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PubMed1986

Butyrate induced reduction of tumor cell laminin receptors.

Laminin, a glycoprotein of basement membranes, binds to the surface of cultured human pancreatic carcinoma cells (PANC-1). The binding is saturable, with a high proportion of specific binding, as determined by competition of labeled ligand with 80-fold excess unlabeled ligand. Pretreatment of the carcinoma cells with butyrate markedly reduces the amount of specific laminin binding. The butyrate effect on laminin binding is dose dependent and is observed at a concentration of butyrate which does not significantly reduce cellular protein synthesis or increase laminin production. Scatchard analysis indicates that butyrate reduces the total number of laminin binding sites without affecting the binding coefficient (Kd = 2 nm). The laminin receptor protein isolated from the PANC-1 cell extract has a molecular weight of approximately 70,000. After butyrate treatment the total amount of extractable laminin receptor protein is significantly reduced. Thus butyrate reduces laminin binding to PANC-1 carcinoma cells by a mechanism which involves decreased expression of laminin receptor proteins in the plasma membrane.

Adenocarcinoma↗
PubMed1985

The effects of sodium butyrate on lymphokine production.

The effect of sodium butyrate on lymphokine production in WEHI-3, LBRM-33, and JURKAT cells, as well as an IL-2-dependent T cell line (I) was studied. Constitutive production of IL-3 by WEHI-3 cells was enhanced by sodium butyrate and was accompanied by the growth arrest of WEHI-3 cells in the G1 phase of the cell cycle. Treatment of I cells with ConA and sodium butyrate led to an increase in IL-3 production and the initiation of IL-2 production. In contrast, the synthesis of IL-2 and IL-3 by the ConA-activated T lymphoma line LBRM-33 was coordinately inhibited by sodium butyrate. Similarly, the synthesis of IL-2 by the human T cell lymphoma JURKAT was inhibited by sodium butyrate. No cell cycle-specific effects of sodium butyrate were observed in LBRM-33 or JURKAT cells.

Animals↗
PubMed1985

Differentiation inducing effects of butyrate and DMSO on human intestinal tumor cell lines in culture.

In the present report, we have studied the effects of butyrate and dimethyl sulfoxide (DMSO) on the characteristics of four human intestinal tumor cell lines in vitro; namely a duodenal adenocarcinoma HTB-40 and three adenocarcinomas of colon: HT-29, CCL-218, and CCL-222. In the presence of concentrations of 2 mM butyrate and 2% DMSO the growth of all these four cell lines was significantly inhibited. Both these agents lengthened the doubling time of these cell lines by about twofold. In addition, the morphology of the treated cells was altered. All four cell lines grow in semisolid agar and form characteristic colonies. Butyrate and DMSO inhibited the colony forming efficiency of these cell lines by 40-60%. Using flow cytometric analysis, the cells that were grown in the presence of butyrate and DMSO were analyzed for their lectin-binding properties. For this purpose the lectins used were concanavalin-A (Con-A), peanut agglutinin (PNA), wheat germ agglutinin (WGA), and succinylated wheat germ agglutinin (SWGA). All four cell lines showed an increase in lectin-binding cells. CCL-218, which showed no PNA binding when grown without these agents, acquired about 25% reactivity when grown in the presence of butyrate or DMSO. All these cell lines showed an increase in the percentage of positive cells for the lectin SWGA that unlike WGA does not bind to sialic acid on the cell surface, suggesting an increase in nonsialated residues on all the treated cells. These results indicate a differentiation inducing effect of butyrate and DMSO on these cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Butyrates↗
PubMed1982

Differential effects of sodium butyrate, dimethyl sulfoxide, and retinoic acid on membrane-associated antigen, enzymes, and glycoproteins of human rectal adenocarcinoma cells.

