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


RESULTS
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.


CONCLUSIONS
We conclude that fusion toxin proteins may be effective for treating AML cells whether or not they are defective in apoptosis.
Horita
Henrick
H
Department of Pharmacology, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
Frankel
Arthur E
AE
Thorburn
Andrew
A
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000922:Immunotoxins / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000473:pathology*; D009336:Necrosis; D014176:Protein Biosynthesis / Q000187:drug effects; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D004167:Diphtheria Toxin; D007093:Imidazoles; D000922:Immunotoxins; D007211:Indoles; D011993:Recombinant Fusion Proteins; C507699:necrostatin-1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053422:Receptor-Interacting Protein Serine-Threonine Kinases