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PubMed1988

Effects of the differentiating agents sodium butyrate and N-methylformamide on the oxygen enhancement ratio of human colon tumor cells.

We have previously shown that chronic adaptation of human tumor cells to the differentiation-inducing agents N-methylformamide (NMF) and sodium butyrate (NAB) increases the sensitivity of oxic cells to graded single doses of X rays. These studies were carried out to define the sensitivity of hypoxic cells after adaptation. Clone A colon tumor cells were grown for three passages in medium containing 170 mM NMF or 2 mM NAB and irradiated in suspension culture, after gassing with either oxygen (60 min) or ultrapure nitrogen (90 min), and complete survival curves were generated. Using the linear-quadratic equation to describe the data, it was found that NMF and NAB produced increased X-ray killing of hypoxic cells. At the 10% level of survival, the dose-modifying factors were about 1.20 and 1.25 for NMF- and NAB-adapted hypoxic cells, respectively, as compared to hypoxic control cells. However, since both oxic and hypoxic cells exhibited increased sensitivity after NMF and NAB adaptation, there was no major change in the oxygen enhancement ratio.

Antineoplastic Agents↗
PubMed1988

Changes in X-ray sensitivity and glutathione content of human colon tumor cells after exposure to the differentiation-inducing agent sodium butyrate.

Clone A human colon cancer cells were exposed to concentrations of sodium butyrate (NAB, 0-2 mM) for three passages in vitro, and responses to either graded single doses or split doses of 250 kVp X rays were determined. The survival data were fit to the single-hit, multitarget model of inactivation. For the graded single dose experiments, we found that NAB produced a decrease in the magnitude of the quasi-threshold (Dq) parameter after a concentration of about 0.9 mM was exceeded. Similarly, in split dose experiments, the amount of sublethal damage recovery (SLDR) was reduced in a concentration-dependent manner as shown by a decrease in the Dq parameter. However, the inhibition of SLDR occurred with no apparent threshold NAB concentration. NAB did not affect potentially lethal damage recovery. Paradoxically, increasing concentrations of NAB produced an exponential increase in the intracellular glutathione content, which could be blocked by exposure of the cells to buthionine sulfoximine (BSO). BSO treatment of NAB-adapted cells led to additional cell killing, again most noted by changes in the Dq parameter. We postulate that these responses are associated with NAB-induced changes in chromatin structure, particularly the association between DNA and nucleosomal histones H3 and H4.

Buthionine Sulfoximine↗
PubMed1987

Transient requirement for prolactin as a growth initiator following treatment of autonomous Nb2 node rat lymphoma cell cultures with butyrate.

A previous study described the development of cultures of Nb2 node rat lymphoma cells which specifically require a lactogenic hormone, e.g., prolactin (PRL), as a growth factor. In the present study, sublines of these cultures have been established, including clones, which do not depend on exogenous lactogens for growth; the cells do not appear to produce autocrine, PRL-like substances. Although these autonomous cells grew readily in the complete absence of lactogens, their growth rate was stimulated (up to approximately 30%) by PRL concentrations greater than or equal to 0.1 ng/ml. When cultures of the lactogen-dependent and of the cloned, autonomous lymphoma cells were incubated for 3 days with sodium n-butyrate (NaBT; 2 mM), cells were arrested in the G1 phase of the cell cycle, as shown by flow cytometric analysis. A substantial proportion of the G1-arrested cells was viable and readily resumed growth, within 1 day, when transferred to NaBT-free medium containing PRL (1-100 ng/ml). The resumption of growth of the cells from the lactogen-dependent cultures was critically dependent on PRL; in its absence cells lysed. Surprisingly, the rapid recovery of the cells from the lactogen-independent cultures also depended on the presence of PRL in the medium; in its absence growth did not resume for at least 2.3 days. The acquired need of the NaBT-treated, autonomous cells for PRL was only transient, since such cells reverted fully to the PRL-independent state within about 3 days of culturing in PRL-containing, NaBT-free medium. It is proposed, as a working hypothesis, that the autonomous lymphoma cells can be mitogenically activated by two different pathways, one requiring exogenous lactogens and another which is independent of lactogens; the latter pathway recovers much more slowly from the treatment with NaBT than the lactogen-dependent pathway. This model could explain the sensitivity of the autonomous lymphoma cells to PRL and their transient dependency on exogenous lactogens during their recovery from NaBT treatment. NaBT would appear to be a useful agent for studying the mechanism(s) by which the autonomous lymphoma cells circumvent the need for mitogenic lactogens.

