Sodium Phenylbutyrate

Sodium Phenylbutyrate is a transcriptional regulators that act by altering chromatin structure via the modulation of HDAC activity.

Averting the foul taste of pediatric medicines improves adherence and can be lifesaving - Pheburane((R)) (sodium phenylbutyrate).[Pubmed:27799750]

Patient Prefer Adherence. 2016 Oct 21;10:2141-2144.

BACKGROUND: Children's aversions to poor and mostly bitter tastes and their inability to swallow tablets and capsules are major challenges in pediatric medicine. Sodium Phenylbutyrate (NaPB) is a lifesaving waste nitrogen, alternative to urea nitrogen, for individuals suffering from urea cycle disorders. A major issue in the use of NaPB is its highly foul taste, which often leads to children being unable to consume it, resulting in ineffective treatment, or alternatively, necessitating the application of the drug through a nasogastric tube or gastrostomy. METHODS: This study reviews the published data on a novel formulation of NaPB, Pheburane((R)) granules, which begin to release their NaPB after a lag time of ~10 seconds followed by a slow release over several minutes. RESULTS: The taste-masked granule formulation of NaPB dramatically improves the acceptability of the drug by children and appears in initial studies to be both safe and effective. CONCLUSION: While more studies are needed to substantiate and enrich these initial trials, the available data provide a telling example where masking the drug taste of medicine for children can sometimes be the difference between life and death.

[Effect of sodium phenylbutyrate on the sensitivity of PC3/DTX-resistant prostate cancer cells to docetaxel].[Pubmed:28109113]

Nan Fang Yi Ke Da Xue Xue Bao. 2017 Novemer 20;37(1):130-134.

OBJECTIVE: To investigate the effect of Sodium Phenylbutyrate (SPB) in modulating docetaxel resistance in human prostate cancer cells in vitro. METHODS: A PC3/docetaxel-resistant human prostate cancer cell line PC3/DTX was induced and examined for proliferation, viability, and cell inhibition rate in the presence of SPB. The concentration of concentration of docetaxel required to kill 50% of PC3/DTX cells incubated with 0, 1, 2, and 4 mmol/L SPB was determined using MTT assay. Cell apoptosis rate was analyzed with flow cytometry and the cellular expressions of p21, cyclin D1 and survivin proteins were detected using Western blotting. RESULTS: Treatment of PC3/DTX cells with 0, 1, 2, and 4 mmol/L of SPB for 48 h resulted in cell viabilities of (99.85-/+2.69)%, (84.68-/+3.87)%, (68.65-/+4.54)% and (43.54-/+5.69)%, and cell inhibition rates of (10.69-/+3.65)%, (25.78-/+4.58)%, (54.68-/+3.98)% and (69.84-/+6.54)%, respectively (P<0.05). The concentration of docetaxel required to kill 50% of PC3/DTX cells cultured in the presence of with 0, 1, 2, and 4 mmol/L SPB was 135.98-/+2.69, 109.65-/+3.87, 87.65-/+3.84 and 64.62-/+2.98 nmol/L, respectively (P<0.05), and the cell apoptosis rates were (7.2-/+0.8)%, (10.2-/+0.9)%, (19.8-/+2.1)% and (27.4-/+2.5)%, respectively. SPB treatment promoted the protein expression of p21 and suppressed the expressions of cyclin D1 and survivin in PC3/DTX cells. CONCLUSION: SPB can affect the expressions of p21, cyclin D1, and survivin in PC3/DTX cells and increase the sensitivity to the drug-resistant cells to docetaxel.

Sodium 4-Phenylbutyrate Attenuates Myocardial Reperfusion Injury by Reducing the Unfolded Protein Response.[Pubmed:27909014]

J Cardiovasc Pharmacol Ther. 2017 May;22(3):283-292.

