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Targeted Oncology

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Open Access 01-12-2016 | Original Research Article

Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines

Authors: Maria Pinkerneil, Michèle J. Hoffmann, Hella Kohlhof, Wolfgang A. Schulz, Günter Niegisch

Published in: Targeted Oncology | Issue 6/2016

Abstract

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 (IC₅₀ 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.

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Title: Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines
Authors: Maria Pinkerneil
Michèle J. Hoffmann
Hella Kohlhof
Wolfgang A. Schulz
Günter Niegisch
Publication date: 01-12-2016
Publisher: Springer International Publishing
Published in: Targeted Oncology / Issue 6/2016
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-016-0444-7

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