title: Bortezomib and TRAIL: a perfect match for apoptotic elimination of tumour cells?
abstract: 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-κB 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.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: L H A M
authors.initials: LH
authors.lastname: de Wilt
authors.forename: J
authors.initials: J
authors.lastname: Kroon
authors.forename: G
authors.initials: G
authors.lastname: Jansen
authors.forename: S
authors.initials: S
authors.lastname: de Jong
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
authors.forename: F A E
authors.initials: FA
authors.lastname: Kruyt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; D000069286:Bortezomib