The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair.
Acute myeloid leukemia (AML) is a clonal disorder characterized by the accumulation of myeloid blasts in the bone marrow. Here, we report the effects of the novel histone deacetylase inhibitor panobinostat (LBH589) in combination with doxorubicin on AML cells. Panobinostat exhibited potent anti-AML activity in all AML cell lines tested and in primary AML cells from patients (IC(50)<20 nM). In addition, panobinostat potentiated the action of several standard-of-care anti-AML compounds, particularly, doxorubicin. The molecular effects induced by panobinostat and doxorubicin treatment were investigated by analyzing gene expression, cell cycle, apoptosis and signaling pathways. Analyses of gene expression profiles identified 588 genes whose expression was exclusively affected by the combination of panobinostat and doxorubicin. The combination induced AML cell death by an increase in the mitochondrial outer membrane permeability and release of cytochrome c from the mitochondria, resulting in caspase-dependent apoptosis and accompanied by the upregulation of Bax, Bak and, particularly, Bad. The drug combination provoked a strong activation of a DNA damage response, indicating that this combination may trigger cell death by a mechanism that induced DNA double-strand breaks. These data indicate that the combination of panobinostat and doxorubicin may be an effective therapy for the treatment of AML.
Maiso
P
P
Department of Hematology, Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Avda. Universidad de Coimbra s/n, Salamanca, Spain. p_maiso@hotmail.com
Colado
E
E
Ocio
E M
EM
Garayoa
M
M
Martín
J
J
Atadja
P
P
Pandiella
A
A
San-Miguel
J F
JF
D000903:Antibiotics, Antineoplastic; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008928:Mitochondria / Q000187:drug effects; D000077767:Panobinostat; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D004317:Doxorubicin; D000077767:Panobinostat