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TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells.
- Source :
-
Blood [Blood] 2003 May 01; Vol. 101 (9), pp. 3658-67. Date of Electronic Publication: 2002 Dec 27. - Publication Year :
- 2003
-
Abstract
- Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) have been implicated in antitumor immunity and therapy. In the present study, we investigated the sensitivity of Philadelphia chromosome (Ph1)-positive leukemia cell lines to TRAIL- or FasL-induced cell death to explore the possible contribution of these molecules to immunotherapy against Ph1-positive leukemias. TRAIL, but not FasL, effectively induced apoptotic cell death in most of 5 chronic myelogenous leukemia-derived and 7 acute leukemia-derived Ph1-positive cell lines. The sensitivity to TRAIL was correlated with cell-surface expression of death-inducing receptors DR4 and/or DR5. The TRAIL-induced cell death was caspase-dependent and enhanced by nuclear factor kappa B inhibitors. Moreover, primary leukemia cells from Ph1-positive acute lymphoblastic leukemia patients were also sensitive to TRAIL, but not to FasL, depending on DR4/DR5 expression. Fas-associated death domain protein (FADD) and caspase-8, components of death-inducing signaling complex (DISC), as well as FLIP (FLICE [Fas-associating protein with death domain-like interleukin-1-converting enzyme]/caspase-8 inhibitory protein), a negative regulator of caspase-8, were expressed ubiquitously in Ph1-positive leukemia cell lines irrespective of their differential sensitivities to TRAIL and FasL. Notably, TRAIL could induce cell death in the Ph1-positive leukemia cell lines that were refractory to a BCR-ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571; Novartis Pharma, Basel, Switzerland). These results suggested the potential utility of recombinant TRAIL as a novel therapeutic agent and the possible contribution of endogenously expressed TRAIL to immunotherapy against Ph1-positive leukemias.
- Subjects :
- Amino Acid Chloromethyl Ketones pharmacology
Apoptosis Regulatory Proteins
Benzamides
CASP8 and FADD-Like Apoptosis Regulating Protein
Carrier Proteins physiology
Caspase 1 physiology
Death Domain Receptor Signaling Adaptor Proteins
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Enzyme Inhibitors pharmacology
Fas Ligand Protein
Fatty Acid Desaturases physiology
Fusion Proteins, bcr-abl antagonists & inhibitors
Humans
Imatinib Mesylate
Leupeptins pharmacology
Membrane Glycoproteins physiology
NF-kappa B antagonists & inhibitors
Neoplasm Proteins antagonists & inhibitors
Neoplasm Proteins physiology
Neoplastic Stem Cells pathology
Peptides pharmacology
Piperazines pharmacology
Pyrimidines pharmacology
Receptors, TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor physiology
Recombinant Proteins pharmacology
TNF-Related Apoptosis-Inducing Ligand
Tumor Cells, Cultured drug effects
Tumor Cells, Cultured pathology
Tumor Necrosis Factor-alpha physiology
Apoptosis drug effects
Arabidopsis Proteins
Intracellular Signaling Peptides and Proteins
Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology
Membrane Glycoproteins pharmacology
Neoplastic Stem Cells drug effects
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Tumor Necrosis Factor-alpha pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 101
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 12506034
- Full Text :
- https://doi.org/10.1182/blood-2002-06-1770