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• W2058477322 abstract "You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 2015MP49-11 TREHALOSE 6,6 DIMYCOLATE CYTOTOXICITY IN BOTH BCG SENSITIVE AND BCG RESISTANT CELL LINES OCCURS VIA A “BCG DISTINCT” PATHWAY Gopitkumar Shah, Justin Benabdallah, Fanghong Chen, Guangjian Zhang, Balaraman Kalyanaraman, and William See Gopitkumar ShahGopitkumar Shah More articles by this author , Justin BenabdallahJustin Benabdallah More articles by this author , Fanghong ChenFanghong Chen More articles by this author , Guangjian ZhangGuangjian Zhang More articles by this author , Balaraman KalyanaramanBalaraman Kalyanaraman More articles by this author , and William SeeWilliam See More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.515AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The mycobacterial cell wall glycolipid trehalose-6,6-dimycolate (TDM) is an effective adjuvant for induction of protective T cell immunity. In vivo studies have shown that TDM injection resulted in suppression of tumor growth in hepatoma and ocular squamous cell carcinoma. To date, the effect of TDM on Urothelial carcinoma (UC) cells has not been studied. The objectives of this study were to measure the cytotoxic effects of TDM on BCG sensitive and BCG resistant UC cell lines and determine its mechanism of action relative to BCG. METHODS BCG sensitive (253J, T24) and BCG resistant (RT4) UC cell lines were used to study the effect of TDM. The biologic response to TDM was compared with the response to BCG. Response endpoints included viability, LDH release, HMGB1 release, caspase-3 activity, intracellular signaling pathways (NF-κB), gene transactivation and global profiling of reactive oxygen species(ROS) and nitrogen species (RNS). RESULTS TDM cytotoxicity was similar in both BCG sensitive and resistant cell lines. TDM significantly decreased viability (T24, p < 0.001; 253J, p < 0.005, RT4 p < 0.001) with 50 % cells remained viable after 24h. TDM exposure resulted in a 3-6 fold increase in LDH release, 24h post TDM treatment (T24 and 253J, p < 0.005, RT4 p < 0.01). Significant release of HMGB1 was observed (T24, p < 0.001; 253J, p < 0.05) after 24h. TDM exposure resulted in 4-6 fold increase in caspase-3 activity (T24 and 253J, p < 0.001) after 24h. Significant increase in transgene activation of IL-6, iNOS and p21 genes (T24 and 253J, p < 0.05) was observed after 6h. NF-κB activation was not altered upon TDM exposure (T24 and 253J, p = 0.2). Global profiling of ROS/RNS at 6h and 12h showed significant decrease in H2O2 levels post TDM exposure (T24 and 253J, p < 0.05) but no significant changes in nitric oxide (NO) and superoxide levels. CONCLUSIONS TDM is cytotoxic to both BCG sensitive and BCG resistant UC cell lines. TDM treatment results in apoptotic as well as necrotic cell death as it induces both caspase activation and HMGB1 release. Similar to BCG, it activates iNOS, p21 and IL-6 gene expression. However, Contrary to BCG, the lack of NF-κB activation and NF-κB dependent gene expression suggests that TDM functions through an NF-κB independent pathway. Lack of NF-κB activation may be related to the absence of H2O2 and NO generation with a reduction in oxidative stress relative to BCG. TDM treatment might provide new avenues for BCG refractory tumors. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e606-e607 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gopitkumar Shah More articles by this author Justin Benabdallah More articles by this author Fanghong Chen More articles by this author Guangjian Zhang More articles by this author Balaraman Kalyanaraman More articles by this author William See More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ..." @default.
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• W2058477322 title "MP49-11 TREHALOSE 6,6 DIMYCOLATE CYTOTOXICITY IN BOTH BCG SENSITIVE AND BCG RESISTANT CELL LINES OCCURS VIA A “BCG DISTINCT” PATHWAY" @default.
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