Targeted Oncology, 2016, Vol.11(6), pp.783-798
To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s11523-016-0444-7 Byline: Maria Pinkerneil (1), Michele J. Hoffmann (1), Hella Kohlhof (2), Wolfgang A. Schulz (1), Gunter Niegisch (1) 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 (IC.sub.50 0.15--0.51 [micro]M), 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. Author Affiliation: (1) Department of Urology, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225, Duesseldorf, Germany (2) 4SC AG, Martinsried, Germany Article History: Registration Date: 10/05/2016 Online Date: 02/06/2016 Article note: 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.
Cell Death – Analysis ; Cell Death – Health Aspects ; Carcinoma – Analysis ; Carcinoma – Health Aspects;
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