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
Institution
Heinrich Heine University
Country
Germany
Year
2016
Journal
Targeted Oncology
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.