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PubMed1986

Effect of butyric acid on lung-colonizing ability of cloned low-metastatic Lewis lung carcinoma cells.

The lung-colonizing ability of low-metastatic Lewis lung carcinoma cells (P-29) was enhanced by their in vitro treatment with butyric acid and its sodium salt, sodium butyrate. Of the short chain fatty acids tested, butyric acid was the most effective in enhancing the lung-colonizing ability of P-29 cells; propionic acid and valeric acid were slightly effective, but acetic acid and caproic acid were ineffective. The enhancing effect of butyric acid on the lung-colonizing ability of P-29 cells was reversible, indicating that the result was the consequence of epigenetic alterations. Treatment of P-29 cells with butyric acid resulted in enhancement of secretion of plasminogen activator, cellular cathepsin B activity, and cellular adhesiveness. The phenotypes of cells treated with butyric acid were compared with those of cells treated with dimethyl sulfoxide, which was reported to enhance the lung-colonizing ability of P-29 cells. Significant differences were found in the phenotypes, especially that of cellular adhesiveness; that is, butyric acid enhanced mainly homotypic aggregation of the cells, while dimethyl sulfoxide enhanced mainly heterotypic adhesion, such as adhesion to monolayers of endothelial cells. In addition, butyric acid reversibly caused hyperacetylation of core histones in P-29 cells, while dimethyl sulfoxide did not.

Animals↗
PubMed1994

Permissive effect of cyclic AMP and cycloheximide for induction by sodium butyrate of the glycoprotein hormone alpha-subunit gene in choriocarcinoma cells.

Expression of the chorionic gonadotropin alpha-subunit (alpha CG) gene is regulated differently in human tumor cell lines derived from trophoblastic and nontrophoblastic tissues. This is based, at least in part, on the observations that production of alpha CG is increased by cAMP but not by sodium butyrate in choriocarcinoma cells (JEG-3), whereas production of alpha CG is increased by butyrate but not by cAMP in cervical carcinoma cells (HeLa). Data presented herein confirm that the steady-state levels of alpha CG mRNA are increased approximately 10-fold by cAMP in JEG-3 cells, but additionally demonstrate that these levels can be further increased (to 25-fold) by sodium butyrate in conjunction with the cyclic nucleotide. Similar effects were achieved with the phorbol ester 12-0-tetradecanoylphorbol-13-acetate, which also acted synergistically with cAMP to increase alpha CG mRNA levels (24-fold). Butyrate and 12-0-tetradecanoylphorbol-13-acetate had little or no effect when added alone (1.5-fold and 2.5-fold, respectively) or in combination with one another (3.8-fold). Induction of the alpha CG gene by cAMP was independent of protein synthesis, as mRNA levels were comparable when JEG-3 cells were treated with cAMP in the absence and presence of cycloheximide (CHX). Unexpectedly, alpha CG mRNA levels were also elevated 8- to 10-fold in response to a combination of butyrate and CHX, but CHX alone or in combination with 12-0-tetradecanoylphorbol-13-acetate had no effect. Gel mobility shift assays demonstrated changes in the pattern of proteins binding to a cAMP response element and to a trophoblast-specific element with nuclear extracts from cells treated with CHX but not with cAMP or sodium butyrate. Together, these results suggest that induction patterns of the alpha CG gene by butyrate and cAMP in trophoblast- and nontrophoblast-derived tumor cell lines are less distinct than suggested previously and indicate that CHX, which is permissive for induction by butyrate, causes a significant shift in electrophoretic mobility of trans-acting factors involved in alpha CG gene expression.

Base Sequence↗
PubMed1993

Fetal hemoglobin induction with butyric acid: efficacy and toxicity.

Butyric acid induces fetal hemoglobin (HbF), a property of potential therapeutic advantage in patients with disorders of globin chain synthesis. We performed dose escalation studies of this compound in baboons to assess whether clinically significant increases in HbF are achievable, and to define the associated toxicities. Additionally, the effect of butyrate in combination with erythropoietin on HbF induction was assessed. HbF induction in response to butyrate was dependent on the dose and duration of treatment. Doses of butyrate less than 4 g/kg/d were associated with minimal toxicity (hypokalemia) and significant HbF induction in these nonanemic animals, with 1 g/kg/d producing an increase in HbF-containing reticulocytes (F reticulocytes) from 0.9% to 8.7% and an increase in HbF from 0.8% to 1.4%. A dose of 2 g/kg/d resulted in an increase in F reticulocytes from 2.1% to 27.8% and an increase in HbF from 0.7% to 2.2%. Doses of 4 g/kg/d in another animal produced an increase in F reticulocytes from 1% to 21.6% and in HbF from 1.9% to 5.3%. Infusions in excess of 4 g/kg/d were complicated (after a variable amount of time) by a decreased level of alertness (caused by hyperosmolality or butyrate itself) and hematologic toxicity (with declines in reticulocyte, white blood cell, and platelet counts). Prolonged infusions of high doses of butyrate (8 to 10 g/kg/d) were associated with peak F reticulocyte percentages reaching 38% to 64.5% and HbF reaching levels in excess of 20%. These high doses (8 to 10 g/kg/d) were complicated in two animals with a striking and unique neuropathologic picture and, in one animal, multiorgan system failure. Erythropoietin in combination with butyrate, induced F reticulocytosis in an additive manner. We conclude that butyric acid is a strong inducer of HbF, particularly when administered in combination with erythropoietin. As chronic toxicities remain undefined, patients in future clinical trials of this and similar compounds should be monitored closely for evidence of neurologic toxicity.

Animals↗
PubMed1997

Induction of caspase-3 protease activity and apoptosis by butyrate and trichostatin A (inhibitors of histone deacetylase): dependence on protein synthesis and synergy with a mitochondrial/cytochrome c-dependent pathway.

The induction of apoptosis of tumor cells by the colonic fermentation product butyrate is thought to be an important mechanism in protection against colorectal cancer. Because a major action of butyrate is to inhibit histone deacetylase (leading to chromatin relaxation and altered gene expression), butyrate may induce apoptosis by derepression of specific cell death genes. Here we show that butyrate and trichostatin A (a more selective inhibitor of histone deacetylase) induce the same program of apoptosis in Jurkat lymphoid and LIM 1215 colorectal cancer cell lines that is strictly dependent on new protein synthesis (within 10 h) and that leads to the conversion of the proenzyme form of caspase-3 to the catalytically active effector protease (within 16 h) and apoptotic death (within 24 h). Cells primed with a low concentration of butyrate that itself did not induce activation of caspase-3 or apoptosis were, nevertheless, rendered highly susceptible to induction of apoptosis by staurosporine (an agent that has recently been shown to act by causing mitochondrial release of cytochrome c). Synergy between butyrate and staurosporine was due to the presence of a factor in the cytosol of butyrate-primed cells which enhanced over 7-fold the activation of caspase-3 induced by the addition of cytochrome c and dATP to isolated cytosol. We propose that changes at the level of chromatin structure, induced by a physiological substance butyrate, lead to the expression of a protein that facilitates the pathway by which mitochondria activate caspase-3 and trigger apoptotic death of lymphoid and colorectal cancer cells.

Apoptosis↗
PubMed1997

Butyrate and the colonocyte. Production, absorption, metabolism, and therapeutic implications.

