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  • Title: Apoptosis by leukemia cell-targeted diphtheria toxin occurs via receptor-independent activation of Fas-associated death domain protein.
    Author: Thorburn J, Frankel AE, Thorburn A.
    Journal: Clin Cancer Res; 2003 Feb; 9(2):861-5. PubMed ID: 12576460.
    Abstract:
    PURPOSE: We examined the mechanism of action of a targeted fusion toxin consisting of diphtheria toxin fused to granulocyte macrophage colony stimulating factor (GMCSF) (DT(388)-GMCSF), which was designed to selectively kill acute myeloid leukemia cells. EXPERIMENTAL DESIGN AND RESULTS: U937 cells treated with DT(388)-GMCSF underwent apoptosis as shown by chromatin degradation and cellular and nuclear fragmentation. This apoptosis was prevented by a general caspase inhibitor. DT(388)-GMCSF treatment resulted in activation of the initiator caspases 8 and 9 and effector caspases. A selective caspase 8 inhibitor prevented activation of caspase 9, whereas a selective caspase 9 inhibitor did not prevent activation of caspase 8, indicating that caspase 8 activation is the proximal event in DT(388)-GMCSF-induced apoptosis. Caspase 8 was activated through a Fas-associated death domain protein (FADD)-dependent mechanism as demonstrated by inhibition of DT(388)-GMCSF-induced apoptosis on expression of a dominant negative FADD molecule. However, unlike most FADD-dependent apoptosis, this pathway may not involve death receptors, including Fas, tumor necrosis factor receptor 1, or tumor necrosis factor-related apoptosis-inducing ligand receptors, because inhibitors of the receptors did not prevent DT(388)-GMCSF-induced apoptosis. CONCLUSIONS: These data indicate that targeted toxins induce apoptosis by activating components of the death receptor pathway in a receptor-independent manner.
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