Targeting aml through dr4 with a novel variant of rhtrail
Szegezdi, Eva Reis, Carlos R. Sloot, Almer M. van der Natoni, Alessandro O’Reilly, Aoife Reeve, Janice Cool, Robbert H. O’Dwyer, Michael Knapper, Steven Serrano, Luis
Szegezdi, Eva
Reis, Carlos R.
Sloot, Almer M. van der
Natoni, Alessandro
O’Reilly, Aoife
Reeve, Janice
Cool, Robbert H.
O’Dwyer, Michael
Knapper, Steven
Serrano, Luis
Publication Date
2011-09-26
Keywords
apoptosis, death receptor 4 (dr4), dr5, tumour necrosis factor-related apoptosis-inducing ligand (trail), acute myelogenous leukaemia (aml), receptor-selective trail variant, primary aml blast, apoptosis-inducing ligand, acute myeloid-leukemia, receptor-selective mutants, trail-induced apoptosis, factor-kappa-b, bcl-x-l, cell-lines, decoy receptors, down-regulation, cancer-cells
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Article
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Citation
Szegezdi, Eva; Reis, Carlos R. Sloot, Almer M. van der; Natoni, Alessandro; O’Reilly, Aoife; Reeve, Janice; Cool, Robbert H.; O’Dwyer, Michael; Knapper, Steven; Serrano, Luis; Quax, Wim J.; Samali, Afshin (2011). Targeting aml through dr4 with a novel variant of rhtrail. Journal of Cellular and Molecular Medicine 15 (10), 2216-2231
Abstract
Despite progress in the treatment of acute myelogenous leukaemia (AML) the outcome often remains poor. Tumour necrosis factor related apoptosis-inducing ligand (TRAIL) is a promising therapeutic agent in many different types of tumours, but AML cells are relatively insensitive to TRAIL-induced apoptosis. Here we show that TRAIL-induced apoptosis in AML cells is predominantly mediated by death receptor 4 (DR4) and not DR5. Therefore, we constructed a variant of TRAIL (rhTRAIL-C3) that is a strong inducer of DR4-mediated apoptosis. TRAIL-C3 demonstrated much stronger pro-apoptotic activity than wild-type (WT) TRAIL in a panel of AML cell lines as well as in primary AML blasts. The higher pro-apoptotic potential was further enhanced when the TRAIL mutant was used in combination with BMS-345541, a selective inhibitor of inhibitor-kappa B kinases. It illustrates that combination of this TRAIL variant with chemotherapeutics or other targeted agents can kill AML with high efficacy. This may represent a major advantage over the currently used therapies that have serious toxic side effects. The high efficacy of rhTRAIL-C3 containing therapies may enable the use of lower drug doses to reduce the toxic side effects and improve patient outcome. Our findings suggest that the rational design of TRAIL variants that target DR4 potentiate the death-inducing activity of TRAIL and offer a novel therapeutic strategy for the treatment of AML.
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Publisher
Wiley-Blackwell
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Attribution-NonCommercial-NoDerivs 3.0 Ireland