Abstract
Nuclear factor kappaB (NF-kappaB) plays a major role in the pathogenesis of human T-cell lymphotrophic virus I-associated malignancy. Proteasome inhibitors provide a rational approach to control constitutively activated NF-kappaB in human T-cell lymphotrophic virus I-infected T cells. We report that the proteasome inhibitor PS-341 decreased NF-kappaB DNA binding activity by preventing degradation of IkappaB(alpha). In our murine model of adult T-cell leukemia, PS-341 used alone did not yield prolongation of the survival of tumor-bearing mice. However, when combined with the current clinically approved drug humanized anti-Tac, therapy with PS-341 was associated with a complete remission in a proportion of treated animals, whereas only a partial response was observed in animals treated with humanized anti-Tac alone.
MeSH terms
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Adult
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal, Humanized
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Antibody-Dependent Cell Cytotoxicity / drug effects
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Antibody-Dependent Cell Cytotoxicity / immunology
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Boronic Acids / administration & dosage
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Boronic Acids / pharmacology*
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Bortezomib
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Cysteine Endopeptidases
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DNA, Neoplasm / metabolism
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DNA-Binding Proteins / metabolism
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Daclizumab
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Drug Synergism
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Humans
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I-kappa B Proteins*
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Immunoglobulin G / administration & dosage
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Immunoglobulin G / pharmacology
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Leukemia-Lymphoma, Adult T-Cell / drug therapy*
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Leukemia-Lymphoma, Adult T-Cell / enzymology
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Leukemia-Lymphoma, Adult T-Cell / immunology
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Monocytes / immunology
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Multienzyme Complexes / antagonists & inhibitors
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism
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Neutrophils / immunology
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Protease Inhibitors / pharmacology*
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Proteasome Endopeptidase Complex
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Pyrazines / administration & dosage
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Pyrazines / pharmacology*
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Receptors, IgG / immunology
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Receptors, IgG / metabolism
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Boronic Acids
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DNA, Neoplasm
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DNA-Binding Proteins
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I-kappa B Proteins
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Immunoglobulin G
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Multienzyme Complexes
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NF-kappa B
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NFKBIA protein, human
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Nfkbia protein, mouse
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Protease Inhibitors
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Pyrazines
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Receptors, IgG
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NF-KappaB Inhibitor alpha
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Bortezomib
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Daclizumab
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex