Inhibition of Histone Deacetylases in Inflammatory Bowel Diseases

Abstract

This review, comprised of our own data and that of others, provides a summary overview of histone deacetylase (HDAC) inhibition on intestinal inflammation as well as inflammation-mediated carcinogenesis. Experimental colitis in mice represents an excellent in vivo model to define the specific cell populations and target tissues modulated by inhibitors of HDAC. Oral administration of either suberyolanilide hydroxamic acid (SAHA) or ITF2357 results in an amelioration in these models, as indicated by a significantly reduced colitis disease score and histological score. This effect was paralleled by suppression of proinflammatory cytokines at the site of inflammation as well as specific changes in the composition of cells within the lamina propria. In addition, tumor number and size was significantly reduced in two models of inflammation-driven tumorigenesis, namely interleukin (IL)-10-deficient mice and the azoxymethane-dextran sulfate sodium (DSS) model, respectively. The mechanisms affected by HDAC inhibition, contributing to this antiinflammatory and antiproliferative potency will be discussed in detail. Furthermore, with regard to the relevance in human inflammatory bowel disease, the doses of ITF2357 considered safe in humans and the corresponding serum concentrations are consistent with the efficacious dosing used in our in vivo as well as in vitro experiments. Thus, the data strongly suggest that HDAC inhibitors could serve as a therapeutic option in inflammatory bowel disease.

Identification of novel compounds that enhance colon cancer cell sensitivity to inflammatory apoptotic ligands

“…47,51 This sensitizing activity may account for the reported ability of SAHA/Vorinostat to selectively enhance apoptosis in AOM-induced colon tumors and suppress their formation and growth. 47,[52][53][54] It is not clear, however, whether HDAC inhibitors are ideal for this purpose since they also cause changes in histone acetylation and gene expression systemically.…”

Impact of valproic acid on dendritic cells function

“…From a therapeutic perspective, the immunomodulatory effects of VPA and other HDAC inhibitors might prove useful in different clinical settings where regulation of immunity is eagerly needed as in chronic inflammatory diseases (Glauben and Siegmund 2011) or in graft vs. host disease (GVHD) after allogeneic stem cell transplantation (Choi and Reddy 2011). Pioneering work from Reddy et al (2008) demonstrated that injection of DCs treated ex vivo with HDAC inhibitors reduced experimental GVHD in a murine allogeneic bone-marrow transplantation model, likely in relation with increased expression of indoleamine 2,3-dioxygenase (IDO), a suppressor of DC function, after exposure to HDAC inhibitors, in a signal transducer and activator of transcription-3 (STAT-3) dependent manner (Sun et al 2009).…”

Regulation of intestinal serotonin transporter expression via epigenetic mechanisms: role of HDAC2

“…However, given that HDAC inhibitors act against several or all 11 HDAC family members, clinical phase I trials have documented many side effects, such as diarrhea, electrolyte changes, weight loss, disordered clotting, fatigue, and cardiac arrhythmias (6). Similarly, recent studies have reported the use of HDAC inhibitors for amelioration of intestinal inflammation (22). However, the use of these drugs may be limited by other reports describing their effect as immunosuppressive drugs that block innate immunity and increase susceptibility to severe infections in vivo (4).…”