Butyrate, a SCFA generated by microbial fermentation of dietary substrates, is produced in the colon of humans and may influence colonic disease. It is possible to manipulate the diet in order to enhance levels of butyrate in various regions of the large intestine. Butyrate is absorbed by colonocytes in the proximal colon via passive diffusion and by active transport mechanisms which are linked to various ion exchange transporters. In the distal colon, the main mechanism of absorption is passive diffusion of the lipid-soluble form. Butyrate and other SCFA are important for the absorption of electrolytes by the large intestine and may play a role in preventing certain types of diarrhea. The mechanism by which butyrate and other SCFA exerts control over fluid and electrolyte fluxes in the colon is not well delineated though it may occur through an energy generated fuel effect, the up-regulation of various electrolyte transport systems, as well as possible effects on neuroendocrine factors. Butyrate has been shown to have beneficial effects on some colonic pathologies. This SCFA may be protective against colorectal neoplasia. Butyrate regulates colonic motility, increases colonic blood flow and may enhance colonic anastomosis healing. Butyrate may reduce the symptoms from ulcerative colitis and diversion colitis and it may prevent the progression of colitis in general. Further investigations are needed to confirm these findings in controlled, randomized, double blinded clinical studies.

Butyrates↗
PubMed1998

Butyrate inhibits colon carcinoma cell growth through two distinct pathways.

BACKGROUND: Dietary fiber and the resultant increase in colonic butyrate levels protect against colon carcinogenesis. Previous studies have shown that p21 and histone hyperacetylation are important in basal growth inhibition by butyrate. This study was designed to elucidate other mechanism underlying the butyrate effects on cell growth. METHODS: HT-29 colon carcinoma cells (standard medium or medium lacking serum) were treated with sodium butyrate (NaBu), epidermal growth factor (EGF), or both. Northern blot analyses were performed with cDNA probes specific for c-fos, c-jun, and actin. Cell growth was measured by 3H-thymidine incorporation. Enzyme-linked immunosorbent assay (ELISA) was used to quantify EGF receptor levels. RESULTS: Butyrate and serum starvation (SS) both induced a cell cycle withdrawal by 24 hours. In response to EGF treatment, SS cells exhibited a growth spurt and induced c-fos and c-jun proto-oncogene expression, whereas butyrate-treated cells exhibited minimal growth response to EGF. This relative unresponsiveness to EGF in butyrate-treated cells corresponded to a dramatic decline in EGF receptor levels when compared to untreated controls. CONCLUSIONS: Butyrate appears to inhibit colon cancer cell growth by two mechanisms, one involving histone hyperacetylation and p21 induction and the other related to impaired EGF-responsiveness.

Actins↗
PubMed1998

Loss of butyrate-induced apoptosis in human hepatoma cell lines HCC-M and HCC-T having substantial Bcl-2 expression.

We have demonstrated that sodium butyrate induces differentiation in human hepatoma cells; however, recent studies have shown that this agent causes apoptosis in some types of cancer cells. In this study, we examined whether sodium butyrate causes apoptosis in the human hepatoma cell lines, HCC-M and HCC-T. The growth of human hepatoma cells was dose-dependently reduced by sodium butyrate. Flow cytometric analysis showed cell-cycle arrest at the G1 phase in the sodium butyrate-treated cells. Apoptotic change was never found in treated cells at concentration levels of less than 5 mmol/L. Sodium butyrate decreased p53 expression and increased p21WAF-1 expression in HCC-T and HCC-M cells having the wild-type p53 gene. Western blot analysis showed that Bcl-2 was expressed in the HCC-T and HCC-M cells, and its expression was increased after exposure to sodium butyrate. Antisense oligodeoxynucleotide against bcl-2 easily caused apoptosis. These results indicate that sodium butyrate hardly induces apoptotic change in the human hepatoma cell lines, HCC-T and HCC-M, with the increase of Bcl-2 expression. Cell-cycle arrest in the G1 phase caused by sodium butyrate was suggested to be induced by the increase in p21WAF-1 expression, but this change did not link with the p53 increase.

Apoptosis↗
PubMed2000

Expression of 5-lipoxygenase by human colorectal carcinoma Caco-2 cells during butyrate-induced cell differentiation.

