| Ursodeoxycholic acid and F(6)-D(3) inhibit aberrant crypt proliferation in the rat azoxymethane model of colon cancer: roles of cyclin D1 and E-cadherin. | |
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MedLine Citation:
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PMID: 12496057 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have previously demonstrated that ursodeoxycholic acid(UDCA) and a fluorinated analogue of vitamin D(3), F(6)-D(3),inhibited colonic carcinogenesis in the azoxymethane (AOM) model. Generalized colonic mucosal hyperproliferation and aberrant crypt foci (ACF) are intermediate biomarkers of colon cancer. Using these biomarkers, in this study we examined the anticarcinogenic mechanisms of these chemopreventive agents. Rats were maintained on AIN-76A chow or supplemented with 0.4% UDCA or F(6)-D(3) (2.5 nmol/kg chow) and treated weekly with AOM 20 mg i.p./kg wt or saline x 2 weeks. F(6)-D(3) was continued for an additional 2 weeks and UDCA for the duration of the study. At 40 weeks, animals received bromodeoxyuridine (BrdUrd) i.p. 2 h before sacrifice. A portion of each tumor was fixed in formalin and the remainder flash frozen. Colons were divided longitudinally and half-fixed in formalin and half in ethanol. The size and location of methylene blue-stained ACF were recorded. Cell proliferation (BrdUrd labeling) and apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling assay) were measured in colonic crypts and tumors. Protein expression levels of several regulators of cell proliferation were analyzed by immunostaining and Western blotting. Colonic crypt cyclin D1 and E-cadherin mRNA levels were measured by real-time PCR. In saline injected controls, neither UDCA nor F(6)-D(3) alone had any effect on cytokinetic parameters or on the expression of mitogenic regulators. AOM significantly increased the proliferation (percentage of BrdUrd-positive cells) of both ACF (23.1 +/- 1.7%) and non-ACF crypts (17.6 +/- 1.6%), compared with normal colonic crypts (4.5 +/- 0.8%; P < 0.05). This hyperproliferation was accompanied by a 5-fold increase in cyclin D1 and >50% decrease in E-cadherin protein (P < 0.05) in ACF, both of which are predicted to be growth-enhancing alterations. UDCA and F(6)-D(3) significantly (P < 0.05) inhibited AOM-induced crypt cell hyperproliferation, ACF development, and tumor burden. These chemopreventive agents also significantly blocked AOM-induced alterations in cyclin D1 and E-cadherin protein in ACF and tumors. In ACF, changes in mRNA levels of cyclin D1, but not E-cadherin, paralleled alterations in protein expression. Cyclooxygenase-2 and inducible nitric oxide synthase were increased in AOM tumors but not in ACF, and these changes were blocked by UDCA and F(6)-D(3). UDCA and F(6)-D(3) significantly inhibited ACF development and hyperproliferation, in part, by preventing carcinogen-induced alterations in cyclin D1 and E-cadherin. In established tumors, UDCA and F(6)-D(3) also limited inductions of cyclooxygenase-2 and inducible nitric oxide synthase, which together with their effects on cyclin D1 and E-cadherin, contribute to their chemopreventive actions. |
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Authors:
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Ramesh K Wali; Sharad Khare; Maria Tretiakova; Greg Cohen; Lan Nguyen; John Hart; Julia Wang; Ming Wen; Akila Ramaswamy; Loren Joseph; Michael Sitrin; Thomas Brasitus; Marc Bissonnette |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Volume: 11 ISSN: 1055-9965 ISO Abbreviation: Cancer Epidemiol. Biomarkers Prev. Publication Date: 2002 Dec |
Date Detail:
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Created Date: 2002-12-23 Completed Date: 2003-04-04 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9200608 Medline TA: Cancer Epidemiol Biomarkers Prev Country: United States |
Other Details:
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Languages: eng Pagination: 1653-62 Citation Subset: IM |
Affiliation:
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Department of Medicine, University of Chicago Hospitals and Clinics, Chicago, Illinois 60637, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Azoxymethane Base Sequence Biopsy, Needle Blotting, Western Cadherins / drug effects, metabolism* Cell Division / drug effects, physiology Cholecalciferol / pharmacology* Colonic Neoplasms / drug therapy*, pathology Cyclin D1 / drug effects, metabolism* Disease Models, Animal Immunohistochemistry Injections, Intraperitoneal Intestinal Mucosa / drug effects, pathology Male Molecular Sequence Data Neoplasms, Experimental Polymerase Chain Reaction RNA, Messenger / analysis Random Allocation Rats Rats, Inbred F344 Reference Values Sensitivity and Specificity Tumor Markers, Biological / analysis* Ursodeoxycholic Acid / administration & dosage* |
| Grant Support | |
ID/Acronym/Agency:
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CA36745/CA/NCI NIH HHS; CA69532/CA/NCI NIH HHS; DK39573/DK/NIDDK NIH HHS; P30DK42086/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cadherins; 0/RNA, Messenger; 0/Tumor Markers, Biological; 128-13-2/Ursodeoxycholic Acid; 136601-57-5/Cyclin D1; 25843-45-2/Azoxymethane; 67-97-0/Cholecalciferol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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