Scientific Abstract

Proposal No.   IBD-0108
Principal Investigator:  Britta Siegmund, M.D.
Applicant Organization:   Charité Universitätsmedizin Berlin, Campus Benjamin Franklin (Germany)
Project Title:  Specific inhibition of histone deacetylases as a novel anti-inflammatory and anti-proliferative approach in experimental colitis in mice
Period of Award:  April 1, 2004 – July 31, 2006

We will investigate the anti-proliferative, anti-neoplastic and anti-inflammatory potency of a new pharmacological compound class, namely the inhibitors of histone deacetylases (HDAC), in experimental colitis.

Inhibitors of HDAC have been described for their suppression of proliferation of cancer cells in vitro and reduction of growth of experimental tumors in vivo.  Several compounds are currently in phase I clinical trials for solid tumors.  In addition to these well-described effects, HDAC inhibitors may affect other intracellular pathways.  A recent study from our own group provides strong evidence for the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) to exhibit anti-inflammatory properties in vitro as well as in several inflammation models in vivo (PNAS 2002; 99:2995).  In addition, our preliminary data indicate that SAHA treatment of wild-type mice results in a dose-dependent amelioration of acute dextran sulphate sodium (DSS)-induced colitis.  SAHA-treated DSS-exposed animals presented with less weight loss, bleeding and diarrhea and showed a significant decrease in the inflammatory infiltrate than control animals.

We will take advantage of the two main properties of HDAC inhibitors: the anti-inflammatory and the anti-proliferative effects.  Two HDAC inhibitors, SAHA and trichostatin A or valproic acid will be examined in experimental models of colitis.  Both inhibitors will be investigated in two models of chronic inflammation known to be associated with development of dysplasias or adenocarcinomas and the anti-proliferative as well as the anti-inflammatory potency will be assessed.

The results obtained from the proposed study will provide further insight into the new compound class of HDAC inhibitors, which might present a novel therapeutic strategy for patients with chronic inflammatory bowel disease.