title: Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells.
abstract: A significant proportion of men diagnosed with prostate cancer (PCa) eventually develop metastatic disease, which progresses to castration resistance, despite initial response to androgen deprivation. As anticancer therapy has become increasingly effective, acquired drug resistance has emerged, limiting efficacy. Combination treatment, utilizing different drug classes, exemplifies a possible strategy to foil resistance development. The effects of the triple application of the histone deacetylase (HDAC) inhibitor valproic acid (VPA), the mammalian target of rapamycin inhibitor everolimus and low dosed interferon alpha (IFNα) on PCa cell growth and dissemination capacity were investigated. For that purpose, the human PCa cell lines, PC-3, DU-145 and LNCaP were treated with the combined regimen or separate single agents. Cell growth was investigated by the MTT dye reduction assay. Flow cytometry served to analyse cell cycle progression. Adhesion to vascular endothelium or immobilized collagen, fibronectin and laminin was quantified. Migration and invasion characteristics were determined by the modified Boyden chamber assay. Integrin α and β subtypes were investigated by flow cytometry, western blotting and RT-PCR. Integrin related signalling, Epidermal Growth Factor Receptor (EGFr), Akt, p70S6kinase and extracellular signal-regulated kinases (ERK)1/2 activation were also assessed. The triple application of VPA, everolimus and low dosed IFNα blocked tumour cell growth and dissemination significantly better than any agent alone. Antitumour effects were associated with pronounced alteration in the cell cycle machinery, intracellular signalling and integrin expression profile. Combining VPA, everolimus and low dosed IFNα might be a promising option to counteract resistance development and improve outcome in PCa patients.
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Igor
authors: I
authors: Tsaur
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Lukasz
authors: L
authors: Hudak
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Jasmina
authors: J
authors: Makarević
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Eva
authors: E
authors: Juengel
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Jens
authors: J
authors: Mani
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Hendrik
authors: H
authors: Borgmann
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Kilian M
authors: KM
authors: Gust
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: David
authors: D
authors: Schilling
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Georg
authors: G
authors: Bartsch
authors: Department of Vascular and Endovascular Surgery, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Karen
authors: K
authors: Nelson
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Axel
authors: A
authors: Haferkamp
authors: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors: Roman A
authors: RA
authors: Blaheta
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D016326:Extracellular Matrix Proteins; D056572:Histone Deacetylase Inhibitors; D016023:Integrins; D016898:Interferon-alpha; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases
keywords: combination therapy; everolimus; interferon alpha; prostate cancer; valproic acid