Abstract
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell death with minimal damage to normal cells; however, some cancer cells are resistant to TRAIL. TRAIL resistance may be overcome by agonistic antibodies to TRAIL receptors. In this study, we report the toxic effects of a novel recombinant agonistic human anti–TRAIL receptor 1 (DR4) monoclonal antibody Fab fragment, DR4-4, on various TRAIL-resistant and -sensitive cancer cell lines. The mechanisms of DR4-4 Fab–induced cell death in a human T cell leukemia cell line (Jurkat) were investigated using cell viability testing, immunoblotting, immunoassays, flow cytometry, and morphological observation. DR4-4 Fab–induced caspase-independent necrosis was observed to occur in Jurkat cells in association with p38 mitogen-activated protein kinase activation, cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein degradation, decreased mitochondrial membrane potential, and increased mitochondrial reactive oxygen species production. Increased cytotoxic effects of DR4-4 Fab were observed in combination with TRAIL or γ-irradiation. Our results indicate that the novel DR4-4 Fab might overcome TRAIL-resistance and induce death in leukemia cells via cellular mechanisms different from those activated by TRAIL. DR4-4 Fab may have application as a potential therapeutic antibody fragment in single or combination therapy for cancer.
Highlights
Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL), known as Apo2 ligand, exists in either a membrane-bound or soluble form
We demonstrated the toxic activity of a novel agonistic anti-DR4 Fab in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant and mildly TRAIL-resistant cells, including leukemia and lymphoma cell lines (Jurkat, THP-1, Molt-4, and U937), as well as TRAIL-sensitive leukemia cells (HL60), but not in normal human cells
The results indicate that DR4-4 Fab can overcome TRAIL resistance in some cancer cells
Summary
Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL), known as Apo ligand, exists in either a membrane-bound or soluble form. STRAIL can bind both TRAIL DRs and decoy receptors (DcR1 and DcR2), which lack death domains and are expressed in normal cells at high levels, leading to the inhibition of cell death [10]. Several intracellular signaling molecules, including cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP), inhibitor of apoptosis proteins, p38 mitogen-activated protein kinase (p38 MAPK), and nuclear factor (NF)-κB, have been implicated in the regulation of TRAIL resistance in tumor cells [11,12,13,14,15]. The binding of sTRAIL to DRs can induce various types of cell death in tumor cells, including apoptosis [16], autophagy [17,18], and necrosis [19,20]. The effective application of TRAIL as a cancer therapeutic agent will depend on its rational combination with drugs overcoming TRAIL resistance
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