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

• Published in: The Journal of surgical research Vol. 142; no. 2; pp. 239 - 245
• Main Authors: Fichera, Alessandro, M.D, Little, Nathaniel, B.A, Dougherty, Urszula, B.A, Mustafi, Reba, Ph.D, Cerda, Sonia, Ph.D, Li, Yan Chun, Ph.D, Delgado, Jorge, M.D, Arora, Amrita, Campbell, Lucas K., M.D, Joseph, Loren, M.D, Hart, John, M.D, Noffsinger, Amy, M.D, Bissonnette, Marc, M.D
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01.10.2007; Elsevier
• Subjects: Adenocarcinoma - complications; Adenocarcinoma - pathology; Adenocarcinoma - prevention & control; Animals; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; c-Myc; Cell Division - drug effects; Cell Line, Tumor; chemoprevention; Cholecalciferol - analogs & derivatives; Cholecalciferol - pharmacology; Colitis - complications; Colitis - pathology; Colitis - prevention & control; Colon - metabolism; Colon - pathology; Colonic Neoplasms - complications; Colonic Neoplasms - pathology; Colonic Neoplasms - prevention & control; colorectal cancer; COX-2; Cyclooxygenase 2 - metabolism; Disease Models, Animal; ERK; Extracellular Signal-Regulated MAP Kinases - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; General aspects; HCA-7; Humans; inflammatory bowel diseases; Interleukin-1beta - pharmacology; Male; MAP Kinase Signaling System - drug effects; Medical sciences; Mice; Mice, Inbred A; Other diseases. Semiology; Proto-Oncogene Proteins c-myc - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Surgery; Up-Regulation - drug effects; vitamin D; colorectal cancer; chemoprevention; inflammatory bowel diseases; COX-2; c-Myc; vitamin D; HCA-7; ERK; Chemoprophylaxis; Rectal disease; Extracellular signal-regulated protein kinase; Cyclooxygenase 2; Colorectal cancer; Carcinogenesis; Inflammatory disease; Prevention; Vitamin D; Surgery; Intestinal disease; Protooncogene; Enzyme; Mitogen-activated protein kinase; Malignant tumor; Retinol; Colonic disease; Medicine; Crohn disease; Chemotherapy; Treatment; Analog; C-Onc gene; myc Gene; Digestive diseases; Inhibitor; Models; Oxidoreductases; Ulcerative colitis
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2007.02.038

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 μg/kg body wt/day × 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 × 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-1β). 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-1β-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.