BACKGROUND: The unfolded protein response (UPR) plays a pivotal role in ischemia-reperfusion (I/R) injury in various organs such as heart, brain, and liver. Sodium 4-phenylbutyrate (PBA) reportedly acts as a chemical chaperone that reduces UPR. In the present study, we evaluated the effect of PBA on reducing the UPR and protecting against myocardial I/R injury in mice. METHODS: Male C57BL/6 mice were subjected to 30-minute myocardial I/R, and were treated with phosphate-buffered saline (as a vehicle) or PBA. RESULTS: At 4 hours after reperfusion, mice treated with PBA had reduced serum cardiac troponin I levels and numbers of apoptotic cells in left ventricles (LVs) in myocardial I/R. Infarct size had also reduced in mice treated with PBA at 48 hours after reperfusion. At 2 hours after reperfusion, UPR markers, including eukaryotic initiation of the factor 2alpha-subunit, activating transcription factor-6, inositol-requiring enzyme-1, glucose-regulated protein 78, CCAAT/enhancer-binding protein (C/EBP) homologous protein, and caspase-12, were significantly increased in mice treated with vehicle compared to sham-operated mice. Administration of PBA significantly reduced the I/R-induced increases of these markers. Cardiac function and dimensions were assessed at 21 days after I/R. Sodium 4-phenylbutyrate dedicated to the improvement of cardiac parameters deterioration including LV end-diastolic diameter and LV fractional shortening. Consistently, PBA reduced messenger RNA expression levels of cardiac remodeling markers such as collagen type 1alpha1, brain natriuretic peptide, and alpha skeletal muscle actin in LV at 21 days after I/R. CONCLUSION: Unfolded protein response mediates myocardial I/R injury. Administration of PBA reduces the UPR, apoptosis, infarct size, and preserved cardiac function. Hence, PBA may be a therapeutic option to attenuate myocardial I/R injury in clinical practice.

TXNIP mediates the differential responses of A549 cells to sodium butyrate and sodium 4-phenylbutyrate treatment.[Pubmed:28033672]

Cancer Med. 2017 Feb;6(2):424-438.

Sodium butyrate (NaBu) and sodium 4-phenylbutyrate (4PBA) have promising futures in cancer treatment; however, their underlying molecular mechanisms are not clearly understood. Here, we show A549 cell death induced by NaBu and 4PBA are not the same. NaBu treatment induces a significantly higher level of A549 cell death than 4PBA. A gene expression microarray identified more than 5000 transcripts that were altered (>1.5-fold) in NaBu-treated A549 cells, but fewer than 2000 transcripts that were altered in 4PBA. Moreover, more than 100 cell cycle-associated genes were greatly repressed by NaBu, but slightly repressed by 4PBA; few genes were significantly upregulated only in 4PBA-treated cells. Gene expression was further validated by other experiments. Additionally, A549 cells that were treated with these showed changes in glucose consumption, caspase 3/7 activation and histone modifications, as well as enhanced mitochondrial superoxide production. TXNIP was strongly induced by NaBu (30- to 40-fold mRNA) but was only slightly induced by 4PBA (two to fivefold) in A549 cells. TXNIP knockdown by shRNA in A549 cells significantly attenuated caspase 3/7 activation and restored cell viability, while TXNIP overexpression significantly increased caspase 3/7 activation and cell death only in NaBu-treated cells. Moreover, TXNIP also regulated NaBu- but not 4PBA-induced H4K5 acetylation and H3K4 trimethylation, possibly by increasing WDR5 expression. Finally, we demonstrated that 4PBA induced a mitochondrial superoxide-associated cell death, while NaBu did so mainly through a TXNIP-mediated pathway. The above data might benefit the future clinic application.

HDAC inhibitor 4-phenylbutyrate preserves immature phenotype of human embryonic midbrain stem cells: implications for the involvement of DNA methyltransferase.[Pubmed:21894430]

Int J Mol Med. 2011 Dec;28(6):977-83.