Butyrate, a short-chain fatty acid, modulates proliferation and differentiation of normal and neoplastic colonocytes. We examined the expression of 5-lipoxygenase (5-LO) and its metabolites in human colorectal carcinoma (Caco-2) cells, exposed to differentiation-inducing doses of butyrate. Treatment with butyrate significantly increased 5-lipoxygenase mRNA and protein in comparison to nontreated cells. Cyclooxygenases (COX)-1 and COX-2 mRNA were not significantly influenced by the treatment. However, 5-LO activity, low in nontreated cells, increased only minimally after butyrate, and its metabolic product (5-HETE) was detectable neither in control nor in treated cells. In contrast, 15-HETE (a product of 15-LO, which is also upregulated by butyrate) rose significantly. We conclude that, although being overexpressed by butyrate on mRNA and protein level, 5-LO remains inactive in differentiating Caco-2 cells. This is likely to be due either to some associated actions of butyrate, or to 5-LO-inhibition by 15-HETE, concomitantly induced by butyrate treatment.

5-Lipoxygenase-Activating Proteins↗
PubMed2001

1,25-Dihydroxycholecalciferol enhances butyrate-induced p21(Waf1/Cip1) expression.

Butyrate, a short-chain fatty acid produced in the colon, as well as its prodrug tributyrin, reduce proliferation and increase differentiation of colon cancer cells. p21(Waf1/Cip1) and p27(Kip1) are negative regulators of cell cycle and are thought to have a key function in the differentiation of various cell lines. We studied the effects of butyrate on differentiation, VDR expression, as well as on p21(Waf1/Cip1) and p27(Kip1) expression in human colon cancer cells (Caco-2). Butyrate induced cell differentiation, which was further enhanced after addition of 1,25-dihydroxycholecalciferol. Synergistic effect of butyrate and dihydroxycholecalciferol in Caco-2 cells was due to butyrate-induced overexpression of VDR. While butyrate as well as dihydroxycholecalciferol increased p21(Waf1/Cip1) and p27(Kip1) expression, in contrast combined exposure of butyrate and dihydroxycholecalciferol resulted in a synergistic amplification of p21(Waf1/Cip1), but not of p27(Kip1) expression. These data imply that butyrate selectively increases p21(Waf1/Cip1) expression via upregulation of VDR in Caco-2 cells.

Alkaline Phosphatase↗
PubMed1990

Characterization of butyrate-dependent electroneutral Na-Cl absorption in the rat distal colon.

Recent studies have established that mucosal butyrate stimulates electroneutral sodium-chloride (Na-Cl) absorption in the distal colon of the rat and a model in which Na-hydrogen (H) and Cl-butyrate exchanges are coupled has been proposed as the mechanism of butyrate-dependent electroneutral Na-Cl absorption. These studies were designed to examine butyrate-dependent electroneutral Na-Cl absorption in experimental conditions in which HCO3-dependent electroneutral Na-Cl absorption is inhibited: in Na-depleted (aldosterone-treated) animals and in the presence of increased mucosal cyclic adenosine monophosphate (AMP). Butyrate-dependent electroneutral Na-Cl absorption was markedly reduced in Na-depleted rats. In contrast, the inhibition of both net Na and net Cl absorption by 5 mM serosal theophylline was significantly less in butyrate-containing, HCO3-free Ringer solution than in butyrate-free- HCO3-containing Ringer solution. These studies indicate that cyclic AMP does not inhibit butyrate-dependent electroneutral Na-Cl absorption and we propose that the mechanism of cyclic AMP inhibition of HCO3-dependent electroneutral Na-Cl absorption may be a result of its inhibition of Cl-HCO3, not Na-H exchange.

Aldosterone↗
PubMed1995

Isomerization of n- and i-butyrate in anaerobic methanogenic systems.

