Epigenetic regulation of angiogenesis

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent anti-angiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, little work has been done to understand the effect of this combination on physiological and tumoral angiogenesis. We designed a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities and tested in relevant models of angiogenesis in vitro (Human Umbilical Vein Endothelial Cells – HUVEC and aortic ring) and in vivo (chick chorioallantoic membrane and Zebrafish). We have identified a lead compound (EPI) affecting global histone acetylation and having quantifiable anti-angiogenic action without cytotoxic and apoptotic effect. In order to elucidate its anti-angiogenic mechanism, we characterized gene expression pattern simultaneously with the methylation profile of HUVEC cells treated with EPI and reference epigenetic modulators. This approach based on parallel microarray analyses permitted us to underscore a list of genes exclusively affected by EPI but not by other HDAC or DNMT inhibitors. These genes were then analyzed using the Ingenuity Pathway Analysis software revealing potential involvement of a subset of genes in angiogenesis. Our present aim is to validate the expression levels of a series of genes with respect to epigenetic mechanisms (histone modifications and DNA methylation). Finally, the biological relevance of the target genes will be explored by RNA silencing. Hence, we are using these novel epigenetic modulators as a tool to understand the regulatory mechanism of angiogenesis and to develop effective approaches to treat cancer

Novel HDAC/DNMT Twin inhibitors interfere with angiogenesis

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent anti-angiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, little work has been done to understand the effect of this combination on physiological and tumoral angiogenesis. We have designed and tested a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities in relevant models of angiogenesis in vitro (Human Umbilical Vein Endothelial Cells – HUVEC and aortic ring) and in vivo (chick chorioallantoic membrane and Zebrafish). We have identified a lead compound having quantifiable anti-angiogenic effect without cytotoxicity affecting global histone acetylation and DNA methylation levels. In order to elucidate its anti-angiogenic mechanism, we characterized gene expression pattern simultaneously with the methylation profile of HUVEC cells treated with the lead compound and reference epigenetic modulators. This approach based on parallel microarray analyses permitted us to underscore a list of genes exclusively affected by the lead compound but not by other HDAC or DNMT inhibitors. These genes were then analyzed using the Ingenuity Pathway software revealing potential involvement of a subset of genes in angiogenesis. Our present aim is to validate the expression levels of a series of genes with respect to epigenetic mechanisms (histone modifications and DNA methylation). Finally, the biological relevance of the target genes will be explored by RNA silencing. Hence, we are using these novel epigenetic modulators as a tool to understand the regulatory mechanism of angiogenesis and to develop effective approaches to treat cancer

Understanding angiogenesis through novel epigenetic modulators

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent anti-angiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, little work has been done to understand the effect of this combination on physiological and tumoral angiogenesis. We have designed and tested a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities in relevant models of angiogenesis in vitro (Human Umbilical Vein Endothelial Cells – HUVEC and aortic ring) and in vivo (chick chorioallantoic membrane and Zebrafish). We have identified a lead compound having quantifiable anti-angiogenic effect without cytotoxicity affecting global histone acetylation and DNA methylation levels. In order to elucidate its anti-angiogenic mechanism, we characterized gene expression pattern simultaneously with the methylation profile of HUVEC cells treated with the lead compound and reference epigenetic modulators. This approach based on parallel microarray analyses permitted us to underscore a list of genes exclusively affected by the lead compound but not by other HDAC or DNMT inhibitors. These genes were then analyzed using the Ingenuity Pathway software revealing potential involvement of a subset of genes in angiogenesis. Our present work is focused on exploring the exact role of these genes on angiogenesis using RNA silencing and vectors cloned with genes of interest. We are using these novel epigenetic modulators as a tool to understand the regulatory mechanism of angiogenesis and to develop effective approaches to treat cancer

Novel HDAC/DNMT twin inhibitors interfere with angiogenesis

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent antiangiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, very little work has been done to understand the effect of this combination on normal and tumoral angiogenesis. We have designed and tested a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities in relevant models of angiogenesis in vitro (endothelial cells, pericytes and the 3D aortic ring assay) and in vivo (the chick chorioallantoic membrane assay). We have identified a lead compound having quantifiable antiangiogenic effect without cytotoxicity associated with increased global acetylation and decreased DNA methylation levels. This compound is presently used to develop effective approaches to treat cancer by modulating the process of angiogenesis

N-Hydroxy-6-(5-Nitro- Naphtalimide)-Hexanamide Inhibits Lysine Deacetylation, Mitigates Angiogenesis and Reduces Tumor Growth

peer reviewedIn this report, we present a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human umbilical vein endothelial cells (HUVEC), 3D aortic ring assay) and in vivo (chick chorioallantoic membrane (CAM), Zebrafish). Transcriptomic profiling reveals a set of ES8 specific genes that are not affected by the prototypical HDACi suberoylanilide hydroxamic acid (SAHA). Finally, ES8 also reduced tumor growth in mouse models of small cell lung cancer. Availability of a novel compound not centered exclusively on inhibition of angiogenic factors and inducing a characteristic transcription profile may be of interest to overcome resistance to currently used chemotherapies