A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases

Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3003-7. doi: 10.1073/pnas.95.6.3003.


Hybrid polar compounds (HPCs) have been synthesized that induce terminal differentiation and/or apoptosis in various transformed cells. We have previously reported on the development of the second-generation HPCs suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bishydroxamide (CBHA) that are 2,000-fold more potent inducers on a molar basis than the prototype HPC hexamethylene bisacetamide (HMBA). Herein we report that CBHA and SAHA inhibit histone deacetylase 1 (HDAC1) and histone deacetylase 3 (HDAC3) activity in vitro. Treatment of cells in culture with SAHA results in a marked hyperacetylation of histone H4, but culture with HMBA does not. Murine erythroleukemia cells developed for resistance to SAHA are cross-resistant to trichostatin A, a known deacetylase inhibitor and differentiation inducer, but are not cross-resistant to HMBA. These studies show that the second-generation HPCs, unlike HMBA, are potent inhibitors of HDAC activity. In this sense, HMBA and the second-generation HPCs appear to induce differentiation by different pathways.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetamides / pharmacology
  • Animals
  • Carcinoma / metabolism
  • Cell Differentiation*
  • Cell Line, Transformed / drug effects
  • Cell Transformation, Neoplastic
  • Cinnamates / pharmacology*
  • Drug Resistance
  • Histone Deacetylase 1
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Leukemia, Erythroblastic, Acute / metabolism
  • Malonates / pharmacology
  • Mice
  • Urinary Bladder Neoplasms / metabolism
  • Vorinostat


  • Acetamides
  • Cinnamates
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Malonates
  • carboxycinnamic acid bishydroxamide
  • diethyl-bis(pentamethylene-N,N-dimethylcarboxamide)malonate
  • trichostatin A
  • Vorinostat
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases
  • histone deacetylase 3
  • hexamethylene bisacetamide