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

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Chemoprevention of Urothelial Cell Carcinoma Growth and Invasion by the Dual COX–LOX Inhibitor Licofelone in UPII-SV40T Transgenic Mice Published OnlineFirst May 2, 2014; DOI: 10.1158/1940-6207.CAPR-14-0087 Cancer Prevention Research Article Research Chemoprevention of Urothelial Cell Carcinoma Growth and Invasion by the Dual COX–LOX Inhibitor Licofelone in UPII-SV40T Transgenic Mice Venkateshwar Madka1, Altaf Mohammed1, Qian Li1, Yuting Zhang1, Jagan M.R. Patlolla1, Laura Biddick1, Stan Lightfoot1, Xue-Ru Wu2, Vernon Steele3, Levy Kopelovich3, and Chinthalapally V. Rao1 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–lipox- ygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n ¼ 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. Cancer Prev Res; 7(7); 708–16. Ó2014 AACR. Introduction pose a very high risk for distant metastases (2). Chemopre- Urinary bladder cancer is one of the common cancers vention has been applied to many different tumor types, worldwide, with the highest incidence rates in industrial- including TCC of the bladder, and has been proposed as a ized countries. In United States, it is the second most management strategy for patients with cancer at risk of frequently diagnosed genitourinary cancer, with an estimat- developing second primary tumors (3). Inflammation is ed 563,640 people currently living with bladder cancer. In a known risk factor for many cancers, particularly epithelial 2014, about 74,690 new cases of bladder cancer are antic- cancers such as those of the urothelium. It plays important ipated (about 56,390 in men and 18,300 in women), and roles at different stages of tumor development, including approximately 15,580 are expected to die of this cancer (1). initiation, promotion, invasion, and metastasis (4). Chron- The majority (90%–95%) of bladder cancers are transition- ic inflammation is associated directly with muscle-invasive al cell carcinomas (TCC). Of these, 70% to 75% are non- bladder cancer, particularly that due to urinary tract infec- invasive, low-grade, papillary TCC, whereas up to 30% of all tion in invasive squamous cell carcinoma (5). diagnosed tumors are classified as invasive TCCs, which The metabolism of arachidonic acid by COX-2 and 5- lipoxygenase (5-LOX) generates prostaglandins and hydro- xyeicosatetraenoic acids, respectively, that mediate a wide Authors' Affiliations: 1Center for Cancer Prevention and Drug Develop- variety of physiologic processes, including cell prolifera- ment, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, tion, immune surveillance, cell differentiation, and inflam- Oklahoma; 2Department of Urology, NYU Medical Center, New York, New mation. Clinically, aberrant expression of the COX-2 and 5- 3 York; and Division of Cancer Prevention, Chemoprevention Agent Devel- LOX enzymes has been observed in urothelial tumors and opment Research Group, National Cancer Institute, Bethesda, Maryland found to be associated with poor prognosis (6, 7). Con- Corresponding Author: Chinthalapally V. Rao, University of Oklahoma Health Sciences Center, 975 NE 10th St., BRC 1203, Oklahoma City, OK centrations of a urinary PGE metabolite (PGE-M) and 73104. Phone: 405-271-3224; Fax: 1-405-271-3225; E-mail: leukotriene E4 (LTE4), biomarkers of the COX-2 and 5-LOX [email protected] pathways, are elevated in smokers (8). In view of the doi: 10.1158/1940-6207.CAPR-14-0087 recognized link between smoking, inflammation, and blad- Ó2014 American Association for Cancer Research. der cancer, targeting the inflammatory pathways seems to 708 Cancer Prev Res; 7(7) July 2014 Downloaded from cancerpreventionresearch.aacrjournals.org on October 4, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst May 2, 2014; DOI: 10.1158/1940-6207.CAPR-14-0087 Licofelone Prevents Urothelial Cancer In Vivo be an ideal approach to reduce the risk of urothelial cancer prep Kit (Invitrogen) and PCR. PCR for the SV40T gene development. Several preclinical studies have suggested that wasdoneusingtheprimer50-CTTTGGAGGCTTCTGG- the combination of a selective