The effects of sodium butyrate, dimethyl sulfoxide (DMSO), and retinoic acid on the growth, morphology, carcinoembryonic antigen content, cell surface membrane-associated enzyme activities, and glycoprotein profiles of a human rectal adenocarcinoma cell line (HRT-18) in culture were compared. All three agents reversibly caused a marked increase in doubling times, a decrease in saturation densities, and a markedly reduced colony-forming efficiency in soft agar. Only butyrate caused gross morphological changes including cell enlargement, flattening, and increased membranous process formation. Carcinoembryonic antigen content was increased during culture in butyrate, while it was reduced by DMSO and unchanged by retinoic acid. The activities of membrane-associated enzymes were altered significantly in the butyrate-treated cells. For example, an increase in the activities of alkaline phosphatase (10-fold), gamma-glutamyl transpeptidase activity (3-fold) and sucrase activity (2-fold) was observed, while those of aminooligopeptidase and K+-stimulated phosphatase actually showed slight decreases. DMSO- or retinoic acid-treated cells showed a marked decrease in alkaline phosphatase activity, but other enzyme activities remained unchanged. Surface protein-labeling patterns of lactoperoxidase-catalyzed iodinated HRT-18 cells showed no significant change from the control cells following treatment with DMSO or retinoic acid. The most prominent change caused by butyrate treatment was the appearance of a major glycoprotein band with an apparent molecular weight of 60,000. These data indicate that the use of butyrate, DMSO, and retinoic acid may provide useful information concerning the identification of differentiation-associated markers of human rectal cancer cells. Furthermore, these agents, although having similar effects on the growth properties, have different effects on the morphology and on the biochemical properties of human rectal cancer cells.

Adenocarcinoma↗
PubMed1994

Concomitant increases in galectin-1 and its glycoconjugate ligands (carcinoembryonic antigen, lamp-1, and lamp-2) in cultured human colon carcinoma cells by sodium butyrate.

Galactoside-binding lectins (galectins) with molecular masses of about 14.5 kilodaltons (galectin-1) and 31 kilodaltons (galectin-3) have been found in a variety of normal and malignant cells and have been implicated in the regulation of cell growth, cell adhesion, and metastasis. The KM12 human colon carcinoma cell line was found to express only galectin-3. Because the levels of both galectins are developmentally regulated and can be modulated during the differentiation of several cultured tumor cell lines, we studied the ability of 11 differentiation-inducing agents to induce galectin-1 expression in the KM12 cells. Treatment of these cells with sodium butyrate, an established differentiation-inducing agent for colon carcinoma cells, resulted in the induction of galectin-1, which was detected by immunoblotting as well as by affinity chromatography. This effect was not seen with any of the 10 other differentiating agents: hexamethylene bisacetamide, dimethyl sulfoxide, dimethyl formamide, herbimycin A, mycophenolic acid, retinoic acid, difluoromethyl ornithine, dibutyryl cAMP, 8-chloro cAMP, and transforming growth factor beta 1. Galectin-1 induction by butyrate was observed in seven other human colon carcinoma cell lines. Further studies with the KM12 cells revealed that butyrate caused cell flattening, suppressed cell proliferation and colony formation in agarose, and increased the level of carcinoembryonic antigen, a marker of human colon carcinoma cell differentiation, within 48 h of treatment. The increase in galectin-1 level was dependent linearly on butyrate concentration (range, 1-4 mM). Galectin-1 mRNA expression was detected by Northern blotting as early as 6 h, and the protein was detected after 24 h of treatment initiation. The level of the constitutively expressed galectin-3 was also increased by butyrate but to a lesser extent than the level of galectin-1. Butyrate-induced galectin-1 was detected on the cell surface by immunoprecipitation from radioiodinated cell surface proteins as well as by indirect immunofluorescence labeling. Affinity-purified human galectin-1 was found to bind to purified polylactosamine-containing glycoproteins and to detergent-solubilized cellular proteins electroblotted onto nitrocellulose membranes. Affinity chromatography of [3H]glucosamine-labeled KM12 cell extracts on immobilized galectin-1 followed by immunoprecipitation from the lactose-eluted material demonstrated that lysosome-associated membrane glycoprotein-1, carcinoembryonic antigen, and nonspecific cross-reacting antigen are the major galectin-1-binding proteins in these cells. These results indicate that galectin-1 expression may be associated with the differentiation of KM12 cells and that several glycoproteins shown to be important in colon carcinoma adhesion and metastasis are capable of functioning as its endogenous ligands.

