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

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.