A Vitamin D Analogue Inhibits Colonic Carcinogenesis in the AOM/DSS Model

Background. The azoxymethane (AOM) model recapitulates many features of human colon cancer, lacking an inflammatory component. Dextran sulfate sodium (DSS) induces colitis and promotes AOM-induced colon cancer in mice. Vitamin D analogues are anti-inflammatory and chemopreventive in models of colon cancer. Our aim was to evaluate the anti-inflammatory and chemopreventive efficacy of the vitamin D analogue Ro26-2198 in the AOM/DSS model and in vitro in HCA-7 colon cancer cells.Materials and methods. A/J mice received Ro26-2198 (0.01 mu g/kg body wt/day x 28 days) or vehicle by mini-osmotic pump. Animals were treated with a single dose of AOM (5 mg/kg body wt) or vehicle 1 week after pump insertion. Mice received 3% DSS or water x 7 days beginning week 3. Animals were sacrificed after 8 weeks and colon segments were fixed in formalin or flash-frozen. Hematoxylin and eosin colonic sections were examined for dysplasia and colonic lysates were assessed for c-Myc, cyclooxygenase 2, and phospho(active) extracellular signal regulated kinase (ERK) by Western blotting. For in vitro studies, HCA-7 cells were treated with Ro26-2198 followed by interleukin-1beta (IL-1 beta). Proliferation was measured by WST-1 assay.Results. Ro26-2198 delayed the onset of clinical colitis. Several dysplastic foci were present in the AOM? DSS group; none were found in the Ro26-2198 group. Compared with control, AOM/DSS significantly increased c-Myc (15-fold), cyclooxygenase 2 (COX-2) (2.5-fold), and pERK (10-fold), and Ro26-2198 abolished these increases. In vitro, Ro26-2198 inhibited IL-1 beta- induced ERK activation and COX-2 induction and decreased HCA-7 cell proliferation.Conclusions. Ro26-2198 inhibited proliferative (ERK, c-Myc) and pro-inflammatory (COX-2) signals and progression to dysplasia, suggesting chemopreventive efficacy in this model of colitis-associated carcinogenesis. (C) 2007 Elsevier Inc. All rights reserved.