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  • Title: Bortezomib sensitizes non-Hodgkin's lymphoma cells to apoptosis induced by antibodies to tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors TRAIL-R1 and TRAIL-R2.
    Author: Smith MR, Jin F, Joshi I.
    Journal: Clin Cancer Res; 2007 Sep 15; 13(18 Pt 2):5528s-5534s. PubMed ID: 17875785.
    Abstract:
    Non-Hodgkin's lymphoma (NHL) is an increasingly common disease that, despite advances in antibody-targeted therapy, still requires novel therapeutic approaches. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates a major nonmitochondrial pathway for tumor cell killing through binding to a receptor family, some activating and some decoy. Agonistic antibodies to the receptors TRAIL-R1 and TRAIL-R2 can mimic many of the effects of TRAIL. We are investigating the effects of such agonistic antibodies, mapatumumab directed at TRAIL-R1 and lexatumumab directed at TRAIL-R2, on NHL cell lines. These antibodies induce apoptosis through caspase-8 but also activate BID to involve the mitochondrial pathway and activate caspase-9. In addition, we find signaling through both the nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways. Because the proteasome inhibitor bortezomib also affects these pathways, we have investigated the combination of TRAIL-R antibodies and bortezomib and show enhanced apoptosis and signaling as well as enhanced killing of NHL cells in a severe combined immunodeficient mouse/human NHL cell line xenograft system. The combination of bortezomib and TRAIL signaling warrants further investigation as a therapeutic regimen. Understanding the multiple intracellular pathways of TRAIL activation may lead to rationally designed therapeutic trials.
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