The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells.

Abstract

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 (IC50)=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 (IC50=2.5-3 micromol/l in 3 out of 4 MM cell lines) in MM cell lines as well as primary MM cells. At 1 micromol/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.

• Authors: Sonja Mandl-Weber, Felix G Meinel, Rüdiger Jankowsky, Fuat Oduncu, Ralf Schmidmaier, Philipp Baumann
• Journal: British journal of haematology (Br J Haematol) Vol. 149 Issue 4 Pg. 518-28 (May 2010) ISSN: 1365-2141 [Electronic] England
• PMID: 20201941 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Histones
• Hydroxamic Acids
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• resminostat
• Proto-Oncogene Proteins c-akt

Topics

• Acetylation (drug effects)
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Synergism
• Histone Deacetylase Inhibitors (pharmacology)
• Histones (metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• Multiple Myeloma (metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Tumor Cells, Cultured