The Inhibitor of Histone Deacetylases Sodium Butyrate Enhances the Cytotoxicity of Mitomycin C

Gospodinov, Anastas; Popova, Stanislava; Vassileva, Ivelina; Anachkova, Boyka

doi:10.1158/1535-7163.mct-12-0193

Cited by 8 publications

(6 citation statements)

References 47 publications

(52 reference statements)

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“…Butyrate has been shown to abrogate the S-phase cell cycle checkpoint, and exhibits colon cancer preventive effects through cell proliferation regulation [ 5 , 6 , 28 , 29 , 30 ]. As there are few reports concerning the apoptotic potential, we propose that butyrate plays differential roles in the cell proliferation of noncancerous NCM460 cell and cancerous HCT116 colon cells through cellular signaling modulation.…”

Section: Discussionmentioning

confidence: 99%

Butyrate Inhibits Cancerous HCT116 Colon Cell Proliferation but to a Lesser Extent in Noncancerous NCM460 Colon Cells

et al. 2017

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Butyrate, an intestinal microbiota metabolite of dietary fiber, exhibits chemoprevention effects on colon cancer development. However, the mechanistic action of butyrate remains to be determined. We hypothesize that butyrate inhibits cancerous cell proliferation but to a lesser extent in noncancerous cells through regulating apoptosis and cellular-signaling pathways. We tested this hypothesis by exposing cancerous HCT116 or non-cancerous NCM460 colon cells to physiologically relevant doses of butyrate. Cellular responses to butyrate were characterized by Western analysis, fluorescent microscopy, acetylation, and DNA fragmentation analyses. Butyrate inhibited cell proliferation, and led to an induction of apoptosis, genomic DNA fragmentation in HCT116 cells, but to a lesser extent in NCM460 cells. Although butyrate increased H3 histone deacetylation and p21 tumor suppressor expression in both cell types, p21 protein level was greater with intense expression around the nuclei in HCT116 cells when compared with that in NCM460 cells. Furthermore, butyrate treatment increased the phosphorylation of extracellular-regulated kinase 1/2 (p-ERK1/2), a survival signal, in NCM460 cells while it decreased p-ERK1/2 in HCT116 cells. Taken together, the activation of survival signaling in NCM460 cells and apoptotic potential in HCT116 cells may confer the increased sensitivity of cancerous colon cells to butyrate in comparison with noncancerous colon cells.

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Section: Discussionmentioning

confidence: 99%

Butyrate Inhibits Cancerous HCT116 Colon Cell Proliferation but to a Lesser Extent in Noncancerous NCM460 Colon Cells

et al. 2017

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“…Sodium butyrate inhibited histone deacetylase leading to hyperacetylation of these basic proteins and loosening of their attachment to DNA. This allowed increased transcription of genes and caused apoptosis in cancer cells (Gospodinov et al, 2012, Luhrs et al, 2002, Smith et al, 1998. In cultured fibroblasts, sodium butyrate treatment increased methylation of DNA (Boffa et al, 1994).…”

Section: Acetylation Of Histones Phosphorylation Of Proteins and Methylation Of Dna By Sodium Butyratementioning

confidence: 99%

Dietary fibers and their fermented short-chain fatty acids in prevention of human diseases

Prasad¹,

Bondy

2019

Bioactive Carbohydrates and Dietary Fibre

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Many studies show that daily consumption of high-fiber diet is associated with a reduced risk of developing kidney stones, inflammatory disease, colon cancer and other malignancies, obesity, type II diabetes, and cardiovascular disease. Dietary fibers are non-digestible polysaccharides that are composed of complex carbohydrates. Based on their relative solubility in water, dietary fibers can be divided into insoluble and soluble forms. An important property of insoluble fibers is their ability to bind with carcinogens, mutagens, and other toxic chemicals that are formed during digestion of food and eliminate them through the feces. Soluble fibers can often be degraded to short-chain fatty acids, such as butyrate, propionate, and acetate by microbial fermentation. This review discusses mechanisms of action of fibers and their beneficial effects on the GI tract as well as on other organs. Among short-chain fatty acids, butyrate has been most extensively studied and the effects of sodium butyrate on cell culture and animal models are discussed in order to emphasize its potential value in prevention of certain diseases.

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“…For example, other investigators have reported that SAHA mediated the production of reactive oxygen species SAHA that contributed to cell death [46;47]. We hypothesized that, if the mechanism of synergy was due primarily to the SAHA-mediated inhibition of HR, then SAHA would synergistically enhance GCV cytotoxicity in the HR-proficient but not in the HR-deficient CHO cells.…”

Section: Discussionmentioning

confidence: 93%

Inhibition of homologous recombination with vorinostat synergistically enhances ganciclovir cytotoxicity

et al. 2013

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The nucleoside analog ganciclovir (GCV) elicits cytotoxicity in tumor cells via a novel mechanism in which drug incorporation into DNA produces minimal disruption of replication, but numerous DNA double strand breaks occur during the second S-phase after drug exposure. We propose that homologous recombination (HR), a major repair pathway for DNA double strand breaks, can prevent GCV-induced DNA damage, and that inhibition of HR will enhance cytotoxicity with GCV. Survival after GCV treatment in cells expressing a herpes simplex virus thymidine kinase was strongly dependent on HR (>14-fold decrease in IC50 in HR-deficient vs. HR-proficient CHO cells). In a homologous recombination reporter assay, the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA; vorinostat), decreased HR repair events up to 85%. SAHA plus GCV produced synergistic cytotoxicity in U251tk human glioblastoma cells. Elucidation of the synergistic mechanism demonstrated that SAHA produced a concentration-dependent decrease in the HR proteins Rad51 and CtIP. GCV alone produced numerous Rad51 foci, demonstrating activation of HR. However, the addition of SAHA blocked GCV-induced Rad51 foci formation completely and increased γH2AX, a marker of DNA double strand breaks. SAHA plus GCV also produced synergistic cytotoxicity in HR-proficient CHO cells, but the combination was antagonistic or additive in HR-deficient CHO cells. Collectively, these data demonstrate that HR promotes survival with GCV and compromise of HR by SAHA results in synergistic cytotoxicity, revealing a new mechanism for enhancing anticancer activity with GCV.

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The Inhibitor of Histone Deacetylases Sodium Butyrate Enhances the Cytotoxicity of Mitomycin C

Cited by 8 publications

References 47 publications

Butyrate Inhibits Cancerous HCT116 Colon Cell Proliferation but to a Lesser Extent in Noncancerous NCM460 Colon Cells

Butyrate Inhibits Cancerous HCT116 Colon Cell Proliferation but to a Lesser Extent in Noncancerous NCM460 Colon Cells

Dietary fibers and their fermented short-chain fatty acids in prevention of human diseases

Inhibition of homologous recombination with vorinostat synergistically enhances ganciclovir cytotoxicity

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