You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2012783 THE EFFECTS OF HDAC-INHIBITION ON TUMOR GROWTH AND INTEGRIN DRIVEN INVASION PROCESSES ARE AUGMENTED BY LOW DOSED INTERFERON ALPHA IN PROSTATE CANCER MODELS IN VITRO AND IN VIVO Steffen Wedel, Lukasz Hudak, Igor Tsaur, Jasmina Makarevic, Jens-Michael Seibel, Eva Juengel, Axel Haferkamp, and Roman Blaheta Steffen WedelSteffen Wedel Frankfurt am Main, Germany More articles by this author , Lukasz HudakLukasz Hudak Frankfurt am Main, Germany More articles by this author , Igor TsaurIgor Tsaur Frankfurt am Main, Germany More articles by this author , Jasmina MakarevicJasmina Makarevic Frankfurt am Main, Germany More articles by this author , Jens-Michael SeibelJens-Michael Seibel Frankfurt am Main, Germany More articles by this author , Eva JuengelEva Juengel Frankfurt am Main, Germany More articles by this author , Axel HaferkampAxel Haferkamp Frankfurt am Main, Germany More articles by this author , and Roman BlahetaRoman Blaheta Frankfurt am Main, Germany More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.871AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES HDAC up-regulation plays a crucial role in the genesis of prostate cancer, malignant growth and dissemination of the tumor cells. Therefore we evaluated anti-tumor properties of the HDAC inhibitor valproic acid (VPA) in prostate cancer cells as well as in a xenograft model. Since there is evidence form other tumors that interferon-α(IFNa) might enhance HDAC inhibitory effects we combined VPA with IFNa in low concentrations which had no cancer blocking effects when applied alone. METHODS VPA and IFNa were applied to PC-3, DU-145 and LNCaP cells, either separately or in combination. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by the MTT dye reduction assay, flow cytometry and western blotting. Tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins was evaluated. Migration and invasion were explored by a modified Boyden chamber assay. Integrin αand β adhesion molecules were analyzed by flow cytometry, western blotting and RT-PCR as well as alterations of cell signaling pathways were analyzed. Finally, effects of the drug treatment on prostate cancer growth in vivo were determined by the NOD/SCID mice model. RESULTS VPA, separately applied, reduced tumor cell adhesion, migration and growth in vitro. A much stronger anti-cancer potential was evoked by the VPA-IFNa combination, although IFNa alone did not exert any growth or adhesion blocking activity. The same effect was seen when tumor growth was evaluated in vivo. Molecular analysis revealed distinct elevation of histone H3 acetylation caused by VPA which was further up-regulated by VPA-IFNa, whereas IFNa alone did not alter H3 acetylation. Combinatorial benefit became obvious on Akt phosphorylation, p21 and p27 and integrin α1, α3 and β1 expression. CONCLUSIONS Application of low-dosed IFNa to a VPA based regimen profoundly boosts the anti-tumor characteristics of VPA. Presumably, IFNa renders prostate cancer cells to become more susceptible to HDAC-inhibition resulting in additive effects on integrin receptors and growth related signaling. We conclude that combined use of VPA and low-dosed IFNa may become an innovative option to treat advanced prostate cancer. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e320 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Steffen Wedel Frankfurt am Main, Germany More articles by this author Lukasz Hudak Frankfurt am Main, Germany More articles by this author Igor Tsaur Frankfurt am Main, Germany More articles by this author Jasmina Makarevic Frankfurt am Main, Germany More articles by this author Jens-Michael Seibel Frankfurt am Main, Germany More articles by this author Eva Juengel Frankfurt am Main, Germany More articles by this author Axel Haferkamp Frankfurt am Main, Germany More articles by this author Roman Blaheta Frankfurt am Main, Germany More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...