Investigational New Drugs

, Volume 30, Issue 4, pp 1715–1724

Synergetic effects of DNA demethylation and histone deacetylase inhibition in primary rat hepatocytes

  • Joanna Edyta Fraczek
  • Mathieu Vinken
  • Dirk Tourwé
  • Tamara Vanhaecke
  • Vera Rogiers
SHORT REPORT

DOI: 10.1007/s10637-011-9659-8

Cite this article as:
Fraczek, J.E., Vinken, M., Tourwé, D. et al. Invest New Drugs (2012) 30: 1715. doi:10.1007/s10637-011-9659-8

Summary

Both, DNA methylation and histone deacetylation play a crucial role in cancer development by silencing the expression of specific tumour suppressor genes. Several studies describe the use of combinations of DNA methyltransferase inhibitors (DNMT-i) and histone deacetylase inhibitors (HDAC-i) as an improved strategy to treat neoplasms. However, no information is available concerning their biological impact on healthy, non-malignant cells, including hepatocytes. Therefore, the effects of the combination of the DNMT-i decitabine (DAC) with the HDAC-i 6-[(4-pyrrolidine-1-ylbenzoyl) amino] hexanoic acid hydroxamate (AN-8) on cell proliferation and differentiation were examined in primary rat hepatocyte cultures. We found that, upon simultaneous exposure of the cells to both compounds, a synergetic anti-proliferative outcome was achieved. This inhibition of DNA synthesis was accompanied by a reduced expression of cyclin-dependent kinase 1 (cdk1), a key cell cycle marker that controls the S/G2/M transition. Compared to exposure of the cells to each agent separately, the combination of lower concentrations of both DAC and AN-8 promoted the maintenance of the differentiated phenotype of the cells as a function of culture time. The functionality of the hepatocytes was evidenced by an increased expression of the phase I biotransformation enzyme cytochrome P 450 (CYP) 1A1 and albumin secretion capacity when both agents were used in combination.

Keywords

Primary hepatocytes Epigenetics DNA methyltransferase inhibitors Histone deacetylase inhibitors 

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Joanna Edyta Fraczek
    • 1
  • Mathieu Vinken
    • 1
  • Dirk Tourwé
    • 2
  • Tamara Vanhaecke
    • 1
  • Vera Rogiers
    • 1
  1. 1.Department of Toxicology, Center for Pharmaceutical Research, Faculty of Medicine and PharmacyVrije Universiteit BrusselBrusselsBelgium
  2. 2.Department of Organic ChemistryVrije Universiteit BrusselBrusselsBelgium

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