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PubMed2002

Differential induction of numerical chromosome changes by sodium butyrate in two transformed cell lines.

Transformed cell lines generally exhibit similar response to a given chemical. However, when two transformed cell lines, the Chinese hamster (CHO 9) and mouse (L929) were treated with sodium butyrate (SB) to investigate its effect on chromosome distribution, the two lines behaved differently from each other. At concentrations as low as 10(-7) M, the CHO 9 cells exhibited polyploidy as well as errors of numerical distributions resulting in aneuploidy. The majority of aneuploid cells were in quasitetraploid range indicating an association between the induction of polyploidy and aneuploidy. Upon staining with spindle antibody, the CHO cells exhibited a disarray of spindle microtubules as well as an abnormal cytoskeleton. In many instances the metaphase chromosomes were found to have a distorted spindle or lack an associated spindle altogether. The L929 cells, however, turned out to be far less sensitive to SB: a 100-fold increase in concentration of sodium butyrate (10(-5) M) did not result in production of polyploid cells. However, when the extent of aneuploidy induction was measured by using a marker chromosome, both loss and gain of the chromosome was noticed. The effect of SB on the spindle was much more modest than it was the case with CHO cells as only minor disarray in cytoskeleton or spindle morphology was observed. The L929 cells, however, showed some effect on microtubule orientation as well as an effect on the segmentation of midbody. The application of SB resulted in less intense and more diffuse phosphorylation; the chromosomes had a punctate appearance of the label compared with the solid appearance on untreated cells. This was ture for both species. In mouse, the centromeric heterochromatin, which generally is intensely labeled, appeared to be labeled only as intensely as euchromatin. The data show that different transformed cell lines do not respond similarly to SB.

Aneuploidy↗

PubMed2001

Prodrugs of butyric acid. Novel derivatives possessing increased aqueous solubility and potential for treating cancer and blood diseases.

The synthesis and biological activities of acidic, basic and neutral types of butyric acid (BA) prodrugs possessing increased aqueous solubility are described. The compounds are butyroyloxyalkyl derivatives of carboxylic acids, which possess functionalities suitable for aqueous solubilization. The anticancer activity of the prodrugs in vitro was evaluated by examining their effect on the growth of human colon, breast and pancreatic carcinoma cell lines, and their solubility in aqueous media was determined. The most promising compounds, with respect to activity and solubility, were found to be the butyroyloxymethyl esters of glutaric 2a and nicotinic acids 4a and phosphoric acid as its diethyl ester 10a, which displayed IC(50) values of 100 microM or lower. These prodrugs are expected to release formaldehyde upon metabolic hydrolysis. The corresponding butyroyloxyethyl esters (2b, 4b and 10b) that release acetaldehyde upon metabolism were significantly less potent. A similar correlation was observed for growth inhibition of the human prostate carcinoma cell lines PC-3 and LnCap and for induction of differentiation and apoptosis in the human myeloid leukemia cell line HL-60. The higher biological activity of the formaldehyde-releasing prodrugs 2a and 10a was further confirmed when induction of hemoglobin (Hb) synthesis in the human erythroleukemic cell line K562 was measured. Moreover, a therapeutic index (IC(50)/ED(50)) of ca. 5 was observed. The acute i.p. toxicity LD(50) in mice for 2a, 2b, 10a and 10b was similar and in the range of 400-600 mg kg(-1). The results obtained support the potential use of the butyric acid prodrugs for the treatment of neoplastic diseases and beta-globin disorders.

Animals↗

PubMed2001

Tumor cell differentiation by butyrate and environmental stress.

The present study shows that stress signaling plays a role in differentiation of K562, PANC1, HT29 and HL60 tumor cells: (1) Butyrate induced differentiation in K562, PANC1, and HT29 cells can be inhibited by SB203580, a specific inhibitor of p38 stress activated protein kinase. (2) Heat shock and hyperosmolarity increase expression of differentiation markers in K562, HT29, HL60 and in K562, PANC1, and HT29 cells, respectively. (3) Conversely, environmental stress induced differentiation in K562, HT29, and PANC1 cells can be inhibited by SB203580 and quercetin, a compound with heat shock pathway inhibiting activity. (4) Butyrate and environmental stress enhance either additively or synergistically differentiation of K562, HT29, PANC1 or HL60 cells, respectively. Stress signaling pathways might be an interesting pharmacologic target for differentiation therapy of malignant disease.

Butyrates↗

PubMed2002

Induction and superinduction of growth arrest and DNA damage gene 45 (GADD45) alpha and beta messenger RNAs by histone deacetylase inhibitors trichostatin A (TSA) and butyrate in SW620 human colon carcinoma cells.

Histone deacetylase (HDAC) inhibitors such as trichostatin (TSA) and butyrate have been shown to inhibit cancer cell proliferation, induce apoptosis and regulate the expression of genes involved in cell cycle. Although the precise mechanism underlying HDAC inhibitor-induced cell growth arrest is not fully understood, induction of cell cycle related genes such as p21(cip/waf), is thought to be important. Here we showed that in the SW620 human colon cancer cell line, TSA and butyrate induced the growth arrest and DNA damage gene 45alpha (GADD45alpha) and GADD45beta. Furthermore, GADD45beta and p21(cip/waf) messenger RNA were induced in the absence of protein synthesis, indicating that both genes were immediate target genes for TSA. Cyclohexamide and TSA super-induced the expression of GADD45alpha and beta, but not p21(cip/waf). Interestingly while mitogen-activated kinase (MEK) inhibitor PD98059 and p38 kinase inhibitor SB242235 were unable to affect GADD45 induction, two serine/threonine protein kinase inhibitors (H7 and H8) as well as curcumin completely blocked the super-induction. Concomitant to the inhibition of GADD45 induction, H7 and H8 also blocked TSA-induced apoptosis. Taken together, these results suggest that GADD45 induction may play important role in TSA-induced cellular effects.

Antigens, Differentiation↗

PubMed2002

Apoptosis sensitivity is not correlated with sensitivity to proliferation inhibition by the histone deacetylase inhibitors butyrate and TSA.

We investigated a set of cell lines as to their sensitivity to proliferation inhibition, on the one side, and apoptosis induction, on the other, by the core histone deacetylase inhibitors butyrate and trichostatin A (TSA), respectively. The results can be summarized as follows: (i) the investigated cell lines can be classified into three groups of high, medium and low sensitivity to proliferation inhibition by the histone deacetylase inhibitors; (ii) there is no correlation between the sensitivities to proliferation inhibition and the sensitivities to apoptosis induction by the histone deacetylase inhibitors; (iii) a comparison of the relative sensitivities to butyrate versus TSA with regard to proliferation inhibition and apoptosis induction, respectively, revealed that besides a good correlation most often encountered, there are also cell lines with conspicuously differing relative sensitivities to the two structurally different histone deacetylase inhibitors.

Apoptosis↗

PubMed2000

TNF-alpha modulates the differentiation induced by butyrate in the HT-29 human colon adenocarcinoma cell line.

The aim of this study was to determine whether and how tumour necrosis factor alpha (TNF-alpha) modulates butyrate effects. After the treatment of human colon adenocarcinoma HT-29 cells with sodium butyrate (NaBt), TNF-alpha or with their combinations we detected cell cycle (flow cytometry), cell proliferation (amidoblack and MTT assays), the amount of dead (floating) and apoptotic cells (flow cytometry and fluorescence microscopy), and the level of differentiation by alkaline phosphatase (ALP) activity (spectrophotometry), relative F-actin content (confocal laser scanning microscopy analysis) and E-cadherin expression (Western blot analysis). Both TNF-alpha and NaBt decreased cell growth in a dose-dependent manner. After combined treatment of the cells with both agents used, either none or additive effects were observed as compared with NaBt treatment alone. The level of dead and apoptotic cells was dose-dependently increased after this combined treatment. In contrast, TNF-alpha suppressed ALP activity and F-actin accumulation induced by NaBt. The results suggest that TNF-alpha does not influence significantly the antiproliferative effects of NaBt but, contrary to its potentiation of apoptosis, it markedly reduces NaBt-induced differentiation of HT-29 colon adenocarcinoma cells.

