The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance.
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.
Maiso
Patricia
P
Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Cientificas, Universidad de Salamanca, Spain.
Carvajal-Vergara
Xonia
X
Ocio
Enrique M
EM
López-Pérez
Ricardo
R
Mateo
Gema
G
Gutiérrez
Norma
N
Atadja
Peter
P
Pandiella
Atanasio
A
San Miguel
Jesús F
JF
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
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