A vitamin D analogue inhibits colonic carcinogenesis in the AOM/DSS model

J Surg Res. 2007 Oct;142(2):239-45. doi: 10.1016/j.jss.2007.02.038. Epub 2007 Jun 15.


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 microg/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-1beta). 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-1beta-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / complications
  • Adenocarcinoma / pathology
  • Adenocarcinoma / prevention & control*
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Cell Division / drug effects
  • Cell Line, Tumor
  • 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*
  • Cyclooxygenase 2 / metabolism
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Interleukin-1beta / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mice, Inbred A
  • Proto-Oncogene Proteins c-myc / metabolism
  • Up-Regulation / drug effects


  • 1,25(OH)2-16-ene-23-yne-26,27-hexafluoro-19-nor-D3
  • Anti-Inflammatory Agents
  • Interleukin-1beta
  • Proto-Oncogene Proteins c-myc
  • Cholecalciferol
  • Cyclooxygenase 2
  • Extracellular Signal-Regulated MAP Kinases