Animals↗
PubMedDate not supplied

Gas chromatographic detection of D-(-)-2,3-butanediol and butyric acid produced by sporeformers in cream-style corn and canned beef noodle soup: collaborative study.

A gas chromatographic method that identifies sporeformers as the cause of spoilage in swollen cans of low-acid foods was collaboratively studied in 2 stages. Two organic compounds produced by sporeformers, D-(-)-2,3-butanediol and butyric acid, are measured in the upper phase after centrifugation of the liquid portion of the can contents. Each sample is assayed on 2 packed columns designed for the assay of aqueous solutions of volatile fatty acids, using flame ionization detectors. For study 1, 16 duplicate inoculated cans of cream-style corn and beef noodle soup were sent to 9 collaborators. For study 2, 7 collaborators received 11 duplicate inoculated cans of the 2 foods. Duplicate uninoculated cans of each food served as negative controls. The inocula were 6 sporeforming organisms (4 Clostridium and 2 gas-forming Bacillus species) and 2 nonsporeformers. After the deletion of marginal samples, the percentages of correctly identified sporeformers and nonsporeformers in beef noodle soup were 83 (110/132) and 90 (54/60), respectively; corresponding percentages for cream-style corn were 80 (98/123) and 100 (35/35). The method has been adopted official first action.

Animals↗
PubMed1984

Production, purification and characterization of the plasminogen activator in teratocarcinoma stem cells induced with sodium butyrate.

Suspension cultures of pluripotent teratocarcinoma cells were induced with sodium butyrate to produce plasminogen activator (PA), generally regarded as a marker enzyme of differentiation of the teratocarcinoma. The induction of plasminogen activator was very efficient, resulting in production of sufficient enzyme to allow its purification. The activator was inactivated by rabbit anti-human melanoma plasminogen activator antiserum, indicating that it was a tissue-type activator (t-PA). The enzyme was purified by column chromatograph on phosphocellulose, zinc-chelate agarose, Con-A Sepharose and Sephadex G-150. The preparation at the final step of purification gave a single peak of enzyme activity at pH 7.3 +/- 0.1 on isoelectric focusing, and showed a molecular weight of approximately 77,000 on SDS PAGE.

Animals↗
PubMed1984

Effects of sodium butyrate, dimethyl sulfoxide, and retinoic acid on glycolipids of human rectal adenocarcinoma cells.

In the present study, we have examined the neutral glycolipids, gangliosides, and sulfoglycolipids of human rectal adenocarcinoma (HRT-18) cells and the alterations produced by the differentiating agents, sodium butyrate, dimethyl sulfoxide, and retinoic acid. Thin-layer chromatography of neutral glycolipids showed that HRT-18 cells contained mono- and diglycosylceramides. Cells treated with differentiating agents had additional glycolipids which comigrated with tri- and tetraglycosylceramides. Labeling of neutral glycolipids with [3H]galactose showed that HRT-18 cells also contain glycosylceramides larger than diglycosylceramides which also were altered by treatment with differentiating agents. In studies of acidic glycolipids, GM3, the major ganglioside in untreated cells, was reduced in cells treated with retinoic acid but not in cells treated with other agents. Upon labeling with radioactive galactose, changes were seen only in the minor ganglioside components of treated cells. Differentiating agents also altered the patterns of sulfogalactolipids and fucolipids in HRT-18 cells. In the case of fucolipids, 2 new bands were observed in the cells treated with dimethyl sulfoxide and retinoic acid. The changes brought about by differentiating agents may identify glycolipids involved in the process of tumorigenicity.

Adenocarcinoma↗
PubMed1995

Granulocyte-macrophage colony-stimulating factor, phorbol ester, and sodium butyrate induce the CD11c integrin gene promoter activity during myeloid cell differentiation.

