2016
DOI: 10.1038/cdd.2015.174
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Onto better TRAILs for cancer treatment

Abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. By cross-linking TRAIL-Receptor (TRAIL-R) 1 or TRAIL-R2, also known as death receptors 4 and 5 (DR4 and DR5), TRAIL has the capability to induce apoptosis in a wide variety of tumor cells while sparing vital normal cells. The discovery of this unique property among TNF superfamily members laid the foundation for testing the clinical potential of TRAIL-R-targeti… Show more

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Cited by 277 publications
(287 citation statements)
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References 211 publications
(342 reference statements)
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“…The picture that emerges from the literature indicates that the membrane serves at least two functions: (i) it anchors the trimeric TNFSF ligands and increases their stability and bioavailability, and (ii) it provides a platform for the arrangement of multiple ligand trimers for simultaneous receptor activation and enhanced signaling. These findings have created renewed interest in the production of stable TNFSF ligand analogs with increased activity, longer half-life, and low immunogenicity (60,95). Future designs will need to incorporate the hexagonal model of activation to design more effective ligand analogs or to use stable trimeric ligands and receptor cross-linking antibody combination therapies.…”
Section: Resultsmentioning
confidence: 99%
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“…The picture that emerges from the literature indicates that the membrane serves at least two functions: (i) it anchors the trimeric TNFSF ligands and increases their stability and bioavailability, and (ii) it provides a platform for the arrangement of multiple ligand trimers for simultaneous receptor activation and enhanced signaling. These findings have created renewed interest in the production of stable TNFSF ligand analogs with increased activity, longer half-life, and low immunogenicity (60,95). Future designs will need to incorporate the hexagonal model of activation to design more effective ligand analogs or to use stable trimeric ligands and receptor cross-linking antibody combination therapies.…”
Section: Resultsmentioning
confidence: 99%
“…Because of its instability, hrTRAIL also has an unfavorable pharmacokinetic profile with a very short half-life of 3 to 5 min and elimination half-life of 20 min (50,59). To overcome these issues and to improve the cancer targeting potential of hrTRAIL, several different approaches are being pursued (60). These approaches fall into three major categories: (i) efforts to increase trimer stability, (ii) the passive targeting of hrTRAIL to cancer cells, and (iii) the active targeting of hrTRAIL to cancer cells (60).…”
Section: Tnfsf Ligands Are Essential For Tnfrsf Signaling-lessons Fromentioning
confidence: 99%
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“…38,40,41 However, it has become evident that first generation TRAIL receptor-agonists do not optimally exploit the unique apoptotic signaling characteristics of the various TRAIL receptors (reviewed in [42][43][44] ). Most notably, apoptotic signaling via TRAIL-R2, one of the two agonistic TRAIL receptors, is not efficiently achieved by soluble homotrimeric rhTRAIL, as TRAIL-R2 requires binding of membrane-bound TRAIL or secondarily cross-linked rhTRAIL.…”
Section: Discussionmentioning
confidence: 99%
“…[1][2][3][4][5] The binding triggers configurational changes in the receptor trimer and leads to formation of the deathinducing signaling complex (DISC). Depending on cellular context, extrinsic and/or intrinsic pathway of apoptosis is induced with an initial activation of caspase-8 and -10 at DISC and a subsequent activation of the effector caspases such as caspase -3 or -7.…”
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confidence: 99%