Targeting AML through DR4 with a novel variant of rhTRAIL

Eva Szegezdi, Carlos R. Reis, Almer M. van der Sloot, Alessandro Natoni, Aoife O'Reilly, Janice Reeve, Robbert H. Cool, Michael O'Dwyer, Steven Knapper, Luis Serrano, Wim J. Quax, Afshin Samali*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

19 Citaten (Scopus)
180 Downloads (Pure)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)2216-2231
Aantal pagina's16
TijdschriftJournal of cellular and molecular medicine
Volume15
Nummer van het tijdschrift10
DOI's
StatusPublished - okt-2011

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