title: Human soluble TRAIL/Apo2L induces apoptosis in a subpopulation of chemotherapy refractory nodal diffuse large B-cell lymphomas, determined by a highly sensitive in vitro apoptosis assay.
abstract: Resistance to chemotherapy in therapy-refractory diffuse large B-cell lymphomas (DLBCL) is related to inhibition of the intrinsic apoptosis pathway. Human soluble tumour necrosis factor (TNF)-related apoptosis-inducing ligand (hsTRAIL/Apo2L) induces apoptosis via the alternative, death-receptor mediated apoptosis pathway and might be an effective alternative form of therapy for these lymphomas. This study investigated whether hsTRAIL/Apo2L could actually induce apoptosis in isolated lymphoma cells of DLBCL biopsies of patients with chemotherapy-refractory DLBCL. Twelve out of a total of 22 DLBCL samples were sensitive to hsTRAIL/Apo2L. These sensitive lymphomas included seven clinically chemotherapy-refractory lymphomas. Furthermore, hsTRAIL/Apo2L induced apoptosis in DLBCL cells and in B-cell lines that showed high expression levels of inhibitors of the intrinsic apoptosis pathway: Bcl-2 and/or X-linked inhibitor of apoptosis (XIAP). hsTRAIL/Apo2L-sensitive lymphoma cells showed expression of the TRAIL receptors R1 and/or R2 and absence of R3 and R4. We conclude that hsTRAIL/Apo2L induced apoptosis in a subpopulation of chemotherapy-refractory nodal DLBCL and that disruption of the intrinsic apoptosis-mediated pathway and expression of Bcl-2 and XIAP did not confer resistance to hsTRAIL/Apo2L-induced apoptosis in DLBCL. Thus, based on our results, further exploration of hsTRAIL/Apo2L as an alternative treatment for patients with chemotherapy-refractory DLBCL should be considered.
authors.affiliation: Department of Clinical Pathology, VU Universrity Medical Centre, Amsterdam, the Netherlands.
authors.forename: Saskia A G M
authors.initials: SA
authors.lastname: Cillessen
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Kitty C M
authors.initials: KC
authors.lastname: Castricum
authors.forename: August H
authors.initials: AH
authors.lastname: Westra
authors.forename: Petra
authors.initials: P
authors.lastname: Niesten
authors.forename: Jettie J F
authors.initials: JJ
authors.lastname: Muris
authors.forename: Hoite F
authors.initials: HF
authors.lastname: Nijdam
authors.forename: Klaas G
authors.initials: KG
authors.lastname: van der Hem
authors.forename: Marcel
authors.initials: M
authors.lastname: Flens
authors.forename: Erik
authors.initials: E
authors.lastname: Hooijberg
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oudejans
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000627:therapeutic use*; D015153:Blotting, Western / Q000379:methods; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005470:Fluorometry; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism; D008207:Lymphatic Metastasis; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000032:analysis / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases