compelling case for adding panobinostat to the list of HDAC inhibitors currently under evaluation as potential modulators of radiation sensitivity414243. We are currently addressing these possibilities to optimise the use of panobinostat in future pre-clinical trials designed to determine whether these combinations would be more effective and less toxic than current regimens. "
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