Acute myeloid leukemia-targeted toxin activates both apoptotic and necroptotic death mechanisms

• Published in: PloS one 2008-12, Vol.3 (12), p.e3909-e3909
• Main Authors: Horita, Henrick, Frankel, Arthur E, Thorburn, Andrew
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Cancer; Caspase; Cell activation; Cell Biology/Cellular Death and Stress Responses; Cell death; Cell Line, Tumor; Cytokines; Cytotoxicity; Diphtheria; Diphtheria toxin; Diphtheria Toxin - pharmacology; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Granulocytes; Humans; Imidazoles - pharmacology; Immunotoxins - pharmacology; Indoles - pharmacology; Investigations; Kinases; Leukemia; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - pathology; Ligands; Myeloid leukemia; Necroptosis; Necrosis; Oncology; Oncology/Hematological Malignancies; Protein biosynthesis; Protein Biosynthesis - drug effects; Protein synthesis; Proteins; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Recombinant Fusion Proteins - pharmacology; Signal transduction; Toxins; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0003909

Acute myelogenous leukemia (AML) is the second most common leukemia with approximately 13,410 new cases and 8,990 deaths annually in the United States. A novel fusion toxin treatment, diphtheria toxin GM-CSF (DT-GMCSF) has been shown to selectively eliminate leukemic repopulating cells that are critical for the formation of AML. We previously showed that DT-GMCSF treatment of U937 cells, an AML cell line, causes activation of caspases and the induction of apoptosis. In this study we further investigate the mechanisms of cell death induced by DT-GMCSF and show that, in addition to the activation of caspase-dependent apoptosis, DT-GMCSF also kills AML cells by simultaneously activating caspase-independent necroptosis. These mechanisms depend on the ability of the targeted toxin to inhibit protein synthesis, and are not affected by the receptor that is targeted or the mechanism through which protein synthesis is blocked. We conclude that fusion toxin proteins may be effective for treating AML cells whether or not they are defective in apoptosis.