Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group

Int J Cancer. 2007 Sep 1;121(5):1138-48. doi: 10.1002/ijc.22751.


Advanced second generation inhibitors of histone deacetylases (HDAC) are currently used in clinical development. This study aimed at comparing the pharmacological properties of selected second generation HDAC inhibitors with the hydroxamate and benzamide head group, namely SAHA, LAQ824/LBH589, CI994, MS275 and MGCD0103. In biochemical assays using recombinant HDAC1, 3, 6 and 8 isoenzymes, SAHA and LAQ824/LBH589 behave as quite unselective HDAC inhibitors. In contrast, the benzamides CI994, MS275 and MGCD0103 are more selective, potent inhibitors of at least HDAC1 and HDAC3. All HDAC inhibitors induce histone H3 hyperacetylation, correlating with inhibition of proliferation, induction of cell differentiation and apoptosis. A broad cytotoxicity is seen across cell lines from different tumor entities with LAQ824/LBH589 being the most potent agents. The apoptosis inducing activity is evident in arrested and proliferating RKO colon cancer cells with inducible, heterologous p21(waf1) expression, indicative for a cell-cycle independent mode-of-action. Differentiation of MDA-MB468 breast cancer cells is induced by benzamide and hydroxamate analogs. The reversibility of drug action was evaluated by pulse treatment of A549 lung cancer cells. Whereas paclitaxel induced irreversible cell cycle alterations already after 6 hr treatment, HDAC inhibitor action was retarded and irreversible after >16 hr treatment. Interestingly, pulse treatment was equally effective as continous treatment. Finally, the efficacy of LAQ824, SAHA and MS275 in A549 nude mice xenografts was comparable to that of paclitaxel at well tolerated doses. We conclude that despite a different HDAC isoenzyme inhibition profile, hydroxamate and benzamide analogs as studied display similar cellular profiles.

MeSH terms

  • Acetylation
  • Apoptosis / drug effects
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Genes, Reporter
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / metabolism
  • Luciferases / genetics
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / pathology


  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Isoenzymes
  • Luciferases
  • Histone Deacetylases