| Synergetic effects of DNA demethylation and histone deacetylase inhibition in primary rat hepatocytes. | |
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MedLine Citation:
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PMID: 21445578 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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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Authors:
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Joanna Edyta Fraczek; Mathieu Vinken; Dirk Tourwé; Tamara Vanhaecke; Vera Rogiers |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-29 |
Journal Detail:
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Title: Investigational new drugs Volume: - ISSN: 1573-0646 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-3-29 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8309330 Medline TA: Invest New Drugs Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Toxicology, Center for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium, jfraczek@vub.ac.be. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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