Chemoprevention of Urothelial Cell Carcinoma Growth and Invasion by the Dual COX–LOX Inhibitor Licofelone in UPII-SV40T Transgenic Mice

Abstract

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.

Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5‐lipoxygenase expression in aggressive subtypes of endometrial cancer

“…Whether this indicates cooperation/synergy between the two enzymes is unclear, since ALOX5 products (5‐HETE and LTB4) are not HPGD substrates, unlike 15‐HETE . Nevertheless, the superior effect of combined PTGS2/ALOX5 knockdown on cancer cell proliferation and VEGF secretion in vitro and the anti‐carcinogenic effect of dual COX/ALOX5 inhibitors in a variety of preclinical cancer models suggest cooperation between PGE 2 and ALOX5 products in carcinogenesis/cancer progression. Strategies targeting ALOX5 in combination with COX/HPGD may therefore have therapeutic value in the treatment of aggressive EC subtypes, possibly in combination with conventional chemotherapy, where they could potentiate the effects of cytotoxic drugs, as has recently been shown for the dual COX/ALOX5 inhibitor licofelone in preclinical mouse models of ovarian cancer .…”

Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo

“…Transgenic mice (UPII-SV40T) expressing a Simian Virus 40 large T antigen (SV40T) specifically in urothelial cells under the control of the Uroplakin II (UPII) promoter and reproducibly developing high-grade carcinoma in situ (CIS) and invasive tumors throughout the urothelium (20–21, 23–25) were used. The required number of UPII-SV40T transgenic mice were generated by breeding as described earlier (25). Animals were housed in ventilated cages under standardized conditions (21°C, 60% humidity, 12h-light/12h-dark cycle, 20 air changes per hour) in the University of Oklahoma Health Sciences Center rodent barrier facility.…”

“…All mice were bred and genotyped as described earlier (25). In brief, male UPII-SV40T mice were crossed with wild-type females to generate offspring.…”

“…Multiple sections from various depths of each urothelial tumor were evaluated histologically by a pathologist blinded to the experimental groups. Tumors were classified into non-invasive TCC (CIS) or invasive carcinomas (lamina propria invasive and muscularis propria invasive) types according to histopathological criteria, as previously described (24–25). …”

“…In the present study, we determined the anti-tumor effects of CP and rapamycin, either individually or in combination, using a transgenic mouse model of urinary bladder cancer (UPII-SV40T); this model has histopathology and molecular features similar to a highly invasive variant of human urinary bladder cancers (20). The use of this mouse model has played a key role in the elucidation of the mechanisms underlying urothelial tumorigenesis (21–22) and in the identification of anti-tumor agents for the treatment of bladder cancer (23–25). …”