Antineoplastic activity of ouabain and pyrithione zinc in acute myeloid leukemia

• DOI: 10.1038/onc.2011.521
• Publication Date: 2011-11-21T14:29:14Z
• Authors: M Tailler; L Senovilla; E Lainey; S Thépot; D Métivier; M Sébert; V Baud; K Billot; P Fenaux; L Galluzzi; S Boehrer; G Kroemer; O Kepp
• Keywords: 0301 basic medicine; Pyridines; Mice, Nude; Antineoplastic Agents; Apoptosis; Xenograft Model Antitumor Assays; Chromatin; 3. Good health; Leukemia, Myeloid, Acute; Mice; 03 medical and health sciences; Treatment Outcome; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Mitochondrial Membranes; Organometallic Compounds; Animals; Humans; Granulocyte Precursor Cells; Ouabain; Signal Transduction

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.