Studies of the degradation of the two isomeric forms of butyrate in different anaerobic environments showed isomerization between n- and i-butyrate. Degradation rates were similar for the different examined systems and degradation rates for n-butyrate degradation were generally higher than for i-butyrate. Degradation rates for n-butyrate ranged from 0.52 to 1.39 day-1, while the rates for i-butyrate were from 0.46 to 1.15 day-1. Production of isomers was not observed when the volatile fatty acid degradation was inhibited by addition of bromoethane sulfonic acid, indicating that isomerization was coupled to the methanogenic degradation of the acid. The degree of isomerization observed during n-butyrate degradation was similar to the degree during i-butyrate degradation. Experiments indicated that the isomerization degree was higher for the thermophilic than for the mesophilic inocula.

Anaerobiosis↗
PubMed2004

The effect of sodium butyrate in combination with ATRA on the proliferation/differentiation of SKM-1.

To explore the molecular mechanisms of sodium butyrate working on SKM-1 cell proliferation/differentiation and to study its synergistic effect with all-trans retinoic acid (ATRA), SKM-1 cells were grown in the absence or presence of sodium butyrate and/or ATRA. The percentage of viable cells was determined by trypan blue exclusion. Differentiation was determined by nitroblue tetrazolium (NBT) reduction and cell surface adhesion molecules was analyzed by FACS. Cell cycle distribution was examined after DNA staining by propidium iodide. D-type cyclins, cdks and P21 mRNA were studied by reverse transcription-polymerase chain reaction. Our results showed that sodiun butyrate and/or ATRA blocked cells mainly in the G0/G1 phase of the cell cycle. ATRA inhibited the mRNA expression of CDK6, CDK4, cyclinD3 and cyclinD1. Sodium butyrate inhibited the mRNA expression of CDK2, cyclinD2 and cyclinD1. ATRA and sodium butyrate inhibited the mRNA expression of CDK6, CDK4, CDK2, cyclinD1, cyclinD2 and cyclinD3. Both ATRA and/or sodium butyrate stimulated p21 expression at the mRNA levels. Our results suggest that the effect of sodium butyrate on cell proliferation/differentiation might be linked to its ability to induce expression of p21 mRNA and inhibit the cyclin-cdk complexes. Our observations support the notion that the sodium butyrate works synergistically with ATRA.

Antineoplastic Agents↗
PubMed2006

PPARgamma is a key target of butyrate-induced caspase-3 activation in the colorectal cancer cell line Caco-2.

BACKGROUND: Butyrate, a potent histone deacetylase inhibitor, belongs to a promising new class of antineoplastic agents with the capacity to induce apoptosis of cancer cells. However, the underlying mechanisms of action have yet not been elucidated. AIM: To further investigate the molecular events involved in butyrate-induced caspase-3 activation in Caco-2 wild-type, empty-vector and dominant-negative PPARgamma mutant cells along the signalling pathway. In this context, the involvement and up-regulation of PPARgamma was examined. RESULTS: Stimulation of cells with butyrate resulted in increased expression of PPARgamma mRNA, protein, and activity as well as phospho-p38 MAPK protein expression and caspase-3 activity. Arsenite, a direct stimulator of p38 MAPK, also led to an increased PPARgamma expression, thereby mimicking the effects of butyrate. In contrast, butyrate-mediated up-regulation of PPARgamma was counteracted by co-incubation with the p38 MAPK inhibitor SB203580. Treatment of cells with butyrate resulted in both increased caspase-8 and -9 activity and reduced expression of XIAP and survivin. However, butyrate-mediated effects on these apoptosis-regulatory proteins leading to caspase-3 activation were almost completely abolished in Caco-2 dominant-negative PPARgamma mutant cells. CONCLUSIONS: Our data clearly unveil PPARgamma as a key target in the butyrate-induced signalling cascade leading to apoptosis via caspase-3 in Caco-2 cells.

Butyric Acid↗
PubMed1993

Bicarbonate-stimulated [14C]butyrate uptake in basolateral membrane vesicles of rat distal colon.

