Cargando…

Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells

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, limi...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549030/
https://www.ncbi.nlm.nih.gov/pubmed/25808196
http://dx.doi.org/10.1111/jcmm.12583
_version_ 1782387255023763456
author 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
author_facet 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
author_sort Tsaur, Igor
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4549030
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher John Wiley & Sons, Ltd
record_format MEDLINE/PubMed
spelling pubmed-45490302015-08-28 Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells 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 J Cell Mol Med Original Articles 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. John Wiley & Sons, Ltd 2015-08 2015-03-26 /pmc/articles/PMC4549030/ /pubmed/25808196 http://dx.doi.org/10.1111/jcmm.12583 Text en © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
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
Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells
title Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells
title_full Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells
title_fullStr Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells
title_full_unstemmed Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells
title_short Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells
title_sort intensified antineoplastic effect by combining an hdac-inhibitor, an mtor-inhibitor and low dosed interferon alpha in prostate cancer cells
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549030/
https://www.ncbi.nlm.nih.gov/pubmed/25808196
http://dx.doi.org/10.1111/jcmm.12583
work_keys_str_mv AT tsaurigor intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT hudaklukasz intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT makarevicjasmina intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT juengeleva intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT manijens intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT borgmannhendrik intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT gustkilianm intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT schillingdavid intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT bartschgeorg intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT nelsonkaren intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT haferkampaxel intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells
AT blahetaromana intensifiedantineoplasticeffectbycombininganhdacinhibitoranmtorinhibitorandlowdosedinterferonalphainprostatecancercells