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.


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.
Fichera
Alessandro
A
Department of Surgery, University of Chicago, Chicago, Illinois 60637, USA. afichera@surgery.bsd.uchicago.edu
Little
Nathaniel
N
Dougherty
Urszula
U
Mustafi
Reba
R
Cerda
Sonia
S
Li
Yan Chun
YC
Delgado
Jorge
J
Arora
Amrita
A
Campbell
Lucas K
LK
Joseph
Loren
L
Hart
John
J
Noffsinger
Amy
A
Bissonnette
Marc
M
D000230:Adenocarcinoma / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology; D003092:Colitis / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C408047:1,25(OH)2-16-ene-23-yne-26,27-hexafluoro-19-nor-D3; D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D016271:Proto-Oncogene Proteins c-myc; D002762:Cholecalciferol; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases