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 µM 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 µM) 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.