RT Journal Article
SR Electronic
T1 The Histone Deacetylase Inhibitor LBH589 Is a Potent Antimyeloma Agent that Overcomes Drug Resistance
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 5781
OP 5789
DO 10.1158/0008-5472.CAN-05-4186
VO 66
IS 11
A1 Maiso, Patricia
A1 Carvajal-Vergara, Xonia
A1 Ocio, Enrique M.
A1 López-Pérez, Ricardo
A1 Mateo, Gema
A1 Gutiérrez, Norma
A1 Atadja, Peter
A1 Pandiella, Atanasio
A1 San Miguel, Jesús F.
YR 2006
UL http://cancerres.aacrjournals.org/content/66/11/5781.abstract
AB 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 (IC50 < 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. (Cancer Res 2006; 66(11): 5781-9) ©2006 American Association for Cancer Research.