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PubMed2000

In vitro effects of cholesteryl butyrate solid lipid nanospheres as a butyric acid pro-drug on melanoma cells: evaluation of antiproliferative activity and apoptosis induction.

Literature data show that butyric acid derivatives bear a dose-dependent differentiative anti-proliferative activity on cancer cell lines and that apoptosis induction may play a major role. Although it was recently shown that solid lipid nanospheres (SLNs) are a suitable tool for several in vivo drug administration routes, there is little available information on melanoma cell lines. This study was aimed at evaluating the anti-proliferative and apoptotic in vitro effects of cholesteryl butyrate (chol-but) SLNs on melanoma cells. Increasing concentrations of chol-but SLNs were used to test two melanoma cell lines. Both cell lines were treated with Na-butyrate (Na-but) and chol-but SLNs for viability. Those tested with chol-but SLNs were more effective than Na-butirate (3 to 72 h). The apoptotic effects of chol-but SLNs were evaluated between 3 and 72 h by annexin-V (ANX-V)/propidium iodide (PI) staining and the antiproliferative effect by PI staining. Apoptosis anti-proliferative-regulatory proteins as bcl-2, Fas/APO1 (CD95) and PCNA (PC10) were also investigated. Flow cytometric analyses evidenced a G(0/1)-S transition block and a 'sub-G(0/1)' apoptotic peak from 0.5 to 1.0 mM butyric acid. In ANX-V/PI flow cytometric staining, a dose- and time-dependent increase in the apoptotic cell percentage (ANX-V+) coupled with a down-regulation of PC10 and bcl-2 and a parallel up-regulation of Fas/APO1 (CD95) were found in both lines started after 3 to 24 h of chol-but SLNs treatment. Results show that chol-but SLNs exerts a dose/time-dependent effect in melanoma cell apoptosis induction between 3 and 24 h and a dose but not time-dependent effect after 24 h of treatment.

Annexin A5↗

PubMed2004

Cholesteryl butyrate solid lipid nanoparticles as a butyric acid pro-drug: effects on cell proliferation, cell-cycle distribution and c-myc expression in human leukemic cells.

Cholesteryl butyrate solid lipid nanoparticles (chol-but SLN) have been proposed as a pro-drug to deliver butyric acid. We compared the effects on cell growth, cell-cycle distribution and c-myc expression of chol-but SLN and sodium butyrate (Na-but) in the human leukemic cell lines Jurkat, U937 and HL-60. In all the cell lines 0.5 and 1.0 mM chol-but SLN provoked a complete block of cell growth. Cell-cycle analysis demonstrated in Jurkat cells that 0.25 mM chol-but SLN caused a pronounced increase of G2/M cells and a decrease of G0/G1 cells, whereas in U937 and HL-60 cells chol-but SLN led to a dose-dependent increase of G0/G1 cells, with a decrease of G2/M cells. In Jurkat and HL-60 cells 0.5 mM chol-but SLN induced a significant increase of sub-G0/G1 apoptotic cells. Cell growth and cell-cycle distribution were unaffected by the same concentrations of Na-but. A concentration of 0.25 mM chol-but SLN was able to cause a rapid and transient down-regulation of c-myc expression in all the cell lines, whereas 1 mM Na-but caused a slight reduction of c-myc expression only in U937 cells. The results show how chol-but SLN affects the proliferation pattern of both myeloid and lymphoid cells to an extent greater than the natural butyrate.

Apoptosis↗

PubMed1990

Butyrate esterase (4-methylumbelliferyl butyrate) spot test, a simple method for immediate identification of Moraxella (Branhamella) catarrhalis [corrected].

A total of 47 Moraxella (Branhamella) catarrhalis strains, 89 strains of Neisseria spp., and 82 strains of miscellaneous bacteria and yeasts were studied by using a fluorogenic spot method which detects butyrate esterase. A positive butyrate esterase spot test correctly differentiated M. catarrhalis from Neisseria spp., which had a negative butyrate esterase spot test reaction. The test is rapid, simple, and easy to perform. The butyrate esterase spot test was useful for direct identification of M. catarrhalis from primary cultures. However, false-positive reactions may occur with mixed cultures.

Bacteriological Techniques↗

PubMed2006

Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces.

Weight loss diets for humans that are based on a high intake of protein but low intake of fermentable carbohydrate may alter microbial activity and bacterial populations in the large intestine and thus impact on gut health. In this study, 19 healthy, obese (body mass index range, 30 to 42) volunteers were given in succession three different diets: maintenance (M) for 3 days (399 g carbohydrate/day) and then high protein/medium (164 g/day) carbohydrate (HPMC) and high protein/low (24 g/day) carbohydrate (HPLC) each for 4 weeks. Stool samples were collected at the end of each dietary regimen. Total fecal short-chain fatty acids were 114 mM, 74 mM, and 56 mM (P < 0.001) for M, HPMC, and HPLC diets, respectively, and there was a disproportionate reduction in fecal butyrate (18 mM, 9 mM, and 4 mM, respectively; P < 0.001) with decreasing carbohydrate. Major groups of fecal bacteria were monitored using nine 16S rRNA-targeted fluorescence in situ hybridization probes, relative to counts obtained with the broad probe Eub338. No significant change was seen in the relative counts of the bacteroides (Bac303) (mean, 29.6%) or the clostridial cluster XIVa (Erec482, 23.3%), cluster IX (Prop853, 9.3%), or cluster IV (Fprau645, 11.6%; Rbro730 plus Rfla729, 9.3%) groups. In contrast, the Roseburia spp. and Eubacterium rectale subgroup of cluster XIVa (11%, 8%, and 3% for M, HPMC, and HPLC, respectively; P < 0.001) and bifidobacteria (4%, 2.1%, and 1.9%, respectively; P = 0.026) decreased as carbohydrate intake decreased. The abundance of butyrate-producing bacteria related to Roseburia spp. and E. rectale correlated well with the decline in fecal butyrate.

Adult↗

PubMed1981

[Studies on toxicity of hydrocortisone 17-butyrate 21-propionate -1. Acute toxicity of hydrocortisone 17-butyrate 21-propionate and its analogues in mice, rats and dogs (author's transl)].

The acute toxicity of hydrocortisone 17-butyrate 21-propionate (HBP), hydrocortisone 17-butyrate (HB17) and hydrocortisone 21-butyrate (HB21) were investigated by three administration routes (s.c., i. p. and p. o.) in mice, rats and dogs. In the case of HBP, LD50 by oral administration was the highest, and followed by subcutaneous and intraperitoneal administration in mice and rats. And LD50 of HB17 and HB21 were not different from HBP in mice by subcutaneous administration. The depression of spontaneous movement and respiratory rate, ptosis, larcrymation and the collapse were commonly observed in all drugs, and it was independent of administration routes. The autopsy revealed the atrophy of thymus, spleen and adrenal glands, the supprative nodules of heart and liver and the ulcers of alimentary tract in mice and rats. But the changes observed in mice and rats were recognized when 1000 mg/kg of HBP was administered to dogs subcutaneously. Many of these changes were common to glucocorticoids, and the LD50 of HBP was rather high compared with other synthetic steroids; therefore, HBP was among less toxic steroid.

Administration, Oral↗

PubMed1996

Esterase inhibitors diminish the modulation of gene expression by butyric acid derivative, pivaloyloxymethyl butyrate (AN-9).

Pivaloyloxymethyl butyrate (AN-9) belongs to the family of acyloxyalkyl ester prodrugs of carboxylic acids which undergo intracellular hydrolysis to yield butyric acid (BA). We have previously shown that AN-9 and BA reduce the level of c-myc and enhance c-jun transcripts in HL-60 cells, and that the differentiation of these cells, induced by AN-9, is dependent on the presence of intracellular esterases. In this study we show that esterase inhibitors abolish the changes induced by AN-9 on c-myc and c-jun expression. In contrast, esterase inhibitors do not change the effects of BA on c-myc or c-jun. Interestingly, these inhibitors affect the modulation induced by both AN-9 and BA on the retinoblastoma tumor suppressor gene. These data suggest that AN-9 is indeed a prodrug of BA and that prior intracellular hydrolysis by esterases is material for AN-9 activity.

