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• W2003408967 abstract "No AccessJournal of UrologyInvestigative Urology1 Sep 2009Oxidative Stress Sensitizes Bladder Cancer Cells to TRAIL Mediated Apoptosis by Down-Regulating Anti-Apoptotic Proteinsis companion ofp53 Predictive Value for pT1-2 N0 Disease at Radical CystectomyComplications and Mortality After Radical Cystectomy for Bladder Transitional Cell Cancer Shai J. White-Gilbertson, Laura Kasman, John McKillop, Tejas Tirodkar, Ping Lu, and Christina Voelkel-Johnson Shai J. White-GilbertsonShai J. White-Gilbertson Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina More articles by this author , Laura KasmanLaura Kasman Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina More articles by this author , John McKillopJohn McKillop Department of Medicine, Medical University of South Carolina, Charleston, South Carolina More articles by this author , Tejas TirodkarTejas Tirodkar Molecular and Cellular Biology and Pathobiology Program, Medical University of South Carolina, Charleston, South Carolina More articles by this author , Ping LuPing Lu Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina More articles by this author , and Christina Voelkel-JohnsonChristina Voelkel-Johnson Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2009.05.005AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: TRAIL, an endogenous protein involved in immunosurveillance and a novel drug in clinical trials, is of particular interest as cancer therapy because it can induce apoptosis in cancer cells but not in normal cells. Since some cancers develop resistance to TRAIL, safe and effective methods of TRAIL sensitization are of clinical interest. We explored how chemotherapy and oxidative stress affect TRAIL sensitivity and expression of proteins in the apoptotic pathway. Materials and Methods: Sensitivity to TRAIL was assessed in viability assays. Apoptosis was measured by caspase-3/7 activity and/or nuclear condensation using Hoechst staining. Western blotting was used to determine cleavage, phosphorylation or alterations in protein expression. Results: TRAIL decreased the viability of 5637 but not of J82 or T24 bladder carcinoma cells (ATCC®). Chemotherapy with doxorubicin or cisplatin (Ben Venue Laboratories, Bedford, Ohio) decreased the expression of the anti-apoptotic protein cFLIPS and increased caspase-8 cleavage, reversing TRAIL resistance in T24 cells. Specific targeting of cFLIPS by siRNA was insufficient for sensitization to TRAIL in T24 cells. However, chemotherapy mediated TRAIL sensitization was mimicked by low concentrations of H2O2, which resulted in the phosphorylation of translation EF2 and decreased the expression of several short half-life, anti-apoptotic proteins, including FLIPS, XIAP and survivin. Conclusions: Inducing oxidative stress by low H2O2 concentrations may reverse TRAIL resistance. This warrants the further exploration of H2O2 as an adjuvant intravesical treatment to lower the apoptotic threshold of bladder cancer cells. References 1 : History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story. J Urol2008; 179: 53. Link, Google Scholar 2 : Role of neutrophils in BCG immunotherapy for bladder cancer. Urol Oncol2008; 26: 341. Google Scholar 3 : The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer2008; 8: 782. Google Scholar 4 : To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest2008; 118: 1979. 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Google Scholar © 2009 by American Urological AssociationFiguresReferencesRelatedDetailsRelated articlesJournal of Urology17 Jul 2009p53 Predictive Value for pT1-2 N0 Disease at Radical CystectomyJournal of Urology17 Jul 2009Complications and Mortality After Radical Cystectomy for Bladder Transitional Cell Cancer Volume 182Issue 3September 2009Page: 1178-1185 Advertisement Copyright & Permissions© 2009 by American Urological AssociationKeywordsapoptosisurinary bladder neoplasmsurinary bladderoxidative stressreceptorsTNF-related apoptosis-inducing ligandAcknowledgmentsDr. Harald Wajant, University of Stuttgart, Stuttgart, Germany, provided plasmids encoding c-FLIP-GFP fusion proteins. Dr. Marcus Peter, University of Chicago, Chicago, Illinois, provided NF-6 supernatant.MetricsAuthor Information Shai J. White-Gilbertson Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina More articles by this author Laura Kasman Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina More articles by this author John McKillop Department of Medicine, Medical University of South Carolina, Charleston, South Carolina More articles by this author Tejas Tirodkar Molecular and Cellular Biology and Pathobiology Program, Medical University of South Carolina, Charleston, South Carolina More articles by this author Ping Lu Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina More articles by this author Christina Voelkel-Johnson Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina More articles by this author Expand All Advertisement PDF DownloadLoading ..." @default.
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