Alkaline Phosphatase↗

PubMed1995

(E)-4-(2-[[3-(indol-5-yl)-1-oxo-2-butenyl]amino]phenoxy)butyric acid derivatives: a new class of steroid 5 alpha-reductase inhibitors in the rat prostate. 1.

A series of (E)-4-(2-[[3-(indol-5-yl)-1-oxo-2-butenyl]amino]phenoxy)butyric acid derivatives was prepared, and the derivatives were demonstrated to be potent inhibitors of steroid 5 alpha-reductase in the rat prostate. The structure-activity relationships were as follows. An alpha-branched alkyl or benzyl substituent of proper size at position 1 of the indole is crucial for optimal enzyme inhibitory activity. N-Methylation of the amide NH resulted in complete loss of activity. Thus, coplanarity of the benzene ring and amide moiety is essential for such activity. Among the compounds prepared, (E)-4-(2-[[3-[1-[bis(4-fluorophenyl)methyl]indol-5-yl]-1-oxo-2- butenyl]-amino]phenoxy)butyric acid (57, KF18678) was one of the most potent compounds (rat prostate 5 alpha-reductase IC50 = 3.3 nM).

5-alpha Reductase Inhibitors↗

PubMed1998

Activity of pivaloyloxymethyl butyrate, a novel anticancer agent, on primary human tumor colony-forming units.

The anti-proliferative effects of pivaloyloxymethyl butyrate (AN-9), a butyric acid (BA) derivative with potent tumor-differentiating properties both in vitro and in vivo, was evaluated against colorectal, breast, lung, ovarian, renal cell, bladder, and other types of tumor colony-forming units in a human tumor cloning assay. A total of 76 evaluable specimens were exposed to AN-9 continuously, 48 of these were also exposed to BA continuously for direct comparison of the two agents, and 20 specimens were exposed to AN-9 for two hours. An in vitro inhibitory response was defined as a > or = 50% decrease in tumor colony formation in treated cells compared to untreated controls. Superior anti-tumor activity was observed with the continuous exposure to AN-9 (39% in vitro response at 100 microM and 70% at 200 microM) than with the two-hour exposure (20% at 100 microM and 25% at 200 microM). At a continuous concentration of 200 microM, AN-9 demonstrated greater tumor-specific activity than BA against melanoma (100% vs. 67%), ovarian (67% vs. 40%), breast (63% vs. 0%), non-small cell lung (60% vs. 10%), and colorectal tumor colony-forming units (62% vs. 20%). AN-9 is a novel differentiating agent with activity against colony-forming units derived from a variety of primary human tumors, including those that are considered relatively chemoresistant, and may thus provide a therapeutic alternative or addition to standard cytotoxic agents, if appropriate drug concentrations can be achieved in patients.

Antineoplastic Agents↗

PubMed2000

The expression of glucose regulated protein-94 in colorectal carcinoma cells treated by sodium butyrate.

The expression of glucose regulated protein 94 (GRP94) during the treatment of human colorectal carcinoma cell line-Clone A cells with sodium butyrate was studied. Sodium butyrate (SB) can cause functional and morphological effects on Clone A cells including growth arrest at G0/G1 stage and cell differentiation as observed by morphological changes, MTT and flow cytometry assays, as well as reduced Grp94 gene expression as shown by Northern blot and Western blot assays. The possible mechanism of the correlation between Grp94 gene expression and tumor growth inhibition and cell differentiation is briefly discussed.

Butyrates↗

PubMed1967

Rates of entry and oxidation of acetate, glucose, D(-)-beta-hydroxybutyrate, palmitate, oleate and stearate, and rates of production and oxidation of propionate and butyrate in fed and starved sheep.

