title: Decreased affinity of recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) D269H/E195R to osteoprotegerin (OPG) overcomes TRAIL resistance mediated by the bone microenvironment.
abstract: The bone marrow microenvironment provides important signals for the survival and proliferation of hematopoietic and malignant cells. In multiple myeloma, plasma cells are surrounded by stromal cells including osteoblasts. These stromal cells protect multiple myeloma cells from apoptosis induced by chemotherapeutic agents. Osteoprotegerin (OPG), a soluble receptor of the cytokine TNF-related apoptosis-inducing ligand (TRAIL), is secreted by osteoblasts and has been implicated in the prevention of cell death induced by TRAIL in malignant cells. Previously, we have designed death receptor-specific TRAIL variants that induce apoptosis exclusively via one of its death receptors. Here, we have studied in detail the interaction between recombinant human (rhTRAIL) variants and OPG. We show that a DR5-specific variant (rhTRAIL D269H/E195R) displays a significantly decreased affinity to OPG. Furthermore, this rhTRAIL variant shows a much higher activity when compared with rhTRAIL WT and retains its effectiveness in inducing cell death in multiple myeloma cell lines, in the presence of OPG secreted by stromal cells. We also demonstrate that stromal cells are largely insensitive to high concentrations of this rhTRAIL variant. In conclusion, rhTRAIL D269H/E195R is a potential therapy for multiple myeloma due to its high effectiveness and diminished binding to OPG.
authors.affiliation: From the Department of Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen and.
authors.forename: Matthieu C J
authors.initials: MC
authors.lastname: Bosman
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Reis
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Schuringa
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Quax
mesh_terms: D019943:Amino Acid Substitution; D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism / Q000494:pharmacology; D009154:Mutation; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D053244:Osteoprotegerin; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand
keywords: Drug Design; Multiple Myeloma; Surface Plasmon Resonance (SPR); Trail; Tumor Microenvironment