317 EFFECT OF ATORVASTATIN ON THE BIOLOGY OF BLADDER CANCER CELLS TREATED WITH BACILLUS CALMETTE-GUERIN

Abstract

You have accessJournal of UrologyUrothelial Cancer: Medical & Surgical Therapy1 Apr 2010317 EFFECT OF ATORVASTATIN ON THE BIOLOGY OF BLADDER CANCER CELLS TREATED WITH BACILLUS CALMETTE-GUERIN Tullika Garg, Guangjian Zhang, Fanghong Chen, Yanli Cao, and William See Tullika GargTullika Garg More articles by this author , Guangjian ZhangGuangjian Zhang More articles by this author , Fanghong ChenFanghong Chen More articles by this author , Yanli CaoYanli Cao More articles by this author , and William SeeWilliam See More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.381AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The commonly employed class of cholesterol lowering agents, statins, functions by inhibiting the HMG-CoA reductase enzyme which is critical to cholesterol biosynthesis. Early clinical reports suggest that BCG efficacy may be decreased in patients taking statins. This study examined the effect of BCG on enzymes in the cholesterol synthesis pathway, the impact of statins on the BCG induced signaling pathways and gene expression, as well as the impact of statins on the in vitro cytotoxicity of BCG on human urothelial carcinoma (UC) cell lines. METHODS The human UC cell lines 253J and T24 were exposed to BCG and analyzed for upregulation of enzymes in the cholesterol biosynthesis pathway using Affymetrix gene expression profiling. The effect of atorvastatin on NFkB signaling and downstream gene expression, alone and in combination with BCG, was compared to non-treated and BCG exposed controls. The two cell lines were utilized to determine the effect of a physiologic concentration of atorvastatin on BCG associated cytotoxicity. RESULTS Analysis of gene expression using functional annotation clustering demonstrated highly significant enrichment of steroid biosynthetic genes in 253J cells following BCG treatment (p = 1.4E-14). While noted, up-regulation of these genes was not significant in T24 cells (p = 0.3). Compared to both BCG exposed and untreated controls, the most pronounced effect of atorvastatin treatment was decreased expression of genes involved in cell cycle regulation (p < 1.0e-40). This effect was independent of whether atorvastatin was used along or in combination with BCG. Atorvastatin significantly increased BCG induced signaling through the NFkB pathway (p<0.001). Parodoxically, atorvastatin significantly decreased the downstream expression of a panel of NFkB dependent, BCG induced genes as measured by quantitative rtPCR (IL-6, IL-8, CCL20, CXC1, P<0.05). Exposure to BCG resulted in decreased proliferation of UC cells in both T24 and 253J cells lines. The addition of atorvastatin to BCG treated cells resulted in significantly decreased BCG cytotoxicity as compared to the BCG alone groups (ANOVA p = 0.001 and p = 0.003 for 253J and T24 respectively). CONCLUSIONS Physiologic concentrations of atorvastatin exert a direct effect on the biology of urothelial carcinoma cells. In the context of BCG exposure, atorvastatin alters BCG induced signaling, inflammatory gene expression, and cytotoxcity. Given a clear in-vitro effect clinicians should consider short term cessation of statins in patients failing to respond to an induction course of BCG. Milwaukee, WI© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e125 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tullika Garg More articles by this author Guangjian Zhang More articles by this author Fanghong Chen More articles by this author Yanli Cao More articles by this author William See More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...