COX-2 inhibitor and a 5-LOX GATGCAACT-30 (sense) and 50-GCATGACTCAAAAAACT- inhibitor is more effective than either agent alone in pre- TAGCAATTCTG-30 (antisense) and amplifying under the venting cancer cell growth or tumor formation (9, 10). Dual following PCR conditions: denaturation at 95Cfor5 inhibitors that block both COX and 5-Lox may provide minutes, followed by 35 cycles at 95Cfor1minute,58C synergistic anti-inflammatory effects and also decrease gas- for 45 seconds, and 72Cfor45seconds.ThePCR trointestinal side effects associated with NSAIDs(11) and products, when separated on a 2% agarose gel, showed select COX-2 inhibitors. a 550-bp band. Licofelone is one such compound that is currently in phase III clinical trials for treatment of pain and inflam- Bioassay mation associated with osteoarthritis (12, 13) and also Genotyped UPII-SV40T transgenic mice were used in has been shown to prevent colon (14, 15), lung (16), and the efficacy study. The experimental protocol is summa- prostate cancers (17). However, no studies have been rized in Fig. 1A. Five-week-old mice were selected and reported on the chemopreventive effects of licofelone in randomized so that the average body weights in each urothelial cancer. Among the preclinical models for group were equal (n ¼ 30 UPII-SV40T mice per group and urothelial cancer, UPII-SV40T transgenic mice develop n ¼ 12 wild-type mice per group) and were fed a modified invasive urothelial tumors due to the expression of Sim- AIN-76A diet for 1 week. At 6 weeks of age, mice were fed ian virus large T antigen (Tag) driven by the urothelium- control or experimental diets containing 0, 150, or 300 specific uroplakin II (UPII) promoter (18). These mice ppm licofelone (Fig. 1B) until termination of the study. have been used as a model to elucidate the mechanism Mice were checked routinely for signs of weight loss, underlying urothelial tumorigenesis (19, 20) as well as in toxicity, or any abnormalities. Previously, we have estab- chemoprevention studies (21, 22). In the present study, lished maximal tolerated doses/optimal dose of licofe- we determined the chemopreventive efficacy of licofelone lone in mice and found to be >500 ppm fed in the using the UPII-SV40T transgenic mouse model for inva- modified AIN-76A diet (15). The food intake and body sive urothelial TCC. weight of each animal were measured once weekly for the first 6 weeks and then once a month until termination. Materials and Methods After 34 weeks on experimental diets (i.e., 40 weeks age), Animals, diet, and care all mice were euthanized by CO2 asphyxiation and All animal experiments were conducted in accordance necropsied, and urinary bladders were collected and with the guidelines of the Institutional Animal Care and weighed to determine the tumor weight. A portion of Use Committee. Transgenic mice (UPII-SV40T) expres- the urinary bladder was fixed in 10% neutral-buffered sing a Simian Virus 40 large T antigen (SV40T) specifically formalin for histopathologic evaluation, and the rest was in urothelial cells under the control of the Uroplakin II snap frozen in liquid nitrogen for further analysis. (UPII) promoter and reproducibly developing high-grade carcinoma in situ (CIS) and invasive tumors throughout Tissue processing and histologic analysis the urothelium (18) were used. The required numbers of Formalin-fixed, paraffin-embedded tissues were sec- m UPII-SV40T transgenic mice were generated by breeding tioned (4- m) and stained with hematoxylin and eosin as described earlier (22). Animals were housed in venti- (H&E). Sections of each urothelial tumor were evaluated lated cages under standardized conditions (21C, 60% histologically by a pathologist blinded to the experimental humidity, 12-hour light/12-hour dark cycle, 20 air changes groups. Carcinomas were classified into noninvasive CIS, per hour) in the University of Oklahoma Health Sciences invasive carcinomas (lamina propria invasive and muscu- Center rodent barrier facility. Semipurified modified AIN- laris propria invasive) types according to histopathologic 76A diet ingredients
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