1. Rates of entry and oxidation of a range of metabolites have been measured in tracheostomized sheep (diet, 800g. of lucerne chaff and 100g. of maize/day) by combining isotope-dilution techniques with the continuous measurement of total respiratory gas exchange, and (14)CO(2) production during the intravenous or intraruminal infusion of (14)C-labelled substrates. 2. Mean entry rates in fed and starved (24hr.) sheep respectively, expressed as mg./min./kg. body wt.(0.75), were: glucose, 5.0 (range 4.8-5.1, 2 observations) and 3.8 (3.2-4.2, 4); acetate, 10.8 (9.1-13.5, 4) and 5.8 (1); d(-)-beta-hydroxybutyrate, 1.4 (1) and 1.5 (0.8-2.4, 4); palmitate, oleate and stearate (starved sheep only) 1.0 (0.6-1.9, 7), 0.9 (0.2-1.6, 10) and 0.9 (0.5-1.1, 11) respectively. 3. Production rates of propionate and butyrate in continuously feeding sheep were 6.4 (4.7-8.3, 4) and 4.3 (3.4-6.1, 4) mg./min./kg.(0.75) respectively, and in starved (24hr.) sheep were 2.5 (2.2-2.9, 2) and 1.0 (0.8-1.2, 2) mg./min./kg.(0.75) respectively. 4. Calculated terminal values for the specific radioactivity of respiratory (14)CO(2) during measurements of entry rates and production rates were used to calculate the contributions of individual substrates to overall oxidative metabolism. Mean values for fed and starved sheep respectively were: glucose, 9.1 (8.6-9.6, 2) and 11.2 (5.9-15.1, 4)%; acetate, 31.6 (26.8-38.1, 4) and 22.1 (1)%; d(-)-beta-hydroxybutyrate, 10.4 (1) and 4.8 (1.9-7.7, 4)%; propionate, 23.0 (13.8-29.9, 4) and 7.1 (6.8-7.4, 2)%; butyrate, 16.5 (13.7-20.5, 4) and 5.3 (5.2-5.3, 2)%; palmitate, oleate and stearate (starved sheep only), 4.7 (2.0-7.7, 7), 4.0 (1.2-6.6, 10) and 4.4 (3.8-5.8, 9)% respectively. The sum of these values for individual substrates in fed and starved sheep, excluding that of beta-hydroxybutyrate and after correction of the glucose value for the known interrelations of this substrate with propionate, accounted for 76% and 58% respectively of total production of carbon dioxide. 5. Calculations based on the proportion of substrate entry directly oxidized indicated that the substrates studied accounted for 63% (fed sheep) and 43% (starved sheep) of total energy expenditure measured by oxygen uptake. The contribution of beta-hydroxybutyrate was excluded, and corrections were made for glucose-propionate interrelations, and for the different rates of oxidation of the methyl and carboxyl fragments of acetate. 6. The present results have been combined with those obtained earlier in this Laboratory to examine the relationships between rates of substrate entry and oxidation, and concentrations of substrate in blood. Rates of entry of acetate, glucose, d(-)-beta-hydroxybutyrate, palmitate and oleate (but not stearate) were well correlated with concentration in blood, and substrate contribution to production of carbon dioxide showed a similar correlation to blood concentration, except with glucose. 7. It was concluded that the general technique is of potential value in providing valid quantitative parameters of animal metabolism.

Acetates↗

PubMed1977

Effects of lactation of ketogenesis from oleate or butyrate in rat hepatocytes.

