p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells

Teru Hideshima, Klaus Podar, Dharminder Chauhan, Kenji Ishitsuka, Constantine Mitsiades, Yu-Tzu Tai, Makoto Hamasaki, Noopur Raje, Hiromasa Hideshima, George Schreiner, Aaron N Nguyen, Tony Navas, Nikhil C Munshi, Paul G Richardson, Linda S Higgins, Kenneth C Anderson

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

112 Citations (Scopus)

Abstract

Although PS-341 (bortezomib) is a promising agent to improve multiple myeloma (MM) patient outcome, 65% of patients with relapsed and refractory disease do not respond. We have previously shown that heat shock protein (Hsp)27 is upregulated after PS-341 treatment, that overexpression of Hsp27 confers PS-341 resistance, and that inhibition of Hsp27 overcomes PS-341 resistance. Since Hsp27 is a downstream target of p38 mitogen-activated protein kinase (MAPK)/MAPK-mitogen-activated protein kinase-2 (MAPKAPK2), we hypothesized that inhibition of p38 MAPK activity could augment PS-341 cytotoxicity by downregulating Hsp27. Although p38 MAPK inhibitor SCIO-469 (Scios Inc, CA, USA) alone did not induce significant growth inhibition, it blocked baseline and PS-341-triggered phosphorylation of p38 MAPK as well as upregulation of Hsp27, associated with enhanced cytotoxicity in MM.1S cells. Importantly, SCIO-469 enhanced phosphorylation of c-Jun NH 2-terminal kinase (JNK) and augmented cleavage of caspase-8 and poly(ADP)-ribose polymerase. Moreover, SCIO-469 downregnlated PS-341-induced increases in G2/M-phase cells, associated with downregulation of p21 Cip1 expression. Importantly, SCIO-469 treatment augmented cytotoxicity of PS-341 even against PS-341-resistant cell lines and patient MM cells. These studies therefore provide the framework for clinical trials of SCIO-469 to enhance sensitivity and overcome resistance to PS-341, thereby improving patient outcome in MM.

Original languageEnglish
Pages (from-to)8766-8776
Number of pages11
JournalOncogene
Volume23
Issue number54
DOIs
Publication statusPublished - 18 Nov 2004
Externally publishedYes

Keywords

  • Antineoplastic Agents/pharmacology
  • Boronic Acids/pharmacology
  • Bortezomib
  • Cell Line, Tumor
  • Down-Regulation
  • Heat-Shock Proteins/metabolism
  • Humans
  • Multiple Myeloma/pathology
  • Pyrazines/pharmacology
  • p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
  • SCIO-469
  • Hsp27
  • Multiple myeloma
  • PS-341
  • p38 MAPK inhibitor

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Cancer Research

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