Concepts in the use of TRAIL/Apo2L: an emerging biotherapy for myeloma andother neoplasias

TNF-related apoptosis inducing ligand/Apo2 ligand (TRAIL/Apo2L) is a member of the TNF superfamily of death ligands that selectively induces apoptosis in tumour cells of diverse origins. in this report, we have reviewed recen t studies examining TRAIL/Apo2L-induced apoptosis in multiple myeloma (MM), a B-cell malignancy which, in spite of its initial sensitivity to steroids , cytotoxic and high-dose chemotherapy, remains incurable. Recently, we dem onstrated that TRAILApo2L induces apoptosis of steroid- and chemotherapy-se nsitive and resistant MM cell lines. Moreover, TRAIL/Apo2L selectively indu ced apoptosis of patient MM tumour cells while sparing nonmalignant bone ma rrow and peripheral blood mononuclear cells. In addition, TRAIL/Apo2L inhib ited the growth of human plasmacytomas xenografted into mice. Importantly, TRAIL/Apo2L-induced apoptosis was unaffected by IL-6, a potent growth and s urvival factor for MM cells which, as we and others have previously shown, blocks various pro-apoptotic signals including Fas ligand, which like TRAIL /Apo2L is also a member of the TNF family of ligands. In view of the potent ial clinical application of TRAIL/Apo2L to the treatment of MM, we have att empted to discern intracellular mechanisms of action and resistance for TRA IL/Apo2L in MM, along with strategies to increase sensitivity and overcome resistance of MM cells to TRAIL/Apo2L. These studies demonstrated that doxo rubicin, an agent which is commonly used to treat MM patients, upregulated the expression of the DR5 death-signalling TRAIL receptor and synergistical ly enhanced the pro-apoptotic effect of TRAIL on MM cells. Moreover, NF-kap paB inhibitors such as SN50 (a cell permeable inhibitor of NF-kappaB nuclea r translocation) as well as the proteasome inhibitor PS-341, which is curre ntly in Phase II clinical trials, also enhanced the pro-apoptotic activity of TRAIL/Apo2L in MM cells. Lastly, TRAIL/Apo2L-induced apoptosis in MM cel ls was dependent on caspase-8 activation and inhibited by the caspase regul atory proteins FLIP and cIAP2. These studies provide a framework for the us e of TRAIL/Apo2L as a single agent or as part of combination therapy for th e treatment of MM.