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

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*

*Corresponding author for this work

Research output: Journal article (peer-reviewed)Journal article

51 Citations (Scopus)

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-α or tumour growth factor-β1. 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.

Original languageEnglish
Pages (from-to)414-423
Number of pages10
JournalBritish Journal of Haematology
Volume136
Issue number3
DOIs
Publication statusPublished - Feb 2007
Externally publishedYes

Keywords

  • BIRB 796
  • Bone marrow microenvironment
  • Heat shock protein
  • Multiple myeloma
  • p38 mitogen-activated protein kinase

ASJC Scopus subject areas

  • Hematology

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