Abstract 1244: Licofelone, a dual COX-LOX inhibitor prevents transitional cell carcinoma of urinary bladder in UPII-SV40T transgenic mice

Abstract

Abstract Urinary bladder cancer is the sixth most commonly diagnosed cancer and significant proportion of the patients diagnosed with bladder cancer have high-grade tumors that are at potential risk for post-surgical recurrence and metastasis, where 5-year survival is very low. Hence it is important to identify and develop regimens that prevent urothelial tumorigenesis. Inflammatory pathways particularly, cyclooxygenase (COX-2) and lipoxygenase (5-LOX) mediated metabolites are known to play important role in bladder tumor progression. Consistent with that epidemiological and clinical observations suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. Here we determined the chemopreventive efficacy of a Licofelone, a dual COX-LOX inhibitor, in a transgenic UPII-SV40T mouse model of bladder transitional cell carcinoma (TCC). Six-week old transgenic 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; urinary bladders were collected to determine urothelial tumor weights and histopathological grading. Results suggest that bladders of the control diet fed transgenic mice weighed 3-5 fold more than that of the wild type mice. However, treatment of transgenic mice with licofelone led to a significant, dose dependent inhibition of the urothelial tumor weights (65.2 - 82.7%, p<0.0001 in males; 35.0 - 49.0%, p<0.0001 in females) compared to the control group. Importantly, mice fed licofelone diet significantly reduced development of invasive tumors. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; p<0.01) and females mice (up to 46%; p<0.003). Molecular analysis of urothelial tumors by immuno-histochemisty, qPCR and/or western immunoblotting for the expression of various markers that effect tumor growth and progression showed an increase in apoptosis (p53, p21, Bax, Caspase3, Annexin V) with a decrease in proliferation and angiogenesis (PCNA, COX2, 5LOX, mPGES2, VEGF) in the licofelone diet fed mice tumors. These results suggest that licofelone can serve as potential chemopreventive for bladder TCC. (Supported in part by NCI-CN53300) Citation Format: Venkateshwar Madka, Altaf Mohammed, Qian Li, Yuting Zhang, Laura Biddick, Stanley Lightfoot, Xue-Re Wu, Levy Kopelovich, Vernon Steele, Chinthallapally V. Rao. Licofelone, a dual COX-LOX inhibitor prevents transitional cell carcinoma of urinary bladder in UPII-SV40T transgenic mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1244. doi:10.1158/1538-7445.AM2014-1244