title: Reduced tumour progression and angiogenesis in 1,2-dimethylhydrazine mice treated with NS-398 is associated with down-regulation of cyclooxygenase-2 and decreased beta-catenin nuclear localisation.
abstract: Cyclooxygenase (COX)-2 is a key molecular target of colon cancer prevention. However, the mechanisms by which COX-2 inhibitors confer protective effects against tumour development are not completely understood. The aim of this study was to elucidate the effects of NS-398 in the 1,2-dimethylhydrazine (DMH) mouse model with respect to alteration in the expression of COX-2 and E-cadherin-catenin complex. Alterations in cell proliferation, apoptosis, and vascular density were investigated. NS-398 showed reduced COX-2 immunoreactivity in adenomas with a decrease in vascular density in non-dysplastic mucosa. Adenomas revealed increased E-cadherin and beta-catenin reactivity. NS-398 reduced the percentages of tumour cells with nuclear localisation of beta-catenin and cyclin D1. Bromodeoxyuridine (BrdUrd) index in adenomas was significantly higher in untreated animals. NS-398 resulted in significant increase in apoptosis in adenomas. Our results suggest a protective role of NS-398 on tumour development associated with reduced COX-2 expression, reduced vascular density and perturbation of beta-catenin signalling pathway.
authors.affiliation: Division of Histopathology, School of Cellular and Molecular Medicine, Medical Sciences Building and Bristol Royal Infirmary, University Hospitals, Bristol NHS Foundation Trust, University of Bristol , UK.
authors.forename: Nahida A
authors.initials: NA
authors.lastname: Banu
authors.forename: Richard S
authors.initials: RS
authors.lastname: Daly
authors.forename: Andrea
authors.initials: A
authors.lastname: Buda
authors.forename: Moganaden
authors.initials: M
authors.lastname: Moorghen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Baker
authors.forename: Massimo
authors.initials: M
authors.lastname: Pignatelli
mesh_terms: D019813:1,2-Dimethylhydrazine / Q000494:pharmacology; D000236:Adenoma / Q000098:blood supply / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000737:chemistry; D002273:Carcinogens / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D005169:Factor VIII / Q000378:metabolism; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009578:Nitrobenzenes / Q000627:therapeutic use*; D011453:Prostaglandins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use*; D051820:TCF Transcription Factors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; D051820:TCF Transcription Factors; D051176:beta Catenin; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D019938:Cyclin D1; D005169:Factor VIII; D051546:Cyclooxygenase 2; D001973:Bromodeoxyuridine; D019813:1,2-Dimethylhydrazine