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Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585.

Abstract
Pharmacological inhibitors of histone deacetylases (HDACs) are currently being developed and tested as anti-cancer agents and may be useful to enhance the therapeutic efficiency of established anti-myeloma treatments. This study preclinically evaluated the effects of the 'second generation' pan-HDAC inhibitor JNJ-26481585 on human multiple myeloma (MM) cells from established cell lines and primary MM samples (n=42). Molecular responses in both groups of MM cells included histone acetylation, a shift in Bcl2-family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction. Mcl-1 depletion and Hsp72 induction were the most reliable features observed in JNJ-26481585-treated primary MM samples. The drug alone effectively induced myeloma cell death at low nanomolar concentrations. In vitro combination of JNJ-26481585 with anti-myeloma therapeutic agents generally resulted In effects close to additivity. In view of the favourable activity of this novel HDAC-inhibitor towards primary myeloma cells further evaluation in a clinical setting is warranted.
AuthorsThorsten Stühmer, Janine Arts, Manik Chatterjee, Johanna Borawski, André Wolff, Peter King, Hermann Einsele, Eugen Leo, Ralf C Bargou
JournalBritish journal of haematology (Br J Haematol) Vol. 149 Issue 4 Pg. 529-36 (May 2010) ISSN: 1365-2141 [Electronic] England
PMID20331455 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • quisinostat
Topics
  • Acetylation (drug effects)
  • Antineoplastic Agents (pharmacology)
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical (methods)
  • Histone Deacetylase Inhibitors (pharmacology)
  • Histones (metabolism)
  • Humans
  • Hydroxamic Acids (pharmacology)
  • Multiple Myeloma (metabolism, pathology)
  • Tumor Cells, Cultured

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