title: The chemopreventive activity of the histone deacetylase inhibitor tributyrin in colon carcinogenesis involves the induction of apoptosis and reduction of DNA damage.
abstract: The chemopreventive activity of the histone deacetylase inhibitor (HDACi) tributyrin (TB), a prodrug of butyric acid (BA), was evaluated in a rat model of colon carcinogenesis. The animals were treated with TB (TB group: 200mg/100g of body weight, b.w.) or maltodextrin (MD isocaloric control group: 300 mg/100g b.w.) daily for 9 consecutive weeks. In the 3rd and 4th weeks of treatment, the rats in the TB and MD groups were given DMH (40 mg/kg b.w.) twice a week. After 9 weeks, the animals were euthanized, and the distal colon was examined. Compared with the control group (MD group), TB treatment reduced the total number of aberrant crypt foci (ACF; p<0.05) as well as the ACF with ≥4 crypts (p<0.05), which are considered more aggressive, but not inhibited the formation of DMH-induced O6-methyldeoxyguanosine DNA adducts. The TB group also showed a higher apoptotic index (p<0.05) and reduced DNA damage (p<0.05) compared with MD group. TB acted as a HDACi, as rats treated with the prodrug of BA had higher levels of histone H3K9 acetylation compared with the MD group (p<0.05). TB administration resulted in increased colonic tissue concentrations of BA (p<0.05) compared with the control animals. These results suggest that TB can be considered a promising chemopreventive agent for colon carcinogenesis because it reduced the number of ACF, including those that were more aggressive. Induction of apoptosis and reduction of DNA damage are cellular mechanisms that appear to be involved in the chemopreventive activity of TB.
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil; Advanced Research Center in Food Science and Nutrition (NAPAN) and Food Research Center (FoRC), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.
authors.forename: Renato
authors.initials: R
authors.lastname: Heidor
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.
authors.forename: Kelly Silva
authors.initials: KS
authors.lastname: Furtado
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.
authors.forename: Juliana Festa
authors.initials: JF
authors.lastname: Ortega
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.
authors.forename: Tiago Franco
authors.initials: TF
authors.lastname: de Oliveira
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.
authors.forename: Paulo Eduardo Latorre Martins
authors.initials: PE
authors.lastname: Tavares
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vieira
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.
authors.forename: Mayara Lilian Paulino
authors.initials: ML
authors.lastname: Miranda
authors.affiliation: Laboratory of Food Chemistry and Biochemistry, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil; Advanced Research Center in Food Science and Nutrition (NAPAN) and Food Research Center (FoRC), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Purgatto
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil; Advanced Research Center in Food Science and Nutrition (NAPAN) and Food Research Center (FoRC), Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil. Electronic address: rmoreno@usp.br.
authors.forename: Fernando Salvador
authors.initials: FS
authors.lastname: Moreno
mesh_terms: D019813:1,2-Dimethylhydrazine; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000517:prevention & control*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008297:Male; D011230:Precancerous Conditions / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
chemical_list: C518278:7-methyl-8-oxo-2'-deoxyguanosine; D016588:Anticarcinogenic Agents; D056572:Histone Deacetylase Inhibitors; D014280:Triglycerides; D003849:Deoxyguanosine; D019813:1,2-Dimethylhydrazine; C005830:tributyrin
keywords: Aberrant crypt foci; Apoptosis; Colon cancer; DNA damage; Histone acetylation; Tributyrin