title: The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance.
abstract: Multiple myeloma represents an incurable disease, for which development of new therapies is required. Here, we report the effect on myeloma cells of LBH589, a new hydroxamic acid-derived histone deacetylase inhibitor. LBH589 was a potent antimyeloma agent (IC(50) < 40 nmol/L) on both cell lines and fresh cells from multiple myeloma patients, including cells resistant to conventional chemotherapeutic agents. In addition, LBH589 potentiated the action of drugs, such as bortezomib, dexamethasone, or melphalan. Using gene array, quantitative PCR, and Western analyses, we observed that LBH589 affected a large number of genes involved in cell cycle and cell death pathways. LBH589 blocked cell cycle progression, and this was accompanied by p21, p53, and p57 up-regulation. LBH589 induced cell death through an increase in the mitochondrial outer membrane permeability. LBH589 favored apoptosome formation by inducing cytochrome c release, Apaf-1 up-regulation, and caspase-9 cleavage. In addition, LBH589 stimulated a caspase-independent pathway through the release of AIF from the mitochondria. LBH589 down-regulated Bcl-2 and particularly Bcl-X. Moreover, overexpression of Bcl-X in multiple myeloma cells prevented LBH589-induced cell death. All these data indicate that LBH589 could be a useful drug for the treatment of multiple myeloma patients.
authors.affiliation: Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Cientificas, Universidad de Salamanca, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.forename: Xonia
authors.initials: X
authors.lastname: Carvajal-Vergara
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
authors.forename: Ricardo
authors.initials: R
authors.lastname: López-Pérez
authors.forename: Gema
authors.initials: G
authors.lastname: Mateo
authors.forename: Norma
authors.initials: N
authors.lastname: Gutiérrez
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San Miguel
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D007211:Indoles; D008558:Melphalan / Q000008:administration & dosage / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000077767:Panobinostat; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D011719:Pyrazines; D051020:bcl-X Protein; D000069286:Bortezomib; D003907:Dexamethasone; D000077767:Panobinostat; D006655:Histone Deacetylases; D008558:Melphalan