title: Chemoprevention of urothelial cell carcinoma growth and invasion by the dual COX-LOX inhibitor licofelone in UPII-SV40T transgenic mice.
abstract: Epidemiologic and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual COX-lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3 to 5-fold more than did those of the wild-type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6%-80.2%, P < 0.0001 in males; by 36.9%-55.3%, P < 0.0001 in females) compared with the control group. The licofelone diet led to the development of significantly fewer invasive tumors in these transgenic mice. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; P < 0.01) and female mice (41%-44%; P < 0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, and caspase3) with a decrease in proliferation, inflammation, and angiogenesis markers (proliferating cell nuclear antigen, COX-2, 5-LOX, prostaglandin E synthase 1, FLAP, and VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC.
authors.affiliation: Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Venkateshwar
authors.initials: V
authors.lastname: Madka
authors.affiliation: Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.affiliation: Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Jagan M R
authors.initials: JM
authors.lastname: Patlolla
authors.affiliation: Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Laura
authors.initials: L
authors.lastname: Biddick
authors.affiliation: Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.affiliation: Department of Urology, NYU Medical Center, New York, New York; and.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland.
authors.forename: Vernon
authors.initials: V
authors.lastname: Steele
authors.affiliation: Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland.
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.affiliation: Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; cv-rao@ouhsc.edu.
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D015153:Blotting, Western; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D007124:Immunoenzyme Techniques; D008084:Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D060170:Uroplakin II / Q000502:physiology*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D011758:Pyrroles; D012333:RNA, Messenger; C554659:Upk2 protein, mouse; D060170:Uroplakin II; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; C088092:licofelone