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• W2000791609 abstract "You have accessJournal of UrologyKidney Cancer: Basic Research1 Apr 2011236 PREVENTION OF RESISTANCE DEVELOPMENT IN RENAL CELL CARCINOMA BY COMBINED INHIBITION OF HISTONE DEACETYLASE AND MAMMALIAN TARGET OF RAPAMYCIN Eva Juengel, Anna Vogt, Lukasz Hudak, Jasmina Makarevic, Axel Haferkamp, and Roman Blaheta Eva JuengelEva Juengel Frankfurt Main, Germany More articles by this author , Anna VogtAnna Vogt Frankfurt Main, Germany More articles by this author , Lukasz HudakLukasz Hudak Frankfurt Main, Germany More articles by this author , Jasmina MakarevicJasmina Makarevic Frankfurt Main, Germany More articles by this author , Axel HaferkampAxel Haferkamp Frankfurt Main, Germany More articles by this author , and Roman BlahetaRoman Blaheta Frankfurt Main, Germany More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.305AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES During the past years identifying molecular mechanisms involved in renal cell carcinoma (RCC) has led to the development of therapeutic agents which interfere with tumor-specific target structures. These agents may provide a distinct benefit in treating RCC. However, it is not clear whether long-term application may induce resistance development. Therefore, we evaluated the consequences of sustained exposure of RCC cells with the mammalian target of rapamycin (mTOR)-inhibitor RAD001. Furthermore, we investigated the impact of additionally applying the histone deacetylase (HDAC)-inhibitor, valproic acid (VPA), on RCC cell proliferation and differentiation. METHODS RCC cells (Caki-1) were treated short-term (2–3 weeks) or long-term (over 10 weeks) with RAD001 or VPA, alone or in combination. Cell growth and cell cycle progression were determined by MTT-assay and FACscan. Western blotting was done to investigate histone acetylation, Akt and p70S6k signalling, as well as cell cycle regulating protein expression. N- and E-cadherin, differentiation markers, were evaluated by immunostaining and flow cytometry. RESULTS Caki-1 short-term application with RAD001 or VPA resulted in significant inhibition of tumor growth and S-phase blockade. RAD001 deactivated Akt, while VPA induced increased histone H3 and H4 acetylation. Both agents reduced cyclin D3 and enhanced p19. N-cadherin was down-, E-cadherin up-regulated by RAD001 and VPA. Stronger effects on cell growth and differentiation were induced when both agents were combined. Chronic treatment resulted in a non-responsiveness of Caki-1, where growth behaviour was similar to that of untreated control cells. Concomitantly, RAD001 elevated pAkt and p70SA6k over controls and VPA no longer enhanced histone H3 and H4 acetylation. Combined application reduced tumor growth and prevented epithelial-mesenchymal transition observed with long-term single drug application. CONCLUSIONS This study reveals that long-term application of RCC cells with RAD001 triggers processes related to resistance induction. Combined treatment with VPA prevents RAD001 non-responsiveness. Therefore, this mechanism should be considered in clinical trials. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e96 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eva Juengel Frankfurt Main, Germany More articles by this author Anna Vogt Frankfurt Main, Germany More articles by this author Lukasz Hudak Frankfurt Main, Germany More articles by this author Jasmina Makarevic Frankfurt Main, Germany More articles by this author Axel Haferkamp Frankfurt Main, Germany More articles by this author Roman Blaheta Frankfurt Main, Germany More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ..." @default.
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