To analyze the activity of the CD11c promoter during myeloid differentiation without the limitations of transient expression systems, we have stably transfected the myeloid U937 cell line with the pCD11C361-Luc plasmid, in which the expression of the firefly luciferase cDNA is driven by the CD11c promoter region -361/+43, previously shown to confer myeloid specificity to reporter genes. The stable transfectants (U937-C361) retained the ability to differentiate in response to phorbol-ester (PMA), sodium butyrate (SB), granulocyte-macrophage colony-stimulating factor (GM-CSF), and other differentiating agents. U937-C361 differentiation correlated with increased cellular luciferase levels, showing the inducibility of the CD11c promoter during myeloid differentiation and establishing the U937-C361 cells as a suitable system for studying the myeloid differentiation-inducing capacity of cytokines, growth, factors, and other biological response modifiers. Unexpectedly, the inducibility of the CD11c gene promoter showed distinct kinetics and magnitude on the PMA-, SB-, GM-CSF-triggered differentiation. Moreover, SB synergized with either PMA or GM-CSF in enhancing both the CD11c promoter activity and the cell surface expression of p150,95 on differentiating U937 cells. Furthermore, we showed the existence of a c-Myb-binding site at -85, the importance of the -99/-61 region in the CD11c promoter inducibility during PMA- or SB-triggered differentiation, and the dependency of the GM-CSF and PMA responsiveness of the CD11c promoter on an intact AP-1-binding site located at -60. These results, together with the lack of functional effect of mutations disrupting the Sp1-and Myb-binding sites within the proximal region of the CD11c promoter, indicate that the myeloid differentiation pathways indicated by SB and phorbol esters (or GM-CSF) activate a distinct set of transcription factors and show that the myeloid differentiation-inducibility of the CD11c gene maps to the -99/-53 proximal region of the promoter.

Base Sequence↗
PubMed1994

Butyrate-inducible and tumor-restricted gene expression by adenovirus vectors.

Efficient introduction of biologically active genes into tumor cells in vivo would facilitate cancer gene therapy. In this study, recombinant adenoviruses mediated high-level expression of reporter genes in both human and murine tumor cell lines and freshly resected human solid tumors in vitro. When adenovirus vectors were inoculated intratumorally in a living animal, reporter activity was detected only in the tumor nodule and not in other sites, in contrast to intracardiac injections in which expression was found in several organs. Adenovirus-mediated gene expression was further enhanced by butyrate treatment.

Adenoviruses, Human↗
PubMed1994

Reversible transcriptional activation of mdr1 by sodium butyrate treatment of human colon cancer cells.

We investigated the mechanism of sodium butyrate (NaB)-mediated induction of mdr1 mRNA in parental (wild type) and multidrug-resistant (Ad1000) SW620 colon cancer cell lines. NaB treatment resulted in reversible, time-dependent increases in nuclear run-on transcription of endogenous mdr1 in these cell lines that paralleled the reversible increases of mdr1 mRNA in both timing and magnitude. In contrast, NaB treatment had no effect on mdr1 mRNA stability. Thus, the effects of NaB on mdr1 mRNA levels are fully attributable to altered mdr1 transcription. Furthermore, NaB induces the expression of transiently transfected chloramphenicol acetyltransferase reporter plasmids that are under the transcriptional control of the mdr1 promoter (mdrCAT vectors). Transfections using mdrCAT vectors modified by deletion and site-directed mutagenesis of the mdr1 promoter indicate that NaB-mediated induction of these vectors is at least partially dependent upon sequences present in the basal mdr1 promoter between -89 and +11 relative to the start site of transcription. The Y-box motif located between -82 and -73 contributes to NaB inducibility of mdrCAT vector expression in Ad1000 SW620 cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Tributyrin: a prodrug of butyric acid for potential clinical application in differentiation therapy.

Butyric acid (BA) induces cytodifferentiation in vitro of a wide variety of neoplastic cells. The potential clinical utility of BA is limited by the apparent difficulty of achieving effective concentrations because of its rapid metabolism and short plasma half-life. In this study we addressed two approaches that may achieve effective concentrations of BA in vivo. One strategy is to use BA derivatives as prodrugs that can be metabolized to yield effective BA concentrations in vivo over a sustained period of time. Another strategy is to define agents that are synergistic with BA so that the desired effect can be achieved at lower concentrations of BA. In this study monobutyrin (MB) and tributyrin (TB) were studied in vitro for their effects on inducing differentiation of human myeloid leukemia HL60 cells and murine erythroleukemia cells. On a molar basis TB was about 4-fold more potent than either BA or MB for inducing differentiation of HL60 cells. BA, MB, or TB induced erythroid differentiation of murine erythroleukemia cells. On a molar basis TB was 3- to 4-fold more potent than BA, whereas MB was much less potent than BA. Combinations of all-trans-retinoic acid with either BA, MB, or TB induced myeloid differentiation of HL60 cells synergistically. We saw marked reductions in the doses of each agent that were needed in combination to achieve the same effect as single agents. For example, 130 microM TB, 110 nM all-trans-retinoic acid, and a combination of 13 microM TB plus 13 nM all-trans-retinoic acid all induced half-maximal differentiation of HL60 cells. Our results suggest that the readily available TB may be an effective prodrug of BA and may be useful either as a sole agent or in combination with other agents for cytodifferentiation therapy of human malignancies.

