TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells.
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.
Gazitt
Y
Y
University of Texas Health Science Center at San-Antonio, Department of Medicine/Hematology, 7703 Floyd Curl Drive, San Antonio, TX 78284, USA.
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D019254:Genes, bcl-2 / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017493:Leukocyte Common Antigens / Q000032:analysis; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008747:Methylcellulose / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009244:NAD+ Nucleosidase / Q000032:analysis; D017239:Paclitaxel / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D008747:Methylcellulose; D017493:Leukocyte Common Antigens; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D017239:Paclitaxel