Aniline Compounds↗

PubMed1997

Effect of the cytostatic butyric acid pro-drug, pivaloyloxymethyl butyrate, on the tumorigenicity of cancer cells.

Previously we have shown that pivaloyloxymethyl butyrate (AN-9), a pro-drug of butyric acid (BA), is a differentiation-inducing agent in a variety of cells. In this report, we demonstrate that AN-9 is a cytostatic but not cytotoxic agent in a myelomonocytic cell line (WEHI); thus, the cells were growth-arrested and differentiated. These late changes in the cells were preceded by changes in the expression of the early regulatory genes, c-myc and c-jun. Although initiation of all these events had already occurred after 1 h exposure to AN-9, the tumorigenicity of these cells tested in Balb/c mice was not affected. A marked reduction in the tumorigenicity of AN-9-treated cells was observed after 4 h of exposure. Exposure of the highly metastatic subclone of Lewis lung carcinoma (3LLD122) to AN-9 resulted in a very pronounced effect on the tumorigenicity of these cells tested in C57BL mice. Unlike WEHI cells, the tumorigenicity of 3LLD122 was almost completely diminished after 1 h of exposure. In both cell types a 10-fold higher concentration of BA did not affect the tumorigenicity of the cells as did AN-9.

Animals↗

PubMed2003

Characterisation of bacterial cultures enriched on the chlorophenoxyalkanoic acid herbicides 4-(2,4-dichlorophenoxy) butyric acid and 4-(4-chloro-2-methylphenoxy) butyric acid.

The aim of this study was to enrich and characterise bacterial consortia from soils around a herbicide production plant through their capability to degrade the herbicides 4-(2,4-dichlorophenoxy) butyric acid (2,4-DB) and 4-(4-chloro-2-methylphenoxy) butyric acid (MCPB). Partial 16S rRNA gene sequencing revealed members of the genera Stenotrophomonas, Brevundimonas, Pseudomonas, and Ochrobactrum in the 2,4-DB- and MCPB-degrading communities. The degradation of 2,4-DB and MCPB was facilitated by the combined activities of the community members. Some of the members were able to utilise other herbicides from the family of chlorophenoxyalkanoic acids. During degradation of 2,4-DB and MCPB, phenol intermediates were detected, indicating ether cleavage of the side chain as the initial step responsible for the breakdown. This was also verified using an indicator medium. Repeated attempts to amplify putatively conserved tfd genes by PCR indicated the absence of tfd genes among the consortia members. First step cleavage of the chlorophenoxybutyric acid herbicides is by ether cleavage in bacteria and is encoded by divergent or different tfd gene types. The isolation of mixed cultures capable of degrading 2,4-DB and MCPB will aid future investigations to determine both the metabolic route for dissimilation and the fate of these herbicides in natural environments.

2,4-Dichlorophenoxyacetic Acid↗

PubMed2000

Anticancer derivative of butyric acid (Pivalyloxymethyl butyrate) specifically potentiates the cytotoxicity of doxorubicin and daunorubicin through the suppression of microsomal glycosidic activity.

Pivalyloxymethyl butyrate (AN9) is an anticancer derivative of butyric acid. In this study, doxorubicin (DXR) and AN9 synergistically inhibited the growth of lymphoma and lung carcinoma cells, whereas there was no synergy between AN9 and antimetabolites. AN9 did not affect the intracellular uptake of DXR. Among anthracyclines and their derivatives, the synergistic effect was prominent in compounds with a daunosamine moiety, suggesting that AN9 may affect the catabolism of these compounds. The degradation of DXR in the extract from AN9-treated cells was much less than that in extract from untreated cells. AN9 did not directly inhibit the enzyme activity but rather suppressed expression of the enzyme. With respect to the expression of drug resistance-related genes, there was no significant difference between untreated and AN9-treated cells. However, AN9 significantly down-regulated the levels NADPH-cytochrome P450 reductase and DT-diaphorase mRNA in the presence of DXR but not the level of xanthine oxidase mRNA. The enhancement of the sensitivity to anthracyclines was closely associated with the suppression of the mRNA expression.

