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dc.contributor.authorNatoni, Alessandroen
dc.contributor.authorSzegezdi, Evaen
dc.contributor.authorSamali, Afshinen
dc.date.accessioned2011-05-23T10:26:32Zen
dc.date.available2011-05-23T10:26:32Zen
dc.date.issued2010en
dc.identifier.citationC R Reis,C,R.,van der Sloot,A. M., Natoni,A.,Szegezdi,E., Setroikromo,R.,Meijer,M.,Sjollema, K.,Stricher, F.,Cool,R.H.,Samali, A., Serrano,L. & Quax, W. J. (2010) Rapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing TRAIL variants. Cell Death and Disease 1, e83; doi:10.1038/cddis.2010.61en
dc.identifier.urihttp://hdl.handle.net/10379/1930en
dc.description.abstractThe tumour necrosis factor family member TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in a variety of cancer cells through the activation of death receptors 4 (DR4) and 5 (DR5) and is considered a promising anticancer therapeutic agent. As apoptosis seems to occur primarily via only one of the two death receptors in many cancer cells, the introduction of DR selectivity is thought to create more potent TRAIL agonists with superior therapeutic properties. By use of a computer-aided structure-based design followed by rational combination of mutations, we obtained variants that signal exclusively via DR4. Besides an enhanced selectivity, these TRAIL-DR4 agonists show superior affinity to DR4, and a high apoptosis-inducing activity against several TRAIL-sensitive and -resistant cancer cell lines in vitro. Intriguingly, combined treatment of the DR4-selective variant and a DR5-selective TRAIL variant in cancer cell lines signalling by both death receptors leads to a significant increase in activity when compared with wild-type rhTRAIL or each single rhTRAIL variant. Our results suggest that TRAIL induced apoptosis via high-affinity and rapid-selective homotrimerization of each DR represent an important step towards an efficient cancer treatment.en
dc.formatapplication/pdfen
dc.language.isoenen
dc.publisherMacmillan Publishers Limiteden
dc.subjectApoptosisen
dc.subjectTRAILen
dc.subjectDeath receptorsen
dc.subjectHomotrimerizationen
dc.subjectBiochemistryen
dc.titleRapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing TRAIL variantsen
dc.typeArticleen
dc.local.publishedsourcehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035906/en
dc.description.peer-reviewedpeer-revieweden
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