1. Academic Validation
  2. Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines

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

  • Target Oncol. 2016 Dec;11(6):783-798. doi: 10.1007/s11523-016-0444-7.
Maria Pinkerneil 1 Michèle J Hoffmann 1 Hella Kohlhof 2 Wolfgang A Schulz 1 Günter Niegisch 3
Affiliations

Affiliations

  • 1 Department of Urology, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225, Duesseldorf, Germany.
  • 2 4SC AG, Martinsried, Germany.
  • 3 Department of Urology, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225, Duesseldorf, Germany. guenter.niegisch@hhu.de.
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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