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Antineoplastic activity of ouabain and pyrithione zinc in acute myeloid leukemia

Oncogene volume 31, pages 3536–3546 (2012)Cite this article

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Abstract

Despite recent progress in the treatment of acute myeloid leukemia (AML), the prognosis of this rather heterogeneous disease remains poor and novel chemotherapeutics that specifically target leukemic cells must be developed. To address this need at the preclinical level, we implemented a high content imaging-based screen for the identification of small agents that induce AML cell death in vitro. Among a panel of 1040 Food and Drug Administration-approved agents, we identified pyrithione zinc (PZ) and ouabain (OUA) as potential antileukemic compounds. Both PZ and OUA efficiently induced cell death associated with apoptotic chromatin condensation and inhibition of nuclear factor-κB survival signaling, leading to reduced expression of antiapoptotic proteins, in several AML cell lines. PZ- and OUA-induced cell death was associated with the permeabilization of the outer mitochondrial membrane and led to the release of cytochrome c followed by caspase activation. Both PZ and OUA exerted significant anticancer effects in vivo, on human AML cells xenografts as well as ex vivo, on CD34+ (but not CD34−) malignant myeloblasts from AML patients. Altogether, our results suggest that PZ and OUA may exhibit antileukemic effects by inducing the apoptotic demise of AML cells.

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Acknowledgements

This work is supported by grants to GK from the Ligue Nationale contre le Cancer (Equipes labellisée), Agence Nationale pour la Recherche (ANR), European Commission (Active p53, Apo-Sys, ChemoRes, ApopTrain), Fondation pour la Recherche Médicale (FRM), Institut National du Cancer (INCa), Cancéropôle Ile-de-France, Fondation Bettencourt-Schueller and the LabEx Onco-Immunology; to VB from Agence Nationale pour la Recherche, Association pour la Recherche sur le Cancer, Belgian InterUniversity Attraction Pole and Université Paris Descartes. MT is supported by the Ligue Nationale contre le Cancer. LG is funded by Apo-Sys; KB is supported by Agence Nationale pour la Recherche.

Author contributions: MT, LS, EL, ST, DM, MS, VB, KB and OK performed the experiments; MT, LS LG and OK analyzed results and made the figures; PF, SB, LG, OK and GK designed the research and wrote the paper.

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Author notes

  1. G Kroemer and O Kepp: These authors share senior co-authorship.

Authors and Affiliations

  1. INSERM,

    M Tailler, L Senovilla, E Lainey, S Thépot, D Métivier, M Sébert, P Fenaux, L Galluzzi, S Boehrer, G Kroemer & O Kepp

  2. , U848, Villejuif, France

    M Tailler, L Senovilla, E Lainey, S Thépot, D Métivier, M Sébert, P Fenaux, L Galluzzi, S Boehrer, G Kroemer & O Kepp

  3. Institut Gustave Roussy, Villejuif, France

    M Tailler, L Senovilla, E Lainey, D Métivier, L Galluzzi & O Kepp

  4. Université, Paris Sud/Paris XI, Le Kremlin Bicêtre, France

    M Tailler, L Senovilla, E Lainey, S Thépot, D Métivier, M Sébert, P Fenaux, L Galluzzi, S Boehrer & O Kepp

  5. Service d’Hématologie Clinique, Hôpital Avicenne, AP-HP/Université Paris XIII, Bobigny, France

    S Thépot, M Sébert, P Fenaux & S Boehrer

  6. INSERM, U1016, Institut Cochin, Paris, France

    V Baud & K Billot

  7. CNRS, UMR8104, Paris, France

    V Baud & K Billot

  8. Université Paris Descartes, Paris, France

    V Baud, K Billot & G Kroemer

  9. Metabolomics Platform, Institut Gustave Roussy, Villejuif, France

    G Kroemer

  10. Centre de Recherche des Cordeliers, Paris, France

    G Kroemer

  11. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    G Kroemer

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  1. M Tailler
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  12. G Kroemer
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  13. O Kepp
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Correspondence to G Kroemer or O Kepp.

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Tailler, M., Senovilla, L., Lainey, E. et al. Antineoplastic activity of ouabain and pyrithione zinc in acute myeloid leukemia. Oncogene 31, 3536–3546 (2012). https://doi.org/10.1038/onc.2011.521

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