title: 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.
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.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasui
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Janice
authors.initials: J
authors.lastname: Jin
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
authors.forename: Tanyel
authors.initials: T
authors.lastname: Kiziltepe
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okawa
authors.forename: Sonia
authors.initials: S
authors.lastname: Vallet
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishitsuka
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Chris
authors.initials: C
authors.lastname: Pargellis
authors.forename: Neil
authors.initials: N
authors.lastname: Moss
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D003601:Cytotoxicity Tests, Immunologic; D003907:Dexamethasone / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2; D010671:Phenylurea Compounds
chemical_list: D018931:Antineoplastic Agents, Hormonal; D016227:Benzoquinones; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011719:Pyrazines; D011720:Pyrazoles; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C112765:tanespimycin; C452139:doramapimod; D010671:Phenylurea Compounds