title: Effects of a selection of histone deacetylase inhibitors on mast cell activation and airway and colonic smooth muscle contraction.
abstract: Studies of histone deacetylase (HDAC) inhibitors, novel anticancer drugs, in models of autoimmune diseases, asthma, and inflammatory bowel disease suggest that HDAC inhibitors may also have useful anti-inflammatory effects. Accordingly, in vitro studies relevant to asthma and inflammatory bowel disease were conducted using a selection of HDAC inhibitors: suberoylanilide hydroxamic acid (SAHA, Vorinostat), and a related branched hydroxamic acid, diamide (1), MGCD0103 and two short chain fatty acid derivatives: sodium butyrate (of use in inflammatory bowel disease) and sodium valproate. The ability of those HDAC inhibitors to modulate antigen- or agonist-induced contraction of isolated guinea pig tracheal rings and colon, agonist-induced contraction of rat colon, and histamine release from rat peritoneal mast cells was examined. Pre-incubation (up to 6 h) with 10-40 microM of SAHA, diamide (1), or MGCD0103 caused significant inhibition of the antigen-induced contraction of sensitised guinea pig tracheal rings as well as inhibition of the contraction induced by histamine, 5-hydroxytryptamine and carbachol (G-protein coupled receptor agonists), while sodium butyrate (1 mM) and sodium valproate (100 microM) were weak inhibitors. Contraction of tracheal rings by sodium fluoride (NaF, a non-selective G-protein activator), KCl and a peroxyl radical generator was blocked by MGCD0103. Additionally, MGCD0103 significantly inhibited antigen-induced histamine release from IgE antibody-sensitised rat peritoneal mast cells, and NaF-induced histamine release, as well as inhibiting NaF-induced colon contraction. Those various effects appear to involve modulation of cell signaling, probably involving G-protein coupled pathways, and further support the development of HDAC inhibitors as anti-inflammatory agents.
authors.affiliation: Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. e.assem@ucl.ac.uk
authors.forename: El-Sayed K
authors.initials: el-SK
authors.lastname: Assem
authors.forename: Kheng H
authors.initials: KH
authors.lastname: Peh
authors.forename: Beatrice Y C
authors.initials: BY
authors.lastname: Wan
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Middleton
authors.forename: Jon
authors.initials: J
authors.lastname: Dines
authors.forename: Charles M
authors.initials: CM
authors.lastname: Marson
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects / Q000276:immunology; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D000077337:Vorinostat
chemical_list: D001549:Benzamides; D018679:Cholinergic Agonists; D017442:Histamine Agonists; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011743:Pyrimidines; D018490:Serotonin Agents; D012701:Serotonin; D000077337:Vorinostat; D006632:Histamine; D002217:Carbachol; C523184:mocetinostat