Antibiotics, Antineoplastic↗

PubMed2002

A phase I study of pivaloyloxymethyl butyrate, a prodrug of the differentiating agent butyric acid, in patients with advanced solid malignancies.

Pivaloyloxymethyl butyrate (AN-9), an acyloxyalkyl ester prodrug of butyric acid (BA), has demonstrated greater potency than BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological, pharmacological, and pharmaceutical properties than BA in preclinical studies. The principal objective of this study was to determine the feasibility of administering AN-9 as a 6-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced solid malignancies. The study also sought to determine the principal toxicities and maximum tolerated dose of AN-9 on this intermittent schedule, as well as the effects of AN-9 on fetal hemoglobin production, a parameter indicative of RBC differentiation. None of the 28 patients treated with 85 total courses of AN-9 at dosages ranging from 0.047 to 3.3 g/m(2)/day every 3 weeks experienced dose limiting toxicity. Mild to moderate nausea, vomiting, hepatic transaminase elevation, hyperglycemia, fever, fatigue, anorexia, injection site reaction, diarrhea, and visual complaints were observed. Dose escalation of AN-9 was limited by the maximum feasible volume of its intralipid formulation vehicle that could be administered safely on this schedule, resulting in a maximum deliverable dose of 3.3 g/m(2)/day. There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously untreated patient with metastatic non-small cell lung cancer. Additional disease-directed clinical evaluations of AN-9 are necessary to establish the breadth of its antitumor activity and to assess its role as an effective differentiating agent.

Adult↗

PubMed1998

Etherolytic cleavage of 4-(2,4-dichlorophenoxy)butyric acid and 4-(4-chloro-2-methylphenoxy)butyric acid by species of Rhodococcus and Aureobacterium isolated from an alkaline environment.

Bacterial strains were isolated from the concrete rubble of a demolished herbicide production plant. The predominant feature of these strains was the etherolytic cleavage of 4-(2,4-dichlorophenoxy)butyric acid (DCPB)1) and 4-(4-chloro-2-methylphenoxy)butyric acid (MCPB) while liberating 2,4-dichlorophenol (DCP) and 4-chloro-2-methylphenol (MCP) respectively. Some of the isolates were identified by 16S rDNA sequence analysis and shown to belong to the genera Aureobacterium sp. (strain K2-17) and Rhodococcus (Rh. erythropolis K2-12). The other strains isolated clustered into these two groups according to fatty acid analysis. Etherolytic cleavage proceeded under neutral to alkaline conditions with an optimum at around pH 8.5. With Aureobacterium sp. No. K2-17, the degradation rate was zero at a pH of 6 but as much as 60% of the maximum activity was observed at pH 10.5. With Rh. erythropolis K2-12, by contrast, pronounced activity was detected at pH 6.5 while degradation was no longer observed at pH 10.5. The maximum rates of cleavage were about 1 mmol DCPB/h.g dry mass with Aureobacterium sp. No. K2-17 and about 0.6 mmol DCPB/h.g dry mass with Rh. erythropolis K2-12. DCPB and MCPB were utilized to the same extent. Substrate cleavage and product formation (DCP) proceeded at almost equal rates with Aureobacterium sp. No. K2-17 and Rh. erythropolis K2-12, which indicates that this compound was not further metabolized. Only phenoxybutyric acid compounds served as substrates; phenoxyacetic acid and phenoxypropionic acid derivatives were not utilized by these strains.

2-Methyl-4-chlorophenoxyacetic Acid↗

PubMed1999

Sodium butyrate-mediated induction of the glycoprotein hormone alpha-subunit gene: requirement for continued protein synthesis, identification of a butyrate-responsive element, and inhibition of promoter activation by 2-deoxyglucose.

