title: Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines.
abstract: 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.
  
  
  
  The aim of this study was to investigate the therapeutic potential of 4SC-202 in urothelial carcinoma (UC) cell lines.
  
  
  
  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.
  
  
  
  4SC-202 significantly reduced proliferation of all epithelial and mesenchymal UC cell lines (IC500.15-0.51 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.
  
  
  
  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.
authors.affiliation: Department of Urology, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225, Duesseldorf, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Pinkerneil
authors.affiliation: Department of Urology, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225, Duesseldorf, Germany.
authors.forename: Michèle J
authors.initials: MJ
authors.lastname: Hoffmann
authors.affiliation: 4SC AG, Martinsried, Germany.
authors.forename: Hella
authors.initials: H
authors.lastname: Kohlhof
authors.affiliation: Department of Urology, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225, Duesseldorf, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Schulz
authors.affiliation: Department of Urology, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225, Duesseldorf, Germany. guenter.niegisch@hhu.de.
authors.forename: Günter
authors.initials: G
authors.lastname: Niegisch
mesh_terms: D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D056572:Histone Deacetylase Inhibitors; D007132:Immunoglobulin Isotypes