Alkoxyurea-based histone deacetylase inhibitors increase cisplatin potency in chemoresistant cancer cell lines
| Autor: | Finn K. Hansen, Christophe Romier, Linda Marek, Martin Marek, Manfred Jung, Christoph G. W. Gertzen, Johanna Senger, Katharina Stenzel, Viktoria Marquardt, Marc Remke, Thomas Kurz, Alexandra Hamacher, Holger Gohlke, Matthias U. Kassack |
|---|---|
| Přispěvatelé: | Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Histone Deacetylases/*metabolism Antineoplastic Agents Apoptosis Pharmacology Drug Screening Assays Cisplatin/chemistry/*pharmacology Histone Deacetylases Cell Line Dose-Response Relationship Cell Proliferation/drug effects 03 medical and health sciences Structure-Activity Relationship Antineoplastic Agents/chemistry/*pharmacology Cell Line Tumor Drug Discovery medicine Urea Structure–activity relationship Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Histone Deacetylase Inhibitors/chemical synthesis/chemistry/*pharmacology Cell Proliferation Cisplatin Tumor Dose-Response Relationship Drug Molecular Structure Cell growth Chemistry Apoptosis/drug effects HDAC8 Antitumor Squamous carcinoma Histone Deacetylase Inhibitors Molecular Docking Simulation 030104 developmental biology Cell culture Molecular Medicine Histone deacetylase Drug Screening Assays Antitumor Drug medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2017, 60 (13), pp.5334-5348. ⟨10.1021/acs.jmedchem.6b01538⟩ |
| ISSN: | 0022-2623 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.6b01538⟩ |
| Popis: | The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1g-i showed IC50 values in the low muM and sub-muM range. 1g-i revealed low nM IC50 values for HDAC6 with up to 15-fold preference over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of 1g-i significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1g-i interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR. |
| Databáze: | OpenAIRE |
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