Animals↗
PubMed1993

Effect of sodium butyrate on the expression of retinoblastoma (RB1) and P53 gene and phosphorylation of retinoblastoma protein in human colon tumor cell line HT29.

Sodium butyrate is known to induce morphological and biochemical changes associated with cell differentiation in some colon tumor cell lines including HT29. In our present study we observed that sodium butyrate treatment caused a decrease in the level of expression of RB1 gene on day seven of butyrate treatment but a gradual six to sevenfold decrease in the level of expression of p53 gene. Western blot analysis revealed a decrease in the level of the phosphorylated form of Rb protein (pRb) and an increase in the level of underphosphorylated pRb as compared to the control cells. These changes in the phosphorylation level were observed from day three of sodium butyrate treatment. In addition, the flat foci forming large differentiated cells also began to appear after 3 days of sodium butyrate treatment. In this study, we are able to show that, besides induction of differentiation, sodium butyrate treatment can also cause a reversal in the phosphorylation status of the pRb in colon tumor cell line HT29. These results suggest that the phosphorylation level of pRb could be associated with the cell differentiation process in human colonic epithelium and as a consequence in its neoplastic development.

Adenocarcinoma↗
PubMed1993

[Influence of sodium butyrate intake on murine colonic carcinogenesis].

The role of short chain fatty acids (SCFA) in murine colonic carcinogenesis (MCC) has not yet been clarified. In rats, Freeman et al have reported an increased number of colonic tumors induced with dimethylhydrazine (DMH) and sodium butyrate in drinking water. On the other hand, Deschner et al showed that tributyrin intake did not increase MCC induced with azoxymethane. Both of them have reported high levels of fecal butyric acid with sodium butyrate and tributyrin intake. Although salt intake has been positively associated with colorectal cancer some authors do not support this association. We have evaluated the influence of right hemicolectomy (RH) (right colon as main source of SCFA) and the intake of 2%-pH 7 sodium butyrate (S.BUT) and 4 g/l sodium chloride (S.CHL) in drinking water, in MCC. Forty eight male Wistar rats weighing 150 g were divided into 4 groups: RH, S.BUT, S.CHL, control (C). Half of the animals received weekly DMH 20 mg/kg subcutaneously for 12 weeks. Necropsy was performed after 6 months. We have determined fecal SCFA content by gas chromatography. Neoplasm was present in 70% of rats treated with DMH. The number of animals with tumors was: RH 4/6, S.BUT 4/6, S.CHL 3/5, C 6/6. Tumor frequency was: RH 1.17 +/- 0.48, S.BUT 1.50 +/- 0.76, S.CHL 1.20 +/- 0.49, C 1.50 +/- 0.22. S.BUT group, treated with DMH, presented a lower butyric acid concentration (p < 0.05) in comparison with other groups. We have no explanation for this finding; gastric absorption of sodium butyrate may be an important factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Proliferation of human colonic mucosa as an intermediate biomarker of carcinogenesis: effects of butyrate, deoxycholate, calcium, ammonia, and pH.

