Colorectal cancer

Histone deacetylases: novel targets for prevention of colitis-associated cancer in mice

R Glauben¹, A Batra¹, T Stroh¹, U Erben¹, I Fedke¹, H A Lehr², F Leoni³, P Mascagni³, C A Dinarello⁴, M Zeitz¹, B Siegmund^1,4

¹ Department of Medicine I, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
² Institut Universitaire de Pathologie, Centre Universitaire Vaudois, Lausanne, Switzerland
³ Italfarmaco, Spa, Cinisello Balsamo, Italy
⁴ Department of Medicine, University of Colorado, Denver, CO, USA

Dr B Siegmund, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Medicine I, Hindenburgdamm 30, D-12200 Berlin, Germany; britta.siegmund{at}charite.de

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)-B 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 (IFN) 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 and enhanced apoptosis in lamina propria mononuclear cells were found to accompany a histone deacetylase-dependent activation of NF-B.

Conclusions: These results indicate that inhibition of histone deactylases can attenuate inflammation-mediated tumour growth, which is paralled by an inhibition of NF-B. Thus histone deacetylase inhibitors provide a promising strategy that combines anti-inflammatory and proapoptotic modes of action.

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