P38 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells

Jianguo Wen, Haiyun Y. Cheng, Yongdong Feng, Lawrence Rice, Shangfeng Liu, Albert Mo, James Huang, Youli Zu, Douglas J. Ballon, Chung Che Chang

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

The resistance to arsenic trioxide (ATO) treatment is relatively common (55-80%) in multiple myeloma patients. This study found that ATO at clinically achievable concentrations (2-7 μmol/l) activated p38 mitogen-activated protein kinase (MAPK) in both myeloma cell lines and primary myeloma cells, a finding not previously well-documented in myeloma cells. Inhibition of p38 MAPK activation by pharmacological inhibitors (SB203580) or downregulation of p38 MAPK by siRNA significantly increased the apoptosis and/or growth inhibition induced by ATO treatment in myeloma cells. Combination of ATO and p38 MAPK inhibition abolished the interleukin-6 enhanced protection of myeloma cells against ATO treatment. The ATO-resