The class-I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6-independent mechanism

Br J Haematol. 2010 Nov;151(4):387-96. doi: 10.1111/j.1365-2141.2010.08342.x. Epub 2010 Sep 29.


Inhibition of histone deacetylase 6 (HDAC6)-dependent aggresome function by pan HDAC inhibitors was recently reported to be a key mechanism underlying the synergistic activity between proteasome inhibitors and HDAC inhibitors in a variety of tumour types. Because these combinations induce significant thrombocytopenia in vivo, we examined whether less toxic, isotype-selective HDAC inhibitors may still synergize with proteasome inhibitors, and if so, by what mechanisms. Here, we showed that the class I HDAC inhibitor, MGCD0103, has a potent antiproliferative activity in Hodgkin lymphoma (HL) cell lines. Furthermore, MGCD0103 induced tumour necrosis factor α (TNF-α) expression and secretion, which was associated with nuclear factor (NF)-κB activation. Selective inhibition of TNF-α expression by short interfering mRNA, or inhibition of MGCD0103-induced NF-kB activation by proteasome inhibitors enhanced MGCD0103-induced cell death. Thus, our results demonstrate that MGCD0103 may synergize with proteasome inhibitors by HDAC6-independent mechanisms, providing mechanistic rationale for exploring this potentially less toxic combination for the treatment of lymphoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Benzamides / pharmacology*
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Drug Screening Assays, Antitumor / methods
  • Drug Synergism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / physiology
  • Hodgkin Disease / pathology*
  • Humans
  • NF-kappa B / metabolism
  • Protease Inhibitors / pharmacology
  • Pyrazines / pharmacology
  • Pyrimidines / pharmacology*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Up-Regulation / drug effects


  • Antineoplastic Agents
  • Benzamides
  • Boronic Acids
  • Cytokines
  • Histone Deacetylase Inhibitors
  • NF-kappa B
  • Protease Inhibitors
  • Pyrazines
  • Pyrimidines
  • Tumor Necrosis Factor-alpha
  • Bortezomib
  • mocetinostat
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases