title: Enantioselective apoptosis induction in histiocytic lymphoma cells and acute promyelocytic leukemia cells.
abstract: The aim of this study was to identify valproic acid (VPA) analogs with a broad spectrum of anti-cancer activities and an increased apoptosis-inducing potential compared with the parent VPA, which is enrolled as histone deacetylase (HDAC) inhibitor in a large number of clinical trials. We identified a chiral VPA derivative, (S)-2-pentyl-4-pentynoic acid, previously characterized as HDAC inhibitor that induced massive programmed cell death in a strongly enantioselective manner in U937 histiocytic lymphoma cells and NB4 acute promyelocytic leukemia cells. By performing fluorescence-activated cell sorting and Western blotting analyses, we established that enantiomer (S)-2-pentyl-4-pentynoic acid has higher apoptosis-inducing potential than VPA itself. The optic antipode (R)-2-pentyl-4-pentynoic acid and VPA caused under the same conditions only a weak growth inhibition without inducing cell differentiation and apoptosis. (S)-2-pentyl-4-pentynoic acid is more apoptogenic than VPA and displays enantioselective anti-cancer properties that warrant further research regarding the mechanistic basis of its activity and its potential use in cancer therapy.
authors.affiliation: Institute of Genetics and Molecular Biology of the Cell, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, Strasbourg, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Ivanova
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Pablo
authors.initials: P
authors.lastname: Steinberg
authors.forename: Heinz
authors.initials: H
authors.lastname: Nau
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013237:Stereoisomerism; D020298:U937 Cells; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C513636:pentyl-4-pentynoic acid; D014635:Valproic Acid