Multitargeting epi-epi drugs for multidrug reistance

Epigenetic therapy is now a clinical reality with eight approved drugs that target DNA methyltransferases, histone deacetylases (HDACs) and lysine methyltransferases. A further recent development is the concept of epigenetic multitargeting through the rational design of novel agents that combine the inhibition of an epigenetic pathway with a second non-epigenetic target and five such compounds have advanced to clinical development. We are investigating the even newer concept of „epi-epi‟ drugs that inhibit two separate epigenetic pathways. Such dual targeting agents have the potential to achieve higher efficacy against proliferating cancer cells while reducing tunor resistance. In this presentation, we report a selective dual histone deacetylase and demethylase inhibitor with an IC50 LSD1 respectively. The compound was biologically profiled together with control compounds that were either single inhibitors or inactive against either enzyme. The dua inhibitor was active against a panel of leukemia cell lines at a micromolar level and induced apoptosis. Target engagement asays such as CETSA were employed to confirm the inhibition of HDAC6 and LSD1 in cells. Further experiments were carried out to identify synergistic effects with clinically approved agents and promising results were observed with doxorubicin

A preliminary proteomic evaluation of smooth muscle cells in thoracic aortic aneurysms

WOS: 000332944300010Aortic aneurysm is characterized as localized degeneration of the aorta leading to advanced weakening and widening of the vessel. While the exact mechanisms have yet to be determined, current studies indicate that the degradation of extracellular matrix (ECM) proteins and apoptosis of vascular smooth muscle cells (SMCs) may result in extendibility, dilation, and rupture of the vessel. Within the aortic wall, SMCs are implicated as key components involved in disease development, as numerous molecular changes have been reported to occur. Most current studies involve either investigation of proteins constituting a group or pathway in SMCs, or analyses of the whole aortic tissue. In order to determine which proteins are important in the development of thoracic aortic aneurysms (TAAs), we performed comparative proteomic analyses using cultured SMCs from TAAs versus controls. Label-free nano LC-MS/MS analysis of cell extracts resulted in the identification of 256 proteins, 26 of which were differentially regulated by >= 1.4-fold. Both previously described and new proteins were identified that were involved in oxidative stress, ECM formation, energy metabolism, or the 14-3-3 pathway. Among these, differential expression of SerpinH1, a protease inhibitor for collagenases, was further verified via immunoblotting. Here we have attempted to shed light on the cellular mechanisms of TAAs.European Union [200647]This work was supported by the European Union 7th Framework Programme Project entitled Fighting Aneurysmal Disease (FAD), Health-2007-2.4.2-2, Grant Agreement No. 200647, and internal funding through TUBITAK.Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (TÜBİTAK

A preliminary proteomic evaluation of smooth muscle cells in thoracic aortic aneurysms

WOS: 000332944300010Aortic aneurysm is characterized as localized degeneration of the aorta leading to advanced weakening and widening of the vessel. While the exact mechanisms have yet to be determined, current studies indicate that the degradation of extracellular matrix (ECM) proteins and apoptosis of vascular smooth muscle cells (SMCs) may result in extendibility, dilation, and rupture of the vessel. Within the aortic wall, SMCs are implicated as key components involved in disease development, as numerous molecular changes have been reported to occur. Most current studies involve either investigation of proteins constituting a group or pathway in SMCs, or analyses of the whole aortic tissue. In order to determine which proteins are important in the development of thoracic aortic aneurysms (TAAs), we performed comparative proteomic analyses using cultured SMCs from TAAs versus controls. Label-free nano LC-MS/MS analysis of cell extracts resulted in the identification of 256 proteins, 26 of which were differentially regulated by >= 1.4-fold. Both previously described and new proteins were identified that were involved in oxidative stress, ECM formation, energy metabolism, or the 14-3-3 pathway. Among these, differential expression of SerpinH1, a protease inhibitor for collagenases, was further verified via immunoblotting. Here we have attempted to shed light on the cellular mechanisms of TAAs.European Union [200647]This work was supported by the European Union 7th Framework Programme Project entitled Fighting Aneurysmal Disease (FAD), Health-2007-2.4.2-2, Grant Agreement No. 200647, and internal funding through TUBITAK.Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (TÜBİTAK