Cell replacement and gene therapy using neural stem cells (NSCs) have been widely touted as a promising treatment for CNS diseases including brain tumors. Histone deacetylase (HDAC) inhibitors have been used to explore mechanisms behind the lineage-specific differentiation of NSCs and as modulators of gene therapy. We have used the human embryonic midbrain stem cell line NGC-407 and the HDAC inhibitor 4-phenylbutyrate (4-PB) to investigate the differentiation from epigenetic perspectives. NGC-407 cells can differentiate into both neurons and glial cells, evidenced by morphological characteristics as well as up-regulation of the respective markers beta-tubulin III and glial fibrillary acidic protein (GFAP) and simultaneous down-regulation of the NSC-marker nestin. Genomic DNA extracted from the differentiating cells was globally more methylated than that of the proliferating cells. The differentiating cells showed increased expression of the de novo DNA methyltransferase DNMT3B along with strong immunoreactivity in the cell nuclei. When these cells were treated with 4-PB, both the astrocytic and the neuronal differentiation phenotypes were suppressed, which paralleled a substantially weakened DNMT3B immunoreactivity in the cell nuclei. Importantly, 4-PB treatment preserves the immature phenotype of these differentiating cells as indicated by Western blot analysis and immunocytochemical analyses of the NSC markers, nestin and CD133. Nestin becomes entirely degraded 5 days after induction of differentiation, but upon exposure to 4-PB, some of the differentiating cells retain the integrity of nestin and concurrently, CD133 is also up-regulated. Taken together, the data suggests that HDAC activity is necessary for human embryonic NSC differentiation.

Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells.[Pubmed:17164759]

Br J Cancer. 2007 Jan 15;96(1):73-81.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease and one of the cancer entities with the lowest life expectancy. Beside surgical therapy, no effective therapeutic options are available yet. Here, we show that 4-phenylbutyrate (4-PB), a known and well-tolerable inhibitor of histone deacetylases (HDAC), induces up to 70% apoptosis in all cell lines tested (Panc 1, T4M-4, COLO 357, BxPc3). In contrast, it leads to cell cycle arrest in only half of the cell lines tested. This drug increases gap junction communication between adjacent T3M-4 cells in a concentration-dependent manner and efficiently inhibits cellular export mechanisms in Panc 1, T4M-4, COLO 357 and BxPc3 cells. Consequently, in combination with gemcitabine 4-PB shows an overadditive effect on induction of apoptosis in BxPc3 and T3M-4 cells (up to 4.5-fold compared to single drug treatment) with accompanied activation of Caspase 8, BH3 interacting domain death agonist (Bid) and poly (ADP-ribose) polymerase family, member 1 (PARP) cleavage. Although the inhibition of the mitogen-activated protein kinase-pathway has no influence on fulminant induction of apoptosis, the inhibition of the JNK-pathway by SP600125 completely abolishes the overadditive effect induced by the combined application of both drugs, firstly reported by this study.

Histone deacetylase inhibitor 4-phenylbutyrate suppresses GAPDH mRNA expression in glioma cells.[Pubmed:15138583]

Int J Oncol. 2004 Jun;24(6):1419-25.

The histone deacetylase (HDAC) inhibitor 4-phenylbutyrate (4-PB) is a non-toxic compound that can induce differentiation and promote maturation of various types of malignant cells. In the present study we show that 4-PB inhibit glioma cell proliferation, induce apoptosis and decrease mRNA expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in a concentration-dependent manner. Proliferation of established rat glioma cell lines (RG2 and C6) in culture was significantly decreased after treatment with 4-PB (2-40 mM). Low concentrations of 4-PB (2-20 mM) induced cell differentiation followed by apoptosis, whereas higher concentrations of 4-PB (40 mM) induced cell necrosis. Also, low concentrations of 4-PB significantly decreased GAPDH mRNA expression in C6 and RG2 rat glioma cells, suggesting a link between decreased cell proliferation, energy consumption, and down-regulation of GAPDH gene expression. We have found that GAPDH mRNA expression is markedly increased in human glioblastoma tissues. Therefore, the novel effect of 4-PB described here may offer means to suppress growth of glioma cells by diminishing the key reaction in glycolysis as a therapeutic approach for cancer.

Benzenebutyric acid sodium (4-Phenylbutyric acid sodium) is an inhibitor of HDAC and endoplasmic reticulum (ER) stress, used in cancer and infection research.

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