Document Detail

BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth.
MedLine Citation:
PMID:  17173546     Owner:  NLM     Status:  MEDLINE    
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.
Hiroshi Yasui; Teru Hideshima; Hiroshi Ikeda; Janice Jin; Enrique M Ocio; Tanyel Kiziltepe; Yutaka Okawa; Sonia Vallet; Klaus Podar; Kenji Ishitsuka; Paul G Richardson; Chris Pargellis; Neil Moss; Noopur Raje; Kenneth C Anderson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-12-14
Journal Detail:
Title:  British journal of haematology     Volume:  136     ISSN:  0007-1048     ISO Abbreviation:  Br. J. Haematol.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-19     Completed Date:  2007-03-29     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0372544     Medline TA:  Br J Haematol     Country:  England    
Other Details:
Languages:  eng     Pagination:  414-23     Citation Subset:  IM    
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
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MeSH Terms
Antineoplastic Agents, Hormonal / therapeutic use
Apoptosis / drug effects
Benzoquinones / therapeutic use
Boronic Acids / therapeutic use
Cell Adhesion / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Coculture Techniques
Cytotoxicity Tests, Immunologic
Dexamethasone / therapeutic use
Drug Resistance, Neoplasm / drug effects*
HSP90 Heat-Shock Proteins / antagonists & inhibitors,  metabolism
Immunoblotting / methods
Interleukin-6 / secretion
Intracellular Signaling Peptides and Proteins
Lactams, Macrocyclic / therapeutic use
Multiple Myeloma / drug therapy*,  metabolism,  pathology
Naphthalenes / pharmacology,  therapeutic use*
Protein Kinase Inhibitors / pharmacology,  therapeutic use*
Protein-Serine-Threonine Kinases / antagonists & inhibitors*,  metabolism
Pyrazines / therapeutic use
Pyrazoles / pharmacology,  therapeutic use*
Signal Transduction / drug effects*
Stem Cells
Transforming Growth Factor beta / pharmacology
Tumor Necrosis Factor-alpha / pharmacology
Vascular Endothelial Growth Factor A / secretion
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors,  metabolism
Grant Support
IP50 CA10070/CA/NCI NIH HHS; P0-1 78378//PHS HHS; R0-1 CA50947/CA/NCI NIH HHS
Reg. No./Substance:
0/17-(allylamino)-17-demethoxygeldanamycin; 0/Antineoplastic Agents, Hormonal; 0/BIRB 796; 0/Benzoquinones; 0/Boronic Acids; 0/HSP90 Heat-Shock Proteins; 0/Interleukin-6; 0/Intracellular Signaling Peptides and Proteins; 0/Lactams, Macrocyclic; 0/Naphthalenes; 0/Protein Kinase Inhibitors; 0/Pyrazines; 0/Pyrazoles; 0/Transforming Growth Factor beta; 0/Tumor Necrosis Factor-alpha; 0/Vascular Endothelial Growth Factor A; 0/bortezomib; 50-02-2/Dexamethasone; EC 2.7.1.-/MAP-kinase-activated kinase 2; EC Kinases; EC Mitogen-Activated Protein Kinases

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