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Acute Leukemias

The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair

Leukemia volume 23, pages 2265–2274 (2009)Cite this article

Abstract

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 (IC50<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.

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Acknowledgements

This work was supported by a grant from the Ministry of Science and Innovation of Spain (BFU2006-01813/BMC and RD06/0020/0041). The CIC receives support from the European Community through the regional development funding program (FEDER). PM was supported by the FIS-FEDER through projects to JSM, and a Spanish Myeloma Network Program (G03/136). EMO was supported by the ‘Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I)’ and by ‘Instituto de Salud Carlos III-Fondo de Investigación Sanitaria’ with reference number 400001. MG was supported by the ‘Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I)’ and by ‘Instituto de Salud Carlos III-Fondo de Investigación Sanitaria’ with expedient number 05/0279. PA is an employee of Novartis Pharmaceuticals. This work was supported by the ‘Acción Transversal del Cáncer’ project, through an agreement between Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation, and the Cancer Research Foundation of Salamanca University. Our group also receives support from the Junta de Castilla y Léon through ‘Ayudas destinadas a financiar programas de actividad investigadora a realizar por grupos de investigación de excelencia de Castilla y León’.

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Authors and Affiliations

  1. Department of Hematology, Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain

    P Maiso, E M Ocio, M Garayoa, A Pandiella & J F San-Miguel

  2. Department of Hematology, Hospital Universitario de Salamanca, Salamanca, Spain

    E Colado, E M Ocio, J Martín & J F San-Miguel

  3. Novartis Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA

    P Atadja

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  1. P Maiso
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Correspondence to P Maiso.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Maiso, P., Colado, E., Ocio, E. et al. The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair. Leukemia 23, 2265–2274 (2009). https://doi.org/10.1038/leu.2009.182

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