BACKGROUND: The mechanism of short-chain fatty acid (SCFA) absorption by the colon is not known. The aim of these experiments was to identify the transport mechanisms present in the basolateral membrane to develop an overall model of colonic SCFA absorption. METHODS: These studies determined the uptake of [14C]butyrate (used as a model SCFA) by basolateral membrane vesicles prepared from rat distal colonic mucosa. RESULTS: Significantly higher [14C]butyrate uptake under an acidic environment (extravesicular pH [pHo] = intravesicular pH [pHi] = 5.5) than that under alkaline environment (pHo = pHi = 7.5) indicates the presence of nonionic diffusion. In the absence of a pH gradient (pHo/pHi = 7.5/7.5), outward gradients of bicarbonate significantly stimulated [14C]butyrate uptake. Additional presence of a pH gradient (pHo/pHi = 6.0/7.5) further enhanced the bicarbonate gradient-stimulated [14C]butyrate uptake that was not inhibited by voltage clamping but was inhibited substantially by an anion exchange inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) (82%). Both increasing extravesicular butyrate concentration and intravesicular bicarbonate concentration saturated bicarbonate/pH gradient-stimulated [14C]butyrate uptake with an apparent Michaelis constant (Km) for butyrate of 6.9 mmol/L and an apparent Km for bicarbonate of 27.4 mmol/L. CONCLUSIONS: Butyrate uptake by basolateral membrane vesicles represents both nonionic diffusion and a carrier-mediated SCFA-bicarbonate exchange process that differs from the SCFA-bicarbonate exchange recently identified in apical membrane vesicles. Thus, two distinct carrier-mediated anion exchange processes located in apical and basolateral membranes mediate transcellular SCFA transport in colonocytes.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1994

Butyrate is a potent inhibitor of urokinase secretion by normal colonic epithelium in vitro.

BACKGROUND/AIMS: Because the neutral protease urokinase is important in control of cell adhesion and migration, the effects of the physiologically relevant fermentation product butyrate on urokinase secretion by colonic epithelium were examined. METHODS: Secreted and cell-associated levels of urokinase and plasminogen activator inhibitor 1 were measured in colonic crypt cells within 24 hours of isolation from macroscopically normal mucosa of normal or cancer-bearing colons. RESULTS: Butyrate caused a concentration-dependent inhibition of both secreted (56% +/- 4% inhibition after 24-hour exposure to 1 mmol/L butyrate; n = 20; mean +/- SEM; P < 0.001) and cell-associated urokinase content (35% +/- 6%; P = 0.003). Acetate and propionate had minimal effects. Butyrate also stimulated plasminogen activator inhibitor 1 secretion by 25% +/- 7% (P = 0.013). Net urokinase activities were suppressed in supernates and cell homogenates by butyrate. Levels of transcripts for urokinase and the inhibitor changed with butyrate exposure in parallel to the levels of secretion of the respective proteins. Cells from the cancer group showed significantly reduced inhibitor secretion and abnormal responses to butyrate (greater inhibition of urokinase secretion and no stimulation of inhibitor secretion), probably reflecting the diffuse disturbance of colonic epithelial biology associated with colorectal cancer. CONCLUSIONS: Butyrate has dual effects in markedly reducing colonic epithelial urokinase activity, and these may have important implications to understanding colonic epithelial physiology and the pathogenesis and treatment of colonic diseases.

Acetates↗
PubMed1990

Induction of fos and sis proto-oncogenes and genes of the extracellular matrix proteins during butyrate induced glioma differentiation.