Butyrates↗
PubMedDate not supplied

mdr 1 gene-expression and villin synthesis in a colon cancer cell line differentiated by sodium butyrate.

Sodium butyrate (NaBu) but not dimethylsulfoxide (DMSO) induced the synthesis of villin, a protein of the brush border microvilli cytoskeleton, in a rat colon cancer cell line. Neither NaBu nor DMSO altered mdr 1-mRNA expression or multidrug resistance (MDR)--associated cellular transport of doxorubicin. These results show that mdr 1 gene expression and activity are independent of other brush border proteins induced by differentiating agents at the apical pole of the epithelial cell.

Animals↗
PubMed1995

Butyric acid, a metabolic end product of anaerobic bacteria, inhibits B-lymphocyte function.

The effect on B-lymphocytes of butyric acid, a metabolic by-product formed by selected anaerobic bacteria of the subgingival plaque and present in mM amounts in the crevicular fluid of patients affected by adult periodontitis was investigated. A dose-dependent inhibition of both mitogenesis and Ig production in B-cells challenged with formalinized Staphylococcus aureus, strain Cowan I (SAC), was observed. A role of this molecule in the downregulation of the local immune response in periodontal patients is proposed.

Adult↗
PubMed1996

Reduction of LAK-sensitivity and changes in antigen expression on hepatoma cells by sodium butyrate.

We demonstrated that sodium butyrate (SB) induced differentiation of functions in human hepatocellular carcinoma (HCC) cell lines. To investigate relationship between the sensitivity for cellular cytotoxicity and the cellular differentiation of HCC cells, the effect of SB on lymphokine-activated killer (LAK) sensitivity and antigen expression of a human HCC cells were studied. SB induced LAK-resistance of human HCC cell lines, HCC-T and HCC-M, time-dependently. A flowcytometric analysis of cell surface antigens revealed that SB markedly reduced the expression of laminin and fibronectin and increased the expression of liver-specific antigen defined by a mouse monoclonal antibody time-dependently, but did not modify that of major histocompatibility complex antigens, intercellular adhesion molecule (ICAM)-1, or CEA. Leukocyte function-associated antigen (LFA)-3 expression on HCC-T was reduced slightly by SB treatment. LAK sensitivity was inhibited by anti-laminin, but not with anti-beta 2-microglobulin, anti-HLA DR, anti-ICAM-1, anti-fibronectin, or anti-CEA. Anti-LFA-3 reduced LAK sensitivity of HCC-T, but not HCC-M, although the reduction was less than that obtained by anti-laminin treatment. These results provided evidence that SB induced LAK-resistance of human HCC cells according to cellular differentiation and extracellular matrix functionality played an important role in this LAK-mediated cell killing. Moreover, the structure expressed on HCC cells, which contributed to LAK cytolysis, was different for each HCC cell.

Animals↗
PubMed1996

Alterations in pim-1 and c-myc expression associated with sodium butyrate-induced growth factor dependency in autonomous rat Nb2 lymphoma cells.

Whereas Nb2-11 lymphoma cells critically require prolactin (PRL) for growth, Nb2-SFJCD1 subline cells are growth factor independent. Treatment with the differentiating agent, sodium butyrate (NaBT), has been demonstrated previously to lead to growth arrest of Nb2-SFJCD1 cells and a transient reversion to PRL growth requirement following removal of NaBT. In the present study, the relation of NaBT-induced growth arrest to the cell cycle was examined using flow cytometry, and the effect of PRL on expression of the immediate-early proto-oncogenes, pim-1 and c-myc, in NaBT-pretreated cultures was evaluated. Treatment of Nb2-SFJCD1 cells with 2 mM NaBT for 72 h caused growth arrest in the majority of the cells in the G1 phase of the cell cycle, an effect similar to that produced by lactogen deprivation in PRL-dependent Nb2 cultures. The addition of PRL stimulated a concentration-dependent re-entry into the cell cycle. In other experiments, NaBT treatment significantly reduced the steady-state levels of pim-1 and c-myc mRNA. Stimulation with PRL induced a rapid and concentration-dependent biphasic accumulation of each mRNA with similar kinetics. Maximal expression of both proto-oncogenes occurred within 2-4 h and after 12 h. Results from mRNA stability studies suggest that the observed increases in expression of pim-1 and c-myc most likely do not reflect increased stability of the transcripts. The results indicate that NaBT-induced differentiation in autonomous Nb2-SFJCD1 causes growth arrest of the cells in the G1 phase of the cell cycle and reduces the basal levels of pim-1 and c-myc mRNAs. Mitogenic stimulation with PRL reinitiates cell cycle progression characterized by biphasic expression of each proto-oncogene. It is suggested that NaBT is a useful tool for investigation of the malignant progression from growth factor dependency to autonomy in the Nb2 lymphoma paradigm.

Animals↗
PubMed1996

The C-terminal Src kinase (Csk) is widely expressed, active in HT-29 cells that contain activated Src, and its expression is downregulated in butyrate-treated SW620 cells.

Csk expression was examined in human glioma, breast and colon cell lines, along with murine tissues. Relative to colon and glioma cell lines, Csk expression was highest in the breast cell lines. Relative to brain tissue, expression was 100-fold higher in the heart, kidney, liver, lung and spleen. Subcellular fractionation and cellular immunostaining indicated that it was localized in the cytosolic fraction. The expression of Csk was downregulated upon chemical-induced differentiation of SW620 human colon cells by treatment with sodium butyrate. Its expression localization and activity relative to Src are discussed.

Breast Neoplasms↗
PubMed1997

Rapid and sensitive detection of cell-associated HIV-1 in latently infected cell lines and in patient cells using sodium-n-butyrate induction and RT-PCR.

To develop a rapid and sensitive means of detecting cell-associated human immunodeficiency virus (HIV), donor cells from HIV seropositive patients were treated with the potent viral activator sodium-n-butyrate (NaB) and subsequently assayed by both in situ RNA hybridization and a reverse transcriptase polymerase chain reaction (RT-PCR). The sensitivity of RT-PCR was estimated to be equivalent to 1 x 10(-16) grams (0.1 fg) or approximately 64 copies of the input standard viral RNA per reaction. The present study takes advantage of the ability of NaB to introduce changes in chromatin structure of latently infected cells, leading to increased HIV gene expression. Human ACH-2 and U1 cell lines were used as representatives of T-lymphocytic and monocytoid cells harboring latent inducible proviruses. HIV gene expression was readily detected when these cells were treated with NaB. Viral gag RNA was detected by both in situ and RT-PCR assays. When peripheral blood mononuclear cells (PBMCs) from acquired immunodeficiency syndrome (AIDS) patients, who were all negative for in situ hybridization and serum/plasma p24 assays, were used for detection of viral gene expression, four categories with distinct patterns of induction were observed. The first set of patients showed HIV-positive PBMCs by RT-PCR without any added NaB, and suppression by added NaB or PHA. The second set of samples showed induction of viral RNA by NaB alone. The third set could be induced with PHA, but not NaB, and the fourth set required both NaB and PHA for induction of HIV gene expression. Our results suggest that direct treatment of the cells with HIV activators may be useful in increasing sensitivity of the RT-PCR intended to be used for detection of cell-associated viral RNAs. This approach may be used to confirm true status of the HIV infection when p24 results are negative or HIV RNAs in serum/plasma are below the threshold of detection. Moreover, this method may identify the presence of latent proviral genomes possibly reflecting the true rate of cell-associated viral load in vivo and without possible mutations brought about by long-term co-cultivation assays with cells from seronegative donors.

Butyrates↗
PubMedDate not supplied

Effect of sodium butyrate on human breast cancer cell lines.

We have investigated the effects exerted by sodium butyrate (NaBu) on the growth and cell cycle perturbations of four human breast cancer cell lines (MCF7, T47D, MDA-MB231 and BT20) with different steroid receptor profiles. Moreover, since one of the supposed mechanisms of action for NaBu activity involves the induction of apoptosis, we have studied the effects of NaBu on DNA fragmentation by agarose gel electrophoresis and flow cytometry. In all investigated cell lines, NaBu exerted a time- and dose-dependent inhibition of growth and caused a maximum inhibitory effect (85% to 90%) at the concentration of 2.5 mM. The inhibition was already evident after 3 days of treatment. The antiproliferative effect of NaBu was associated with a persistent block of cells in the G2M phase. The block was associated with apoptosis only in oestrogen-receptor positive cell lines. The inhibiting effect of NaBu in hormone-dependent and independent cell lines and its ability to induce apoptosis through a cell cycle perturbation in hormone-dependent cell lines may have important implications in the treatment of human tumours including breast cancer.

Antineoplastic Agents↗