Abstract
We have previously shown that heat shock protein (Hsp) 27 or its upstream activator p38 mitogen-activated protein kinase (MAPK) confers resistance to bortezomib and dexamethasone (Dex) in multiple myeloma (MM) cells. This study examined anti-MM activity of a novel p38 MAPK inhibitor, BIRB 796, alone and in combination with conventional and novel therapeutic agents. BIRB 796 blocked baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. The Hsp90 inhibitor 17-allylamino-17-demethoxy-geldanamycin (17-AAG) upregulated protein expression and phosphorylation of Hsp27; conversely, BIRB 796 inhibited this phosphorylation and enhanced 17-AAG-induced cytotoxicity. Importantly, BIRB 796 inhibited Hsp27 phosphorylation induced by 17-AAG plus bortezomib, thereby enhancing cytotoxicity. In bone marrow stromal cells (BMSC), BIRB 796 inhibited phosphorylation of p38 MAPK and secretion of interleukin-6 (IL-6) and vascular endothelial growth factor triggered by either tumour necrosis factor-alpha or tumour growth factor-beta1. BIRB 796 also inhibited IL-6 secretion induced in BMSCs by adherence to MM cells, thereby inhibiting tumour cell proliferation. These studies therefore suggest that BIRB 796 overcomes drug-resistance in the BM microenvironment, providing the framework for clinical trials of a p38 MAPK inhibitor, alone and in combination with bortezomib, Hsp90 inhibitor, or Dex, to improve patient outcome in MM.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Hormonal / therapeutic use
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Apoptosis / drug effects
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Benzoquinones / therapeutic use
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Boronic Acids / therapeutic use
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Bortezomib
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Cell Adhesion / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Coculture Techniques
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Cytotoxicity Tests, Immunologic
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Dexamethasone / therapeutic use
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Drug Resistance, Neoplasm / drug effects*
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Immunoblotting / methods
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Interleukin-6 / metabolism
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Intracellular Signaling Peptides and Proteins
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Lactams, Macrocyclic / therapeutic use
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Naphthalenes / pharmacology
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Naphthalenes / therapeutic use*
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyrazines / therapeutic use
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Pyrazoles / pharmacology
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Pyrazoles / therapeutic use*
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Signal Transduction / drug effects*
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Stem Cells
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Transforming Growth Factor beta / pharmacology
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Tumor Necrosis Factor-alpha / pharmacology
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Vascular Endothelial Growth Factor A / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antineoplastic Agents, Hormonal
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Benzoquinones
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Boronic Acids
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HSP90 Heat-Shock Proteins
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Lactams, Macrocyclic
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Naphthalenes
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Protein Kinase Inhibitors
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Pyrazines
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Pyrazoles
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Transforming Growth Factor beta
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Tumor Necrosis Factor-alpha
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Vascular Endothelial Growth Factor A
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tanespimycin
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Bortezomib
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Dexamethasone
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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p38 Mitogen-Activated Protein Kinases
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doramapimod