Sodium butyrate has been shown to inhibit the growth and induce the differentiation of F-98 rat glioma cells. In agreement with the morphological changes, we have found that mRNAs for fibronectin and collagen in these cells could be reversibly induced by butyrate. While Ki-ras mRNA levels remained relatively unchanged, mRNAs for fos and sis increased significantly during the course of butyrate induced differentiation. c-fos induction can be detected 30 min after butyrate addition, a peak level (greater than 20 fold) was reached at 2 h, with a subsequent gradual decline. c-sis induction was detectable 24 h after butyrate exposure, at which time the cells have assumed morphological transition. Interestingly, the sis mRNA induction was not reversible upon butyrate withdrawal. The sis mRNA half-life increased from 40 min in the untreated cells to 100 min in the butyrate induced cells indicating that the increase in the stability of sis mRNA contributed, at least in part, to the elevated levels of sis expression. These findings demonstrate a coordinated induction of fibronectin and collagen genes in the butyrate-treated F-98 cells. In addition, fos and sis transcripts were differentially induced; a rapid and transient induction of fos followed by an irreversible induction of sis at a later stage of differentiation.

Animals↗
PubMed2003

Butyrate modulates gene and protein expression in human intestinal endothelial cells.

We hypothesized that sodium butyrate, a product of enteric bacterial fermentation, modulates gene expression in gut microvascular endothelium which plays a central role in mucosal immunity. We examined sodium butyrate's effect on LPS-induced gene and protein expression in primary cultures of human intestinal microvascular endothelial cells. cDNA array analysis revealed that sodium butyrate augmented ICAM-1 mRNA expression, while it inhibited IL-6 and COX-2 expression in response to LPS stimulation. These results were confirmed at the protein level. Prostaglandin E2 production by LPS was also strongly inhibited by butyrate. The pattern of altered gene expression by butyrate was reproduced by the histone deacetylase inhibitor tricostatin A, suggesting that the regulatory mechanism of butyrate on HIMEC gene expression involves histone deacetylase inhibition. IkappaBalpha degradation and NF-kappaB activation were unaffected by butyrate. In addition to effects on epithelium, sodium butyrate modulates the innate mucosal immune response towards LPS through effects on microvascular endothelial function.

Butyrates↗
PubMed2006

Short, discontinuous exposure to butyrate effectively sensitizes latently EBV-infected lymphoma cells to nucleoside analogue antiviral agents.

Antiviral drugs alone have been unsuccessful in the treatment of Epstein-Barr virus (EBV)-associated malignancies because the virus maintains a latent state of replication in these tumors. In recent years, novel therapeutic approaches are being investigated wherein lytic replication of the virus is induced prior to the use of cytotoxic antiviral drugs. The choice of suitable agents to induce lytic replication has been a critical step in this novel approach. We have previously demonstrated that butyrate derivatives induce a lytic pattern of EBV gene expression in patient-derived EBV-positive lymphoblastoid cell lines and, together with nucleoside analogue ganciclovir, effectively reduce or eliminate tumor growth in humans. Butyrate has drawbacks as a therapeutic agent, however, as constant intravenous infusion is required to achieve detectable plasma levels of this drug. In this study, we investigated whether discontinuous exposure to butyrate is capable of initiating lytic phase gene expression and thymidine kinase induction, and sensitizing EBV-positive lymphoma cells to ganciclovir-mediated cell growth arrest and apoptosis. We demonstrate that multiple daily 6-h exposures of the EBV-positive Burkitt's lymphoma cell line P3HR1 to butyrate induced sustained expression of the EBV lytic phase protein BMRF. Viral thymidine kinase was also induced by intermittent exposure, although to a lower level than with continuous exposure treatment. However, discontinuous exposure to butyrate in combination with ganciclovir induced a similar level of tumor cell growth inhibition as did continuous treatment, as measured by serial enumeration of viable cells, MTT cell proliferation assays and measurement of cellular DNA content. We further demonstrated that those cells which survived initial exposure to butyrate plus ganciclovir remained susceptible to further cycles of combination treatment. These findings suggests that continuous infusion of butyrate may not be necessary for maintaining viral thymidine kinase gene expression and sensitization to antiviral agents in EBV-associated tumors, and that therapeutic regimens which employ more convenient, discontinuous exposure to butyrate may also be effective clinically.

Antiviral Agents↗