title: 4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide - A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation.
abstract: Histone deacetylases (HDAC) which play a crucial role in cancer cell proliferation are promising drug targets. However, HDAC inhibitors (HDACi) modelled on natural hydroxamic acids such as trichostatin A frequently lead to resistance or even an increased agressiveness of tumours. As a workaround we developed 4-(1-ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide (etacrox), a hydroxamic acid that combines HDAC inhibition with synergistic effects of the 4,5-diarylimidazole residue. Etacrox proved highly cytotoxic against a panel of metastatic and resistant cancer cell lines while showing greater specificity for cancer over non-malignant cells when compared to the approved HDACi vorinostat. Like the latter, etacrox and the closely related imidazoles bimacroxam and animacroxam acted as pan-HDACi yet showed some specificity for HDAC6. Akt signalling and interference with nuclear beta-catenin localisation were elicited by etacrox at lower concentrations when compared to vorinostat. Moreover, etacrox disrupted the microtubule and focal adhesion dynamics of cancer cells and inhibited the proteolytic activity of prometastatic and proangiogenic matrix metalloproteinases. As a consequence, etacrox acted strongly antimigratory and antiinvasive against various cancer cell lines in three-dimensional transwell invasion assays and also antiangiogenic in vivo with respect to blood vessel formation in the chorioallantoic membrane assay. These pleiotropic effects and its water-solubility and tolerance by mice render etacrox a promising new HDACi candidate.
authors.affiliation: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, Germany. Electronic address: katharina.mahal@uni-bayreuth.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mahal
authors.affiliation: Department of Genetics, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, Germany. Electronic address: philip.kahlen@uni-bayreuth.de.
authors.forename: Philip
authors.initials: P
authors.lastname: Kahlen
authors.affiliation: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, Germany. Electronic address: bernhard.biersack@yahoo.com.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Biersack
authors.affiliation: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, Germany. Electronic address: rainer.schobert@uni-bayreuth.de.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology*; D003599:Cytoskeleton / Q000473:pathology; D022001:Focal Adhesions / Q000187:drug effects / Q000473:pathology; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077337:Vorinostat; D051176:beta Catenin / Q000037:antagonists & inhibitors
chemical_list: C000602310:4-(1-ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide; D000970:Antineoplastic Agents; D002934:Cinnamates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007093:Imidazoles; D051176:beta Catenin; D000077337:Vorinostat; D051057:Proto-Oncogene Proteins c-akt; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C110550:HDAC1 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Antimetastatic activity; Histone deacetylase inhibitors; Hydroxamic acids; Imidazoles; Microtubule acetylation; Transwell migration assay