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.
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.
Smith
Mitchell R
MR
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. M_smith@fccc.edu
Jin
Fang
F
Joshi
Indira
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D053453:Caspase 9 / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects; D011719:Pyrazines / Q000627:therapeutic use*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505640:Tnfrsf10b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; C510234:lexatumumab; D053453:Caspase 9; C507357:mapatumumab