Abstract
TRAIL, the ligand for the newly discovered DR-4 and DR-5 receptor, is a member of the TNF family of death signal transduction proteins with a mechanism of cell death similar to that of Fas and Fas ligand (Fas-L) system. We provide first time evidence that TRAIL is a potent inducer of apoptosis in multiple myeloma (MM) cell lines. TRAIL effectively induced extensive apoptosis in 8226 and ARP-1 MM cells in a time- and dose-dependent manner. Apoptosis with TRAIL reached about 80% within 48 h of treatment with a dose of 160 ng/ml. Furthermore, we provide first time evidence that similar to Fas, TRAIL-induced apoptosis is not blocked by bcl-2 in MM cell lines. Most importantly, TRAIL induced substantial apoptosis in freshly isolated, flow-sorted myeloma cells obtained from different MM patients expressing variable levels of bcl-2. Finally, we demonstrate for the first time that TRAIL is not cytotoxic to purified CD34+/CD45dim hematopoietic stem cells and does not inhibit CFU-GM or BFU-E colony formation in methylcellulose.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP-ribosyl Cyclase
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ADP-ribosyl Cyclase 1
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Antigens, CD*
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Antigens, CD34 / analysis
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Antigens, Differentiation / analysis
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins
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Cell Division / drug effects
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Cells, Cultured
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Colony-Forming Units Assay
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Dose-Response Relationship, Drug
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Flow Cytometry
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Genes, bcl-2 / genetics
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / drug effects*
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / pathology
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Humans
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Leukocyte Common Antigens / analysis
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Membrane Glycoproteins / pharmacology*
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Methylcellulose / metabolism
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology*
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NAD+ Nucleosidase / analysis
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Paclitaxel / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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TNF-Related Apoptosis-Inducing Ligand
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Time Factors
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Transfection
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Antigens, CD
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Antigens, CD34
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Antigens, Differentiation
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Apoptosis Regulatory Proteins
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Membrane Glycoproteins
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Proto-Oncogene Proteins c-bcl-2
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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Methylcellulose
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Leukocyte Common Antigens
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ADP-ribosyl Cyclase
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CD38 protein, human
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NAD+ Nucleosidase
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ADP-ribosyl Cyclase 1
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Paclitaxel