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Bortezomib and TRAIL:A perfect match for apoptotic elimination of tumour cells?

By L. H. A. M. de Wilt, J. Kroon, G. Jansen, S. de Jong, G. J. Peters and F. A. E. Kruyt

Abstract

<p>Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively eradicates tumour cells via specific cell surface receptors and is intensively explored for use as a novel anticancer approach. To enhance the efficacy of TRAIL receptor agonists the proteasome inhibitor bortezomib is one of the most potent sensitizers. Here we review the main mechanisms underlying bortezomib-dependent TRAIL sensitization, including stimulation of apoptosis by increasing expression of TRAIL receptors, reduction of cFLIP and enhancement of caspase 8 activation, and modulation of Bcl-2 family proteins and inhibitor of apoptosis proteins (IAPs). Concomitantly, pro-survival signals are suppressed such as elicited by NF-kappa B and Akt. The different preclinical tumour models explored with this combination, including primary tumour (stem) cells, stroma co-culture and mice models, are discussed, as well as possible hurdles for clinical activity. Collectively, anticipating a solid rationale for bortezomib-TRAIL combination and very promising preclinical results, its clinical activity remains to be demonstrated. (c) 2012 Elsevier Ireland Ltd. All rights reserved.</p>

Topics: TRAIL, Bortezomib; Proteasome inhibitor; Resistance; Primary cells; Cancer stem cells; Ubiquitin; PROTEASOME INHIBITOR BORTEZOMIB; NF-KAPPA-B; LIGAND-INDUCED APOPTOSIS; PROSTATE-CANCER CELLS; RECEPTOR-MEDIATED APOPTOSIS; OVERCOMES DRUG-RESISTANCE; MULTIPLE-MYELO
Year: 2013
DOI identifier: 10.1016/j.critrevonc.2012.08.001
OAI identifier: oai:pure.rug.nl:publications/a83a578b-7b9d-4f0a-ad70-e32f5f77e584
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