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

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

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)239-245
Number of pages7
JournalJournal of Surgical Research
Volume142
Issue number2
DOIs
StatePublished - 1 Oct 2007
Externally publishedYes

Keywords

  • COX-2
  • ERK
  • HCA-7
  • c-Myc
  • chemoprevention
  • colorectal cancer
  • inflammatory bowel diseases
  • vitamin D

ASJC Scopus subject areas

  • Surgery

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