416 IMPACT OF COMBINED HDAC AND MTOR INHIBITION ON THE INVASIVE POTENTIAL OF PROSTATE CANCER CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011416 IMPACT OF COMBINED HDAC AND MTOR INHIBITION ON THE INVASIVE POTENTIAL OF PROSTATE CANCER CELLS Steffen Wedel, Lucasz Hudak, Jasmina Makarevic, Jens-Michael Seibel, Eva Juengel, Axel Haferkamp, and Roman Blaheta Steffen WedelSteffen Wedel Frankfurt am Main, Germany More articles by this author , Lucasz HudakLucasz Hudak 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.2011.02.505AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The concept of molecular tumor targeting has recently become standard in the therapy of renal cell carcinoma and might also provide new hope in the treatment of advanced prostate cancer. We evaluated metastasis blocking properties of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell lines. METHODS RAD001 or VPA were applied to PC-3, DU-145 and LNCaP cells, either separately or in combination. Adhesion to vascular endothelium or to immobilized collagen, fibronectin or laminin was quantified. Migration and invasion were explored by a modified Boyden chamber assay. Integrin α and β subtypes were analyzed by flow cytometry, western blotting and RT-PCR. Effects of drug treatment on integrin related signaling, Akt and p70S6kinase activation, histone H3 and H4 acetylation were also determined. RESULTS Separate application of RAD001 or VPA distinctly reduced tumor cell adhesion, migration and invasion, accompanied by elevated Akt activation and p70S6kinase deactivation. Integrin subtype expression was altered significantly by both compounds (VPA > RAD001). Particularly,β3 coding mRNA was diminished drastically with the combination being superior then single drug treatment. Furthermore, when both drugs were used in concert additive effects were observed on the migratory and invasive behavior of the prostate cancer cells. CONCLUSIONS Separate mTOR or HDAC inhibition slows processes related to tumor metastasis. The RAD001-VPA combination showed advantage over VPA application alone with particular respect to migration and invasion. Ongoing studies are required to assess the relevance of VPA monotherapy versus VPA-RAD001 combination on tumor cell motility. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e167 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Steffen Wedel Frankfurt am Main, Germany More articles by this author Lucasz Hudak 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 ...