1. Rates of ketogenesis from endogenous butyrate or oleate were measured in isolated hepatocytes prepared from fed rats during different reproductive states [virgin, pregnant, early-lactating (2-4 days) and peak-lactating (10-17 days)]. In the peak-lactation group there was a decrease (25%) in the rate of ketogenesis from butyrate, but there were no differences in the rates between the other groups. Wth oleate, the rate of ketogenesis was increased in the pregnant and in the early-lactation groups compared with the virgin group, whereas the rate was 50% lower in the peak-lactation group. 2. Experiments with [1-(14)C]oleate indicated that these differences in rates of ketogenesis were not due to alterations in the rate of oleate utilization, but to changes in the amount of oleoyl-CoA converted into ketone bodies. 3. Although the addition of carnitine increased the rates of ketogenesis from oleate in all groups of rats, it did not abolish the differences between the groups. 4. Measurements of the accumulation of glucose and lactate showed that hepatocytes from rats at peak lactation had a higher rate of glycolytic flux than did hepatocytes from the other groups. After starvation, the rate of ketogenesis from oleate was still lower in the peak-lactation group compared with the control group. This suggests that the alteration in ketogenic capacity in the former group is not merely due to a higher glycolytic flux. 5. It is concluded that livers from rats at peak lactation have a lower capacity to produce ketone bodies from long-chain fatty acids which is due to an alteration in the partitioning of long-chain acyl-CoA esters between the pathways of triacylglycerol synthesis and beta-oxidation. The physiological relevance of this finding is discussed.

Animals↗

PubMed2005

DNA mismatch repair status may influence anti-neoplastic effects of butyrate.

HNPCC (hereditary non-polyposis colon cancer) is an autosomal-dominant disorder characterized by early-onset CRC (colorectal cancer). HNPCC is most often associated with mutations in the MMR (mismatch repair) genes hMLH1, hMSH2, hMSH6 or hPMS2. The mutator phenotype of a defective MMR system is MSI (microsatellite instability), which also occurs in approx. 15-25% of sporadic CRC cases, where it is associated with the hypermethylation of the promoter region of hMLH1. Dietary factors, including excessive alcohol consumption, ingestion of red meat and low folate intake, may increase the risk of MSI high tumour development. In contrast, aspirin may suppress MSI in MMR-deficient CRC cell lines. Butyrate, a short-chain-fatty-acid end product of carbohydrate fermentation in the colon, shares a number of anti-neoplastic properties with aspirin, including inhibiting proliferation and inducing apoptosis of CRC cells. Recent in vitro studies suggest that physiological concentrations of butyrate (0.5-2 mM) may have more potent anti-neoplastic effects in CRC cell lines deficient in MMR, but mechanisms for such a differential response remain to be established.

Anticarcinogenic Agents↗

PubMed1999

Effects of cytokines, butyrate and dexamethasone on serum amyloid A and apolipoprotein A-I synthesis in human HUH-7 hepatoma cells.

Serum amyloid A (SAA) and apolipoprotein A-I (apo A-I) are secreted by the liver. As concentrations of both apolipoproteins are inversely related under normal and acute-phase conditions, human HUH-7 hepatoma cells were stimulated with interleukin (IL)-1alpha (100 and 200 U), IL-6 (50 and 100 U), butyrate (2 mM) and dexamethasone (2 x 10(-7)M and 1 x 10(-6)M), alone or in combination. Changes in SAA and apo A-I synthesis were monitored after metabolic labelling of the cells with [35S]-methionine. Intracellular and secreted SAA and apo A-I were immunoprecipitated, separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), and the radioactivity in the corresponding bands was counted. Intracellular apolipoprotein levels were increased by all stimuli, either alone or in combination, between 2.7- and 5.5-fold (SAA) and between 2.8- and 4.1-fold (apo A-I), respectively. In a similar manner, apolipoprotein levels secreted by HUH-7 cells were increased between 3.1- and 4.3-fold (SAA) and between 1.9- and 3. 3-fold (apo A-I). Co-administration of cytokines, butyrate and/or dexamethasone had no pronounced synergistic effect on intracellular biosynthesis and secretion of SAA and apo A-I. The results from the present study suggest that apo A-I must not necessarily be considered as a negative acute-phase reactant.

Acute-Phase Reaction↗

PubMed2005

Rectal instillation of butyrate provides a novel clinically relevant model of noninflammatory colonic hypersensitivity in rats.

