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

Fichera, Alessandro; Little, Nathaniel; Dougherty, Urszula; Mustafi, Reba; Cerda, Sonia; Li, Yan Chun; Delgado, Jorge; Arora, Amrita; Campbell, Lucas K.; Joseph, Loren; Hart, John; Noffsinger, Amy; Bissonnette, Marc

doi:10.1016/j.jss.2007.02.038

« Previous Next »Journal of Surgical Research
Volume 142, Issue 2 , Pages 239-245, October 2007

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

Alessandro Fichera, M.D.
- Department of Surgery, University of Chicago, Chicago, Illinois
- To whom correspondence should be addressed at Department of Surgery, MC 5031, University of Chicago Hospitals, 5841 S. Maryland Avenue, Chicago, IL 60637.
Nathaniel Little, B.A.
- Department of Medicine, University of Chicago, Chicago, Illinois
Urszula Dougherty, B.A.
- Department of Surgery, University of Chicago, Chicago, Illinois
Reba Mustafi, Ph.D.
- Department of Medicine, University of Chicago, Chicago, Illinois
Sonia Cerda, Ph.D.
- Department of Medicine, University of Chicago, Chicago, Illinois
Yan Chun Li, Ph.D.
- Department of Medicine, University of Chicago, Chicago, Illinois
Jorge Delgado, M.D.
- Department of Medicine, University of Chicago, Chicago, Illinois
Amrita Arora
- Department of Medicine, University of Chicago, Chicago, Illinois
Lucas K. Campbell, M.D.
- Department of Pathology, University of Chicago, Chicago, Illinois
Loren Joseph, M.D.
- Department of Pathology, University of Chicago, Chicago, Illinois
John Hart, M.D.
- Department of Pathology, University of Chicago, Chicago, Illinois
Amy Noffsinger, M.D.
- Department of Pathology, University of Chicago, Chicago, Illinois
Marc Bissonnette, M.D.
- Department of Medicine, University of Chicago, Chicago, Illinois

Received 1 January 2007 published online 18 June 2007.

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.

Key Words: inflammatory bowel diseases, colorectal cancer, vitamin D, chemoprevention, COX-2, c-Myc, ERK, HCA-7