title: Novel valproic acid derivatives with potent differentiation-inducing activity in myeloid leukemia cells.
abstract: The anti-epileptic drug valproic acid harbors anti-tumoral activity in solid and leukemic tumor cell models and is currently evaluated in clinical trials. However, the plasma trough concentrations obtained in patients by common anti-epileptic dose regimens are below concentrations required for exerting anti-tumor effects in vitro. Here, we describe the identification of three novel valproic acid derivatives with superior differentiation-inducing and anti-proliferative activities in K562 bcr/abl-positive chronic myeloid leukemia cells and HL60 promyelocytic leukemia cells at achievable therapeutic VPA concentrations. These compounds reveal potent inhibition of histone deacetylase activity, induction of p21Cip/Waf expression as well as low toxicity on CD34+ bone marrow cells.
authors.affiliation: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hedwig
authors.initials: H
authors.lastname: Deubzer
authors.forename: Barbara
authors.initials: B
authors.lastname: Busche
authors.forename: Gabi
authors.initials: G
authors.lastname: Rönndahl
authors.forename: Daniel
authors.initials: D
authors.lastname: Eikel
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
authors.forename: Sandra
authors.initials: S
authors.lastname: Schulze
authors.forename: Heinz
authors.initials: H
authors.lastname: Nau
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
mesh_terms: D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D018952:Antigens, CD34; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006655:Histone Deacetylases / Q000096:biosynthesis; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000927:Anticonvulsants; D018952:Antigens, CD34; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D014635:Valproic Acid; D016044:Fusion Proteins, bcr-abl; D006655:Histone Deacetylases