BACKGROUND & AIMS: The treatment of irritable bowel syndrome (IBS), characterized by abdominal pain and bloating, is empirical and often poorly efficient. Research lacks suitable models for studying the pathophysiologic mechanisms of the colonic hypersensitivity and new pharmacologic targets. The present study aimed to develop a novel model of colonic hypersensitivity possessing several of the characteristics encountered in patients with IBS. METHODS: Rats received enemas of a butyrate solution (8-1000 mmol/L) twice daily for 3 days. A time course was determined for colonic hypersensitivity (colorectal distention test) and referred cutaneous lumbar hyperalgesia (von Frey hairs). Macroscopic and histologic analyses were performed on colonic mucosa. The efficacy of morphine, U50488H (a kappa opioid agonist), and trimebutine on the 2 pain parameters was determined. Finally, the involvement of peptidergic C-fibers was evaluated using capsaicin-pretreated animals and treatments with calcitonin gene-related peptide (CGRP) and neurokinin 1 receptor antagonists. RESULTS: Butyrate enemas induced a sustained, concentration-dependent colonic hypersensitivity and, to a lesser extent, a referred cutaneous mechanical hyperalgesia, particularly in female rats, but no macroscopic and histologic modifications of the colonic mucosa, as observed in patients with IBS. Both pain parameters were sensitive to morphine, U50488H, trimebutine, neonatal capsaicin treatment, and the CGRP receptor antagonist but not to the neurokinin 1 receptor antagonist. CONCLUSIONS: These results present our noninflammatory model of chronic colonic hypersensitivity as a useful novel tool for studying IBS. The CGRP receptor antagonist-induced reduction of colonic hypersensitivity suggests that CGRP receptors may provide a promising target for treatment of IBS.

Animals↗

PubMed1978

Butyrate suppression of histone deacetylation leads to accumulation of multiacetylated forms of histones H3 and H4 and increased DNase I sensitivity of the associated DNA sequences.

Exposure of HeLa cells to Na butyrate leads to an accumulation of multiacetylated forms of histones H3 and H4. Our studies of histone acetylation in HeLa S-3 cells show that 7 mM butyrate suppresses the deacetylation of histones without influencing the rate of radioactive acetate incorporation. An alteration in nucleosome structure in highly acetylated chromatin is indicated by an increased rate of DNA degradation by DNase I. A close association of acetylated histones with the DNase I-sensitive sequences is confirmed by the finding that histones remaining after limited DNase I digestion are depleted in the multiacetylated forms of histones H3 and H4. DNase I treatment has also been found to selectively release [3H]acetyl-labeled H3 and H4 from avian erythrocyte nuclei under conditions previously shown to preferentially degrade the globlin genes in erthyrocyte chromatin. Our results are consistent with the view that histone acetylation provides a key to the mechanism for altering chromatin structure at the nucleosomal level, and that this may explain the selective DNase I sensitivity of transcriptionally active DNA sequences in different cell types.

Acetylation↗

PubMed2003

Induction of nonmuscle myosin heavy chain II-C by butyrate in RAW 264.7 mouse macrophages.

RAW 264.7 macrophages express nonmuscle myosin heavy chain II-A as the only significant nonmuscle myosin heavy chain isoform, with expression of nonmuscle myosin heavy chain II-B and II-C low or absent. Treatment of the cells with sodium butyrate, an inhibitor of histone deacetylase, led to the dose-dependent induction of nonmuscle myosin heavy chain II-C. Trichostatin A, another inhibitor of histone deacetylase, also induced nonmuscle myosin heavy chain II-C. Induction of nonmuscle myosin heavy chain II-C in response to these histone deacetylase inhibitors was attenuated by mithramycin, an inhibitor of Sp1 binding to GC-rich DNA sequences. Bacterial lipopolysaccharide alone had no effect on basal nonmuscle myosin heavy chain II-C expression, but attenuated butyrate-mediated induction of nonmuscle myosin heavy chain II-C. The effects of lipopolysaccharide were mimicked by the nitric oxide donors sodium nitroprusside and spermine NONOate, suggesting a role for nitric oxide in the lipopolysaccharide-mediated down-regulation of nonmuscle myosin heavy chain II-C induction. This was supported by experiments with the inducible nitric-oxide synthase inhibitor 1400W, which partially blocked the lipopolysaccharide-mediated attenuation of nonmuscle myosin heavy chain induction. 8-Bromo-cGMP had no effect on nonmuscle myosin heavy chain induction, consistent with a cGMP-independent mechanism for nitric oxide-mediated inhibition of nonmuscle myosin heavy chain II-C induction.

