Open AccessIntensified antineoplastic effect by combining an HDAC ‐inhibitor, an mTOR ‐inhibitor and low dosed interferon alpha in prostate cancer cells
Author(s) -
Tsaur Igor,
Hudak Lukasz,
Makarević Jasmina,
Juengel Eva,
Mani Jens,
Borgmann Hendrik,
Gust Kilian M.,
Schilling David,
Bartsch Georg,
Nelson Karen,
Haferkamp Axel,
Blaheta Roman A.
Publication year - 2015
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12583
Subject(s) - everolimus , cancer research , cell growth , pi3k/akt/mtor pathway , histone deacetylase inhibitor , pharmacology , protein kinase b , biology , histone deacetylase , medicine , microbiology and biotechnology , signal transduction , biochemistry , gene , histone
A significant proportion of men diagnosed with prostate cancer ( PC a) 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 ( IFN α) on PC a cell growth and dissemination capacity were investigated. For that purpose, the human PC a cell lines, PC ‐3, DU ‐145 and LNC aP 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 IFN α 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 IFN α might be a promising option to counteract resistance development and improve outcome in PC a patients.