Peer-Reviewed Journal Details
Mandatory Fields
Szegezdi, E,Reis, CR,van der Sloot, AM,Natoni, A,O'Reilly, A,Reeve, J,Cool, RH,O'Dwyer, M,Knapper, S,Serrano, L,Quax, WJ,Samali, A
Journal Of Cellular And Molecular Medicine
Targeting AML through DR4 with a novel variant of rhTRAIL
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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
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.
DOI 10.1111/j.1582-4934.2010.01211.x
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