Acetyltransferases↗

PubMed2005

Sodium butyrate ameliorates histone hypoacetylation and neurodegenerative phenotypes in a mouse model for DRPLA.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disease caused by polyglutamine expansion within the Atrophin-1 protein. To study the mechanism of this disease and to test potential therapeutic methods, we established Atro-118Q transgenic mice, which express in neurons a mutant human Atrophin-1 protein that contains an expanded stretch of 118 glutamines. Consistent with the results from previous studies on transgenic mice that expressed mutant Atrophin-1 with 65 glutamines, Atro-118Q mice exhibited several neurodegenerative phenotypes that are commonly seen in DRPLA patients, including ataxia, tremors, and other motor defects. Overexpression of wild-type human Atrophin-1 could not rescue the motor and survival defects in Atro-118Q mice, indicating that the mutant protein with polyglutamine expansion does not simply function in a dominant negative manner. Biochemical analysis of Atro-118Q mice revealed hypoacetylation of histone H3 in brain tissues and thus suggested that global gene repression is an underlying mechanism for neurodegeneration in this mouse model. We further show that intraperitoneal administration of sodium butyrate, a histone deacetylase inhibitor, ameliorated the histone acetylation defects, significantly improved motor performance, and extended the average life span of Atro-118Q mice. These results support the hypothesis that transcription deregulation plays an important role in the pathogenesis of polyglutamine expansion diseases and suggest that reversion of transcription repression with small molecules such as sodium butyrate is a feasible approach to treating DRPLA symptoms.

Acetylation↗

PubMed2003

Transcriptional upregulation of the insulin-like growth factor binding protein IGFBP-3 by sodium butyrate increases IGF-independent apoptosis in human colonic adenoma-derived epithelial cells.

Sodium butyrate (NaBt) and the pro-apoptotic IGFBP-3 protein, expressed at the top of the normal colonic crypt, have both been implicated in the regulation of apoptosis in colonic epithelial cells. Recent studies in human breast and hepatic cell lines have shown that NaBt can transcriptionally upregulate IGFBP-3 expression. However, the role of butyrate in the regulation of IGFBP-3 expression in the colon is less clear, with reports of both up- and downregulation of the IGFBP-3 protein in colorectal cancer cell lines. In this study we have shown that the level of IGFBP-3 protein expression in colonic epithelial cells correlates with the p53 status of the cells; wildtype p53 cells secrete higher levels of IGFBP3 protein than mutant p53 cell lines. Data presented shows that, when treated with a dose of NaBt that induced significant apoptosis (4 mM for 48 h), there was an upregulation of IGFBP-3 protein in both wildtype and mutant p53 expressing cell lines. The NaBt-induced increase in secreted IGFBP-3 protein was associated with transcriptional upregulation of the IGFBP-3 gene. Using a transfected derivative of the S/RG/C2 adenoma-derived cell line, which stably expressed exogenous IGFBP-3 protein at levels equivalent to that secreted by the 4 mM NaBt-treated parental line (1-3 ng/10(6) cells), we have shown a >2-fold increase in the sensitivity of the cells to NaBt-induced apoptosis when compared with the vector control and parental cell lines. Furthermore, inhibition of the secreted IGFBP-3 protein, by addition of neutralizing antibodies, resulted in a significant decrease in NaBt-induced apoptosis. These data suggest that IGFBP-3 may act as a positive regulator of NaBt-induced apoptosis in colonic epithelial cells, and represents a potentially important mechanism whereby the sensitivity of colonic epithelial cells to NaBt-induced apoptosis can be increased.

Adenoma↗