A high-fat/high-protein diet has been reported to promote colon cancer by increasing luminal bile acid and ammonia concentrations, whereas butyrate, calcium, and low colonic pH may have protective effects. In this study, bromodeoxyuridine labeling of colonic epithelium was investigated after incubating biopsies from the ascending colon of 70 patients with HCl (20 mM, pH 6.0), butyric acid (H-BUT, 20 mM, pH 6.0), sodium butyrate (Na-BUT, 10 mM, pH 8.0), CaCl2 (10 mM), calcium butyrate (Ca-BUT, 10 mM), ammonium butyrate (NH4-BUT, 10 mM), deoxycholic acid (DCA, 5 microM), and a combination of DCA and Na-BUT (DCA/Na-BUT, 5 microM/10 mM). Compared to NaCl, H-BUT and Na-BUT increased the whole crypt-labeling index significantly, whereas HCl and CaCl2 had no effect. Reduced labeling, however, occurred with Ca-BUT in comparison to equimolar Na-BUT. No differences in the labeling indexes were found for NH4-BUT compared to Na-BUT, but increased labeling with expansion of the proliferative zone to the upper 40% of the crypt was seen with DCA compared to NaCl. DCA-induced hyperproliferation was abolished by coincubation with DCA/Na-BUT. These data suggest that butyrate, calcium, and DCA have complex influences on mucosal proliferation. Since luminal concentrations of these compounds are influenced by dietary interventions, the findings of this study may be of particular interest with regard to colon cancer development and prevention.

Adult↗
PubMed1999

Hyaluronic acid as drug delivery for sodium butyrate: improvement of the anti-proliferative activity on a breast-cancer cell line.

The potential clinical utility of sodium butyrate, a natural compound known to inhibit tumor-cell growth, is hampered by the difficulty of achieving effective in-vivo concentrations. The short half-life (about 5 minutes) of sodium butyrate results in rapid metabolism and excretion. To increase the availability of sodium butyrate over a longer period of time, we co-valently linked it to hyaluronic acid (a component of the extracellular matrix). Its major advantages as a drug carrier consist in its high biocompatibility and its ability to bind CD44, a specific membrane receptor frequently over-expressed on the tumor-cell surface. The degree of substitution of hyaluronic acid with butyrate residues ranged from d.s.=0.10 to d.s.=2.24 (1.8-28.4% w/w). The biological activity of hyaluronic-acid-butyric-ester derivatives was evaluated in terms of the inhibition of the growth of the MCF7 cell line and compared with that of sodium butyrate. After 6 days of treatment, we observed a progressive improvement of the anti-proliferative activity up to d.s.=0.20; thereafter, the anti-proliferative effect of the ester derivatives decreased. Fluorescence microscopy showed that after 2 hr of treatment fluorescein-labelled compounds appeared to be almost completely internalized into MCF7 cells, expressing CD44 standard and variant isoforms. These findings indicate that hyaluronic acid could offer an important advantage in drug delivery, in addition to its biocompatibility: the ability to bind to CD44, which are known to be frequently over-expressed on the tumor-cell surface.

Antineoplastic Agents↗
PubMed2002

Fluorescent proteins in animal cells for process development: optimization of sodium butyrate treatment as an example.

Fluorescent proteins expressed in mammalian cells can be quantified quickly and noninvasively with a standard fluorescence plate reader. We have previously exploited this quality in cell growth assessment (Hunt et al., 1999b). In this work, different CHO cell lines constitutively expressing fluorescent proteins were evaluated as model systems for process development and optimization. Our results demonstrate that the fluorescence of these cell lines quickly reveals conditions that might improve the overall productivity. Sodium butyrate, a well-known yet unpredictable enhancer of production, was chosen for this study. Due to the competing effects of sodium butyrate ("butyrate") on expression and cell number, the maximal overall productivity represents a compromise between enhancement of production and toxicity. Based on fluorescence only, it is possible to separate effects on cell number and specific production by combining microplate fluorescence measurements with data obtained by flow cytometry. This allows for rapid screening of different clones without counting cells or quantifying the recombinant protein, a highly attractive feature if the expression of green fluorescent protein (GFP) was correlated to that of a protein of interest. For all clones tested, negative effects of butyrate on proliferation were similar, while net enhancement of expression was characteristic for each clone. Therefore, it is necessary to optimize treatment for each individual clone. This work demonstrates that, based on the fluorescence of GFP-expresssing cell lines, it is possible to examine noninvasively three critical, generic parameters of butyrate treatment: butyrate concentration, exposure time, and culture phase at the time of addition.

