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

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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.

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Acknowledgements

This study was financially supported by Vrije Universiteit Brussel (OZR-VUB), Belgium through a GOA project.

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Authors and Affiliations

  1. Department of Toxicology, Center for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium

    Joanna Edyta Fraczek, Mathieu Vinken, Tamara Vanhaecke & Vera Rogiers

  2. Department of Organic Chemistry, Vrije Universiteit Brussel, Brussels, Belgium

    Dirk Tourwé

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  1. Joanna Edyta Fraczek
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  2. Mathieu Vinken
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Correspondence to Joanna Edyta Fraczek.

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Fraczek, J.E., Vinken, M., Tourwé, D. et al. Synergetic effects of DNA demethylation and histone deacetylase inhibition in primary rat hepatocytes. Invest New Drugs 30, 1715–1724 (2012). https://doi.org/10.1007/s10637-011-9659-8

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  • DOI: https://doi.org/10.1007/s10637-011-9659-8

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