ABSTRACT
Dissymmetric cross metathesis of alkenes as a convergent and general synthetic strategy allowed for the preparation of a new small series of human histone deacetylases (HDAC) inhibitors. Alkenes bearing Boc-protected hydroxamic acid and benzamide and trityl-protected thiols were used to provide the zinc binding groups and were reacted with alkenes bearing aromatic cap groups. One compound was identified as a selective HDAC6 inhibitor lead. Additional biological evaluation in cancer cell lines demonstrated its ability to stimulate the expression of the epithelial marker E-cadherin and tumor suppressor genes like SEMA3F and p21, suggesting a potential use of this compound for lung cancer treatment. Molecular docking on all 11 HDAC isoforms was used to rationalize the observed biological results.
ABSTRACT
Small well-defined spherical gold nanoparticles were synthesized by a simple non-physical method based on a mixture of gold salt, tetraethylene oxide and water, free of any additional reducing chemical agent or physical method. The ratio of tetraethylene oxide to water was optimized to achieve a fast synthesis within 30 min. Transmission electron microscopy images showed well dispersed gold nanospheres with a size ranging from 10 to 15 nm. XPS was used to confirm the oxidation state of gold nanoparticles and the oxidation products from tetraethylene oxide after the reaction. This new protocol performed in sustainable and biocompatible conditions is complementary to the current methods used to synthesize gold nanospheres. In order to use these particles in biological samples, we correlated the atomic absorption with the colorimetric concentration of nanospheres in solution. After 24 h of incubation of cancer or neuronal cell lines with these nanoparticles, transmission electron microscopy images showed similar cellular uptake in both cell lines, especially in cytoplasmic vesicular structures.
Subject(s)
Gold , Metal Nanoparticles , Gold Compounds , Oxides , WaterABSTRACT
BACKGROUND: The epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment. This process involves epigenetic reprogramming for gene expression. We explored global histone modifications during TGF-ß1-induced EMT in two non-small cell lung cancer (NSCLC) cell lines and tested different epigenetic treatment to modulate or partially reverse EMT. RESULTS: Loss of classical epithelial markers and gain of mesenchymal markers were verified in A549 and H358 cell lines during TGF-ß1-induced EMT. In addition, we noticed increased expression of the axonal guidance protein semaphorin 3C (SEMA3C) and PD-L1 (programmed death-ligand 1) involved in the inhibition of the immune system, suggesting that both SEMA3C and PD-L1 could be the new markers of TGF-ß1-induced EMT. H3K79me3 and H2BK120me1 were decreased in A549 and H358 cell lines after a 48-h TGF-ß1 treatment, as well as H2BK120ac in A549 cells. However, decreased H3K79me3 was not associated with expression of the histone methyltransferase DOT1L. Furthermore, H3K79me3 was decreased in tumors compared in normal tissues and not associated with cell proliferation. Associations of histone deacetylase inhibitor (SAHA) with DOT1L inhibitors (EPZ5676 or SGC0946) or BET bromodomain inhibitor (PFI-1) were efficient to partially reverse TGF-ß1 effects by decreasing expression of PD-L1, SEMA3C, and its receptor neuropilin-2 (NRP2) and by increasing epithelial markers such as E-cadherin. CONCLUSION: Histone methylation was modified during EMT, and combination of epigenetic compounds with conventional or targeted chemotherapy might contribute to reduce metastasis and to enhance clinical responses.
Subject(s)
Epithelial-Mesenchymal Transition/drug effects , Histones/metabolism , Lung Neoplasms/metabolism , Transforming Growth Factor beta/pharmacology , A549 Cells , Benzimidazoles/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation , Epigenesis, Genetic/drug effects , Gene Regulatory Networks/drug effects , Histone Deacetylase Inhibitors/pharmacology , Humans , MethylationABSTRACT
Data of this study showed that alphaD-alphaE helices and the conserved interdomain linker are two interfaces essential not only for the self-association but also for the functional properties of rat HSC70. Self-association which is a conserved property of HSP70 seems to be important for the activity of these proteins.
