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The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells
Author(s) -
MandlWeber Sonja,
Meinel Felix G.,
Jankowsky Rüdiger,
Oduncu Fuat,
Schmidmaier Ralf,
Baumann Philipp
Publication year - 2010
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2010.08124.x
Subject(s) - bortezomib , apoptosis , histone deacetylase , chemistry , cell growth , cancer research , cyclin d1 , cell culture , histone deacetylase inhibitor , protein kinase b , cell cycle , proteasome inhibitor , downregulation and upregulation , cell cycle checkpoint , pi3k/akt/mtor pathway , microbiology and biotechnology , multiple myeloma , histone , biology , biochemistry , immunology , genetics , gene
Summary Inhibition of histone deacetylase (HDAC) is a promising mechanism for novel, anti‐myeloma agents. We investigated the effects of the novel HDAC inhibitor resminostat on multiple myeloma (MM) cells in vitro . Resminostat is a potent inhibitor of HDACs 1, 3 and 6 [50% inhibitory concentration (IC 50 ) = 43–72 nmol/l] representing HDAC classes I and II and induces hyperacetylation of histone H4 in MM cells. Low micromolar concentrations of resminostat abrogated cell growth and strongly induced apoptosis (IC 50 = 2·5–3 μmol/l in 3 out of 4 MM cell lines) in MM cell lines as well as primary MM cells. At 1 μmol/l, resminostat inhibited proliferation and induced G0/G1 cell cycle arrest in 3 out of 4 MM cell lines accompanied with decreased levels of cyclin D1, cdc25a, Cdk4 and pRb as well as upregulation of p21. Resminostat decreased phosphorylation of 4E‐BP1 and p70S6k indicating an interference with Akt pathway signalling. Treatment with resminostat resulted in increased protein levels of Bim and Bax and decreased levels of Bcl‐xL. Caspases 3, 8 and 9 were activated by resminostat. Furthermore, synergistic effects were observed for combinations of resminostat with melphalan and the proteasome inhibitors bortezomib and S‐2209. In conclusion, we have identified potent anti‐myeloma activity for this novel HDAC inhibitor.