Production of the glycoprotein hormone alpha-subunit (GPH alpha) was enhanced by sodium butyrate (Btr) in HeLa cells. Induction of the HeLa alpha-subunit gene by Btr was inhibited by the simultaneous addition of cycloheximide (CHX), indicating a requirement for continued protein synthesis. Transient expression assays using plasmids containing the GPH alpha gene promoter fused to the chloramphenicol acetyltransferase (CAT) reporter gene demonstrated that the GPH alpha promoter is inducible by Btr in HeLa cells, and this induction could be prevented by 2-deoxyglucose (dGlc). CAT production driven by the SV-40 early promoter, the cytochrome P-450-IA1 promoter, and the Rous sarcoma virus long terminal repeat was also enhanced by Btr, but the augmented synthesis was not inhibited by the addition of dGlc, demonstrating that the effect is restricted only to some promoters. CAT synthesis could be induced by Btr when the GPH alpha promoter extended upstream to position -169 (relative to the transcription start site at +1) but not when the promoter terminated at -150, classifying the DNA between these termini as a Btr-responsive element (BRE). This region overlaps the composite trophoblast-specific enhancer. Inactivation of enhancer subdomains by site-directed mutagenesis confirmed the deletion analysis and ranked their response to Btr as CRE < TSE < URE < alpha ACT. Electrophoretic mobility shift analysis failed to detect any significant difference among several enhancer binding proteins in nuclear extracts from untreated and Btr-treated cells. Together, these results suggest that Btr-mediated induction of the alpha-subunit gene in HeLa cells is manifest either through the synthesis of a new transcription factor(s), which is inhibited by CHX but required for increased transcription from the GPH alpha gene promoter, or through the activity of existing factors that may require glycosylation or phosphorylation by a modification system that is inducible by Btr and inhibited by dGlc and CHX. These results further suggest that the factor is not an enhancer-binding protein or that Btr increases its transactivation potential without altering its DNA-binding activity.

Base Sequence↗

PubMed1989

On the induction of fetal hemoglobin by butyrates: in vivo and in vitro studies with sodium butyrate and comparison of combination treatments with 5-AzaC and AraC.

To obtain information on the cellular mechanism of induction of fetal hemoglobin (HbF) by sodium butyrate (NaB), we treated adult baboons with NaB and assessed its effects on HbF expression. Infusion of NaB increased F reticulocytes and F-positive CFUe and e-cluster colonies without induction of reticulocytosis or increase in progenitor cell numbers. Addition of NaB in bone marrow cultures increased the frequency of F-positive CFUe and e-clusters without increasing progenitor cell numbers. NaB induced HbF in human adult BFUe cultures and increased the gamma/gamma + beta globin chain and mRNA ratios in short-term incubations of culture-derived erythroblasts. There was a synergistic induction of HbF by NaB and 5-azacytidine (5-azaC), but not when the animal was treated with NaB and cytarabine (AraC). Our results suggest that the activation of gamma-globin expression by NaB reflects an action of this compound on globin genes or globin chromatin.

Aminobutyrates↗

PubMed2001

Butanol effects on gamma-amino butyric acid concentration-responses in human alpha1beta2gamma2L gamma-amino butyric acid type A receptors with a mutation at alpha1S270.

Alcohol enhancement of gamma-amino butyric acid type A receptor (GABA(A)R) gating at low GABA is reduced by a serine-to-isoleucine mutation at residue alphaS270, suggesting that alphaS270 forms an enhancement site. However, whether the alphaS270I mutation strengthens alcohol inhibition of GABA(A)Rs remains unexplored. Furthermore, alphaS270 mutations have not been studied in the most prevalent form of mammalian GABA(A)Rs consisting of alpha1, beta2, and gamma2 subunits. In voltage-clamped Xenopus oocytes expressing recombinant alpha1beta2gamma2L GABA(A)Rs, electrophysiological analysis of GABA concentration-responses demonstrates that the alpha1(S270I) mutation increases apparent GABA affinity and significantly reduces the Hill coefficient of GABA(A)R activation. Butanol-induced leftward-shifts in GABA concentration-responses for both wild-type alpha1beta2gamma2L and alpha1(S270I)beta2gamma2L GABA(A)Rs are equal. At high GABA, butanol neither enhances nor inhibits alpha1(S270I)beta2gamma2L responses. Thus, in the dominant mammalian GABA(A)R isoform, the alphaS270I mutation affects neither enhancement nor inhibition by butanol, but alters the gating mechanism by reducing cooperativity, producing an apparent reduction in alcohol enhancement at low GABA.

1-Butanol↗

PubMed1950