title: Histone deacetylases: novel targets for prevention of colitis-associated cancer in mice.
abstract: OBJECTIVE
  Inhibition of histone deacetylases, well known for its antiproliferative efficacy in vivo, was recently shown to ameliorate inflammation in experimental colitis. Since inflammatory bowel disease is associated with an increased risk of developing colon cancer, here the combined anti-inflammatory and proapoptotic efficacy of histone deacetylase inhibitors was studied in mouse models.
  
  
  METHODS
  The novel histone deacetylase inhibitor ITF2357 was compared with suberoylanilide hydroxamic acid in models of experimental colitis. Effects on tumour growth were studied after treatment of mice with azoxymethane and dextran sulphate sodium, and in interleukin 10 (IL10) knockout mice, respectively. Possible underlying mechanisms involving apoptosis and nuclear factor (NF)-kappaB activation were addressed by flow cytometry and western blot.
  
  
  RESULTS
  In dextran sulphate sodium- and trinitrobenzene sulphonic acid-induced colitis, treatment with ITF2357 was superior to suberoylanilide hydroxamic acid as shown by macroscopic and histological amelioration of inflammation, by reduced production of interferon gamma (IFN gamma) and by increased production of IL10. In both models of inflammation-mediated tumourigenesis, inhibition of histone deacetylases resulted in a significant suppression of tumour growth in terms of size and number, along with reduced signs of inflammation. As for potential mechanisms of ITF2357 action, increased acetylation of histone 3, reduced production of IFN gamma and enhanced apoptosis in lamina propria mononuclear cells were found to accompany a histone deacetylase-dependent activation of NF-kappaB.
  
  
  CONCLUSIONS
  These results indicate that inhibition of histone deactylases can attenuate inflammation-mediated tumour growth, which is paralled by an inhibition of NF-kappaB. Thus histone deacetylase inhibitors provide a promising strategy that combines anti-inflammatory and proapoptotic modes of action.
authors.affiliation: Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Medicine I, Hindenburgdamm 30, D-12200 Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Glauben
authors.forename: A
authors.initials: A
authors.lastname: Batra
authors.forename: T
authors.initials: T
authors.lastname: Stroh
authors.forename: U
authors.initials: U
authors.lastname: Erben
authors.forename: I
authors.initials: I
authors.lastname: Fedke
authors.forename: H A
authors.initials: HA
authors.lastname: Lehr
authors.forename: F
authors.initials: F
authors.lastname: Leoni
authors.forename: P
authors.initials: P
authors.lastname: Mascagni
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: M
authors.initials: M
authors.lastname: Zeitz
authors.forename: B
authors.initials: B
authors.lastname: Siegmund
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D003092:Colitis / Q000201:enzymology / Q000517:prevention & control*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D000077337:Vorinostat; C502418:givinostat hydrochloride