The Open Leukemia Journal

2010, 3 : 34-42
Published online 2010 May 17 . DOI: 10.2174/1876816401003010034
Publisher ID: TOLEUKEMIAJ-3-34

RESEARCH ARTICLE
 Effects of Epigenetic Drugs (Vorinostat, Decitabine) on Metabolism-Related Pathway Factors in Leukemic Cells

Heidrun Karlic1,2 , Julia Varga1,2 , Roman Thaler3 , Cornelia Berger1 , Silvia Spitzer3 , Michael Pfeilstöcker1,2,4 , Klaus Klaushofer3 and Franz Varga3, *
1 Ludwig Boltzmann Cluster Oncology, Vienna, Austria
2 Ludwig Boltzmann Institute for Leukemia Research and Hematology, Hanusch Hospital, Vienna, Austria
3 Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling. 4th Medical Department, Hanusch Hospital, Vienna, Austria
4 3rd Medical Department, Hanusch Hospital, Vienna, Austria

* Address correspondence to this author at the Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling. 4th Medical Department, Hanusch Hospital, Heinrich Collin Str. 30, 1140 Vienna, Austria; Tel: +431 9102186933l Fax: +431 9102186929; E-mail: franz.varga@osteologie.at

ABSTRACT

Novel tools for data-evaluation from gene-expression arrays allow analyses of biochemical pathways which may be influenced by treatment with epigenetic drugs which have originally been designed for re-activation of so-called tumour-suppressor genes that are known as key-molecules regulating differentiation or cell death in malignancy. Considering the fact that these processes are tightly associated with energy metabolism, this study evaluated the expression signature of prominently regulated pathways in the KG-1-leukemia cell line: Following a 3-day incubation, effects of pharmacologic concentrations from the histone-deacetylase inhibitor SAHA (suberoyl anilide hydroxamic acid, vorinostat) and the methylation-inhibitor desoxy-azacytidine (DAC) were comparatively analysed by transcriptional profiling (based on Affymetrix Human GeneChip Gene 1.0 ST microarrays) and quantitative real time PCR. Expression factors for pathways were calculated for comparative analyses. Epigenetic drugs SAHA and DAC had a downregulatory effect on metabolic pathway factors of carbohydrate metabolism and mitochondrial beta oxidation. Our data confirm SAHA-mediated downregulation of the histone deacetylase SIRT which regulates AKT-phosphatase. Associated pathways lead to regulation of numerous genes, including an upregulation of FOXO transcription factors. These regulatory networks are known for their crucial role in stem cell homeostasis and provide a mechanistic explanation for the fact that the number of SAHA-targeted genes (1392 up, 2651 down) exceeds the number of DAC-targeted genes (60 up, 15 down), besides known effects on cell-cycle-arrest and apoptosis induced by both drugs.

Thus, our data underline that epigenetic mechanisms are tightly associated with malignancy-associated metabolic control at least at 3 levels, starting from (i) glucose-uptake over (ii) mitochondrial pathways to (iii) AKT-PTEN-FOXO-signalling. All of them are known to be regulated by caloric restriction. We propose that these interactions should be carefully considered in clinical application, providing the basis for optimization of drug-combinations and complex treatment strategies

Keywords:

Epigenetics, vorinostat, decitabine, energy metabolism, KG1-cells.