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 a...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2006-06, Vol.66 (11), p.5781-5789
Main Authors: MAISO, Patricia, CARVAJAL-VERGARA, Xonia, OCIO, Enrique M, LOPEZ-PEREZ, Ricardo, MATEO, Gema, GUTIDRREZ, Norma, ATADJA, Peter, PANDIELLA, Atanasio, SAN MIGUEL, Jesus F
Format: Article
Language:English
Subjects:
Acetylation - drug effects
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis - drug effects
bcl-X Protein - biosynthesis
Biological and medical sciences
Boronic Acids - administration & dosage
Boronic Acids - pharmacology
Bortezomib
Cell Cycle - drug effects
Cell Line, Tumor
Dexamethasone - administration & dosage
Dexamethasone - pharmacology
Drug Resistance, Neoplasm
Drug Synergism
Hematologic and hematopoietic diseases
Histone Deacetylase Inhibitors
Histone Deacetylases - metabolism
Humans
Hydroxamic Acids - administration & dosage
Hydroxamic Acids - pharmacology
Immunodeficiencies. Immunoglobulinopathies
Immunoglobulinopathies
Immunopathology
Indoles
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
Melphalan - administration & dosage
Melphalan - pharmacology
Multiple Myeloma - drug therapy
Multiple Myeloma - enzymology
Multiple Myeloma - pathology
Pharmacology. Drug treatments
Pyrazines - administration & dosage
Pyrazines - pharmacology
Tumors
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-05-4186