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Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines
BACKGROUND: Targeting of class I histone deacetylases (HDACs) exerts antineoplastic actions in various cancer types by modulation of transcription, upregulation of tumor suppressors, induction of cell cycle arrest, replication stress and promotion of apoptosis. Class I HDACs are often deregulated in...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153417/ https://www.ncbi.nlm.nih.gov/pubmed/27250763 http://dx.doi.org/10.1007/s11523-016-0444-7 |
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author | Pinkerneil, Maria Hoffmann, Michèle J. Kohlhof, Hella Schulz, Wolfgang A. Niegisch, Günter |
author_facet | Pinkerneil, Maria Hoffmann, Michèle J. Kohlhof, Hella Schulz, Wolfgang A. Niegisch, Günter |
author_sort | Pinkerneil, Maria |
collection | PubMed |
description | BACKGROUND: Targeting of class I histone deacetylases (HDACs) exerts antineoplastic actions in various cancer types by modulation of transcription, upregulation of tumor suppressors, induction of cell cycle arrest, replication stress and promotion of apoptosis. Class I HDACs are often deregulated in urothelial cancer. 4SC-202, a novel oral benzamide type HDAC inhibitor (HDACi) specific for class I HDACs HDAC1, HDAC2 and HDAC3 and the histone demethylase LSD1, shows substantial anti-tumor activity in a broad range of cancer cell lines and xenograft tumor models. AIM: The aim of this study was to investigate the therapeutic potential of 4SC-202 in urothelial carcinoma (UC) cell lines. METHODS: We determined dose response curves of 4SC-202 by MTT assay in seven UC cell lines with distinct HDAC1, HDAC2 and HDAC3 expression profiles. Cellular effects were further analyzed in VM-CUB1 and UM-UC-3 cells by colony forming assay, caspase-3/7 assay, flow cytometry, senescence assay, LDH release assay, and immunofluorescence staining. Response markers were followed by quantitative real-time PCR and western blotting. Treatment with the class I HDAC specific inhibitor SAHA (vorinostat) served as a general control. RESULTS: 4SC-202 significantly reduced proliferation of all epithelial and mesenchymal UC cell lines (IC(50) 0.15–0.51 μM), inhibited clonogenic growth and induced caspase activity. Flow cytometry revealed increased G2/M and subG1 fractions in VM-CUB1 and UM-UC-3 cells. Both effects were stronger than with SAHA treatment. CONCLUSION: Specific pharmacological inhibition of class I HDACs by 4SC-202 impairs UC cell viability, inducing cell cycle disturbances and cell death. Combined inhibition of HDAC1, HDAC2 and HDAC3 seems to be a promising treatment strategy for UC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11523-016-0444-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5153417 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-51534172016-12-27 Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines Pinkerneil, Maria Hoffmann, Michèle J. Kohlhof, Hella Schulz, Wolfgang A. Niegisch, Günter Target Oncol Original Research Article BACKGROUND: Targeting of class I histone deacetylases (HDACs) exerts antineoplastic actions in various cancer types by modulation of transcription, upregulation of tumor suppressors, induction of cell cycle arrest, replication stress and promotion of apoptosis. Class I HDACs are often deregulated in urothelial cancer. 4SC-202, a novel oral benzamide type HDAC inhibitor (HDACi) specific for class I HDACs HDAC1, HDAC2 and HDAC3 and the histone demethylase LSD1, shows substantial anti-tumor activity in a broad range of cancer cell lines and xenograft tumor models. AIM: The aim of this study was to investigate the therapeutic potential of 4SC-202 in urothelial carcinoma (UC) cell lines. METHODS: We determined dose response curves of 4SC-202 by MTT assay in seven UC cell lines with distinct HDAC1, HDAC2 and HDAC3 expression profiles. Cellular effects were further analyzed in VM-CUB1 and UM-UC-3 cells by colony forming assay, caspase-3/7 assay, flow cytometry, senescence assay, LDH release assay, and immunofluorescence staining. Response markers were followed by quantitative real-time PCR and western blotting. Treatment with the class I HDAC specific inhibitor SAHA (vorinostat) served as a general control. RESULTS: 4SC-202 significantly reduced proliferation of all epithelial and mesenchymal UC cell lines (IC(50) 0.15–0.51 μM), inhibited clonogenic growth and induced caspase activity. Flow cytometry revealed increased G2/M and subG1 fractions in VM-CUB1 and UM-UC-3 cells. Both effects were stronger than with SAHA treatment. CONCLUSION: Specific pharmacological inhibition of class I HDACs by 4SC-202 impairs UC cell viability, inducing cell cycle disturbances and cell death. Combined inhibition of HDAC1, HDAC2 and HDAC3 seems to be a promising treatment strategy for UC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11523-016-0444-7) contains supplementary material, which is available to authorized users. Springer International Publishing 2016-06-02 2016 /pmc/articles/PMC5153417/ /pubmed/27250763 http://dx.doi.org/10.1007/s11523-016-0444-7 Text en © The Author(s) 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Research Article Pinkerneil, Maria Hoffmann, Michèle J. Kohlhof, Hella Schulz, Wolfgang A. Niegisch, Günter Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines |
title | Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines |
title_full | Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines |
title_fullStr | Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines |
title_full_unstemmed | Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines |
title_short | Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines |
title_sort | evaluation of the therapeutic potential of the novel isotype specific hdac inhibitor 4sc-202 in urothelial carcinoma cell lines |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153417/ https://www.ncbi.nlm.nih.gov/pubmed/27250763 http://dx.doi.org/10.1007/s11523-016-0444-7 |
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