Animals↗
PubMed2003

Extractive fermentation for butyric acid production from glucose by Clostridium tyrobutyricum.

A novel extractive fermentation for butyric acid production from glucose, using immobilized cells of Clostridium tyrobutyricum in a fibrous bed bioreactor, was developed by using 10% (v/v) Alamine 336 in oleyl alcohol as the extractant contained in a hollow-fiber membrane extractor for selective removal of butyric acid from the fermentation broth. The extractant was simultaneously regenerated by stripping with NaOH in a second membrane extractor. The fermentation pH was self-regulated by a balance between acid production and removal by extraction, and was kept at approximately pH 5.5 throughout the study. Compared with conventional fermentation, extractive fermentation resulted in a much higher product concentration (>300 g/L) and product purity (91%). It also resulted in higher reactor productivity (7.37 g/L. h) and butyric acid yield (0.45 g/g). Without on-line extraction to remove the acid products, at the optimal pH of 6.0, the final butyric acid concentration was only approximately 43.4 g/L, butyric acid yield was 0.423 g/g, and reactor productivity was 6.77 g/L. h. These values were much lower at pH 5.5: 20.4 g/L, 0.38 g/g, and 5.11 g/L. h, respectively. The improved performance for extractive fermentation can be attributed to the reduced product inhibition by selective removal of butyric acid from the fermentation broth. The solvent was found to be toxic to free cells in suspension, but not harmful to cells immobilized in the fibrous bed. The process was stable and provided consistent long-term performance for the entire 2-week period of study.

Bioreactors↗
PubMed1983

Effect of coordinated therapeutic assays using C. parvum, interferon and arginine butyrate on spontaneous disease and survival of AKR mice.

AKR mice, known to develop spontaneous leukemia in almost 100% of cases, were studied throughout their life-span. Different treatments combining a potent immune stimulator, Corynebacterium parvum (CP), with interferon (IFN) and arginine butyrate were initiated at the 15th week of life. In a preliminary series of experiments, CP (200 micrograms), IFN (20,000 units) and butyrate 50 mM) were employed in a well-defined chronological order. In controls, the mean survival time (MST) was 35.17 +/- 1.67 weeks and the final survival rates was 0/50 mice for all experiments. Only CP associated with arginine butyrate significantly augmented the MST (42.5 +/- 3.66 weeks) and final survival rate (9/35 mice). In an adjusted set of experiments, reducing the IFN concentration to 10,000 and 5,000 units and that of butyrate to 6 mM greatly improved the results. The MST was substantially increased with the combinations of CP + IFN + butyrate (41.4 +/- 1.86 weeks), CP + IFN (42.73 +/- 3.29 weeks) and butyrate + IFN (41 +/- 2.34 weeks), as well as the final survival rates (8/15, 10/15 and 6/15 mice respectively). An important finding was that when CP and IFN were used separately, they were ineffective.

Animals↗
PubMed1992

Pharmacokinetic studies of N-butyric acid mono- and polyesters derived from monosaccharides.

The pharmacokinetics of seven butyric esters derived from monosaccharides were studied after iv administration of a bolus dose to rabbits. Results obtained showed that a constant plasma level of butyric acid is maintained due to the slow disappearance of butyric acid esters from the plasma in contrast to the case of salts, such as arginine butyrate, which are rapidly cleared. The maintenance of these covalent compounds in the body can increase concentrations of n-butyric acid in the tumor area for more efficient chemotherapy. These results seem to be directly related to the in vitro anticellular activity of butyric esters and the prolonged therapeutic protection in tumor-bearing animals.

Animals↗
PubMed1999

Alternative schemes of butyrate production in Butyrivibrio fibrisolvens and their relationship to acetate utilization, lactate production, and phylogeny.

Butyrivibrio fibrisolvens strains D1 and A38 produced little lactate, but strain 49 converted as much as 75% of its glucose to lactate. Strain 49 had tenfold more lactate dehydrogenase activity than strains D1 or A38, this activity was stimulated by fructose 1,6-bisphosphate, and had a pH optimum of 6.25. A role for fructose 1,6-bisphosphate or pH regulation of lactate production in strain 49 was, however, contradicted by the observations that very low concentrations (< 0.2 mM) of fructose 1,6-bisphosphate gave maximal activity, and continuous cultures did not produce additional lactate when the pH was decreased. The lactate production of strain 49 was clearly inhibited by the presence of acetate in the growth medium. When strain 49 was supplemented with as little as 5 mM acetate, lactate production decreased dramatically, and most of the glucose was converted to butyrate. Strain 49 did not possess butyrate kinase activity, but it had a butyryl-CoA/acetate CoA transferase that converted butyryl-CoA directly to butyrate, using acetate as an acceptor. The transferase had a low affinity for acetate (K(m) of 5 mM), and this characteristic explained the acetate stimulation of growth and butyrate formation. Strains D1 and A38 had butyrate kinase but not butyryl-CoA/acetate CoA transferase, and it appeared that this difference could explain the lack of acetate stimulation and lactate production. Based on these results, it is unlikely that B. fibrisolvens would ever contribute significantly to the pool of ruminal lactate. Since relatives of strain 49 (strains Nor37, PI-7, VV1, and OB156, based on 16S rRNA sequence analysis) all had the same method of butyrate production, it appeared that butyryl-CoA/acetate CoA transferase might be a phylogenetic characteristic. We obtained a culture of strain B835 (NCDO 2398) that produced large amounts of lactate and had butyryl-CoA/acetate CoA transferase activity, but this strain had previously been grouped with strains A38 and D1 based on 16S rRNA sequence analysis. Our strain B835 had a 16S rRNA sequence unique from the one currently deposited in GenBank, and had high sequence similarity with strains 49 and Nor37 rather than with strains A38 or D1.

Acetates↗
PubMed2003

Effects of seasonal changes in food quality and food intake on the transport of sodium and butyrate across ruminal epithelium of reindeer.

Transport of 22Na and 14C-butyrate across the ruminal epithelium of captive reindeer fed a concentrate diet in summer (n=5) and in winter (n=5) and from free-ranging reindeer taken from summer (n=3) and winter pasture (n=5) was measured in vitro in Ussing chambers. Significant amounts of both Na+ and butyrate were transported across the isolated epithelium without any external driving force. The ruminal transport of Na+ and butyrate were interacting, as evidenced by both the observed amiloride-induced reduction of net butyrate-transport and by the positive correlation between net transport of butyrate and Na+. Amiloride also reduced the net transport of Na+ without significantly affecting the short-circuit current, indicating the presence of an apical Na+/H+ exchanger in the ruminal epithelium of reindeer. The captive reindeer increased the dry matter intake of a constant quality concentrate from winter to summer, but this neither affected their ruminal transport capacity nor their ruminal surface enlargement factor (SEF). Free-ranging reindeer increased their ruminal transport capacity for Na+ and butyrate from summer to winter but simultaneously reduced their ruminal SEF. The present data indicate that this food-induced increase in transport capacity was attributed to changes in the nutrient composition of the diet.

Amiloride↗
PubMed2005

The effect of short-chain fatty acids butyrate, propionate, and acetate on urothelial cell kinetics in vitro: potential therapy in augmentation cystoplasty.

The intestinal element of enterocystoplasty is affected by chronic inflammatory changes, which lead to excess mucus production, urinary tract infections, and stone formation. There is also an increased risk of malignancy. These inflammatory changes may be due to diversion colitis, which affects colonic segments excluded from the faecal stream and likewise may respond to intraluminal short-chain fatty acid (SCFA) therapy. The SCFAs have interesting antiproliferative, differentiating, and pro-apoptotic effects, which are protective against colorectal cancer and may influence the risk of malignancy in enterocystoplasty. Before intravesical therapy can be considered, the effect on normal urothelium must be investigated. Primary urothelial cells cultured from biopsy specimens and transformed urothelial (RT112 and MGH-U1) and intestinal cell lines (HT29 and CaCo-2) were incubated with SCFAs. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure the residual viable biomass to assess cell proliferation. Proliferation of primary and transformed urothelial cells in culture was inhibited by all SCFAs in a similar time- and dose-dependent manner. The concentration of SCFA required to inhibit growth of primary cells by 50% (IC50) was 20 mM of butyrate, 120 mM of propionate, and 240 mM of acetate after incubation for 1 h. After 72 h the IC50 was 2 mM of butyrate, 4 mM of propionate, and 20 mM of acetate. Transformed urothelial and colon cancer cell lines demonstrated similar growth inhibition. Butyrate was the most potent inhibitor of cell proliferation, followed by propionate and then acetate. Growth inhibition is not an immediate cytotoxic effect, and urothelial cells show a degree of adaptation to butyrate and growth recovery after incubation with butyrate. In conclusion, butyrate- and propionate-induced growth inhibition is potentially clinically significant and may have therapeutically beneficial implications in vivo.

Acetates↗
PubMed2006

Sodium butyrate induced keratinocyte apoptosis.

Apoptosis of keratinocytes is a key mechanism required for epidermal homeostasis and the renewal of damaged cells. Its dysregulation has been implicated in many skin diseases including cancer and hyperproliferative disorders. In the present study, the effect of sodium butyrate, a histone deacetylase inhibitor, on keratinocyte apoptosis was investigated using the HaCaT human keratinocyte cell line. Sodium butyrate induced morphological changes associated with apoptosis and nuclear fragmentation of HaCaTs. Annexin V staining demonstrated that sodium butyrate induced apoptosis in a dose and time-dependent manner with 50% of HaCaTs apoptotic after exposure to 0.8 mg/ml sodium butyrate for 24 h. Apoptosis was associated with upregulation of cell surface expression of the death receptor Fas and activation of the extrinsic caspase pathway, with induction of caspase 8 activity peaking after 8 h. Caspase 3 activity peaked after 24 h and was associated with cleavage of the caspase 3 substrate, poly (ADP-ribose) polymerase (PARP). The intrinsic caspase pathway was not activated as caspase 9 activity was not detected, and there was no change in the expression of terminal differentiation markers keratin 10 and involucrin following sodium butyrate treatment. Together these results indicate that sodium butyrate is a potent inducer of Fas associated apoptosis via caspase activation in HaCaT keratinocytes, an effect that is independent of the induction of terminal differentiation.

Adult↗
PubMed2005

Butyrate-induced differentiation of colon cancer cells is PKC and JNK dependent.

Butyric acid, a short-chain fatty acid physiologically present in human large gut, is derived from bacterial fermentation of complex carbohydrates. It has been shown to reduce the growth and motility of colon cancer cell lines and to induce cell differentiation and apoptosis. Apoptosis is considered a result of normal colonocyte terminal differentiation in vivo. The aim of this study was to characterize the cellular mechanisms regulating differentiation of colon cancer cells stimulated with sodium butyrate (NaB). The two human colon cancer cell lines Caco-2 and HT-29 were treated with NaB at physiologically relevant concentrations. Alkaline phosphatase (ALP) activity, a marker of colonocyte differentiation, was increased 48 hr after treatment with 1 mM NaB. Higher doses of NaB (5 and 10 mM) induced apoptosis of the cells and failed to stimulate the colonocyte differentiation. Therefore, we assumed that butyrate augments cell differentiation and induces apoptosis, acting via various intracellular mechanisms, and butyrate-mediated programmed cell death cannot be considered a consequence of colonocyte terminal differentiation. The effect of NaB on ALP activity was significantly attenuated in the presence of inhibitors of protein kinase C and JNK. Inhibition of MEK-ERK signal transduction pathways augmented the impact of butyrate on colonocyte differentiation. These results suggest that butyrate could influence the colonocyte differentiation via modulation of the activity of cellular protein kinases and signal transduction.

Apoptosis↗