Chemoprevention of urothelial cell carcinoma growth and invasion by the dual COX-LOX inhibitor licofelone in UPII-SV40T transgenic mice
Menée à partir d'un modèle murin transgénique de carcinome urothélial, cette étude évalue l'efficacité de la licofélone, un inhibiteur de la lipoxygénase et de la cyclo-oxygénase, pour réduire la croissance et l'invasion tumorales
Résumé en anglais
Epidemiological 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 cyclooxygenase (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 3-5-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 females mice (41-44%; p<0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, Caspase3) with a decrease in proliferation, inflammation and angiogenesis markers (proliferating cell nuclear antigen (PCNA), COX2, 5LOX, prostaglandin E synthase 1 (mPGES1), FLAP, and vascular endothelial growth factor (VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC.
