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.

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
Abstract/OtherAbstract:	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.

Authors:	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
Affiliation:	Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:	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 Humans Immunoblotting / methods Interleukin-6 / secretion Intracellular Signaling Peptides and Proteins Lactams, Macrocyclic / therapeutic use Multiple Myeloma / drug therapy, metabolism, pathology Naphthalenes / pharmacology, therapeutic use Phosphorylation 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
ID/Acronym/Agency:	IP50 CA10070/CA/NCI NIH HHS; P0-1 78378//PHS HHS; R0-1 CA50947/CA/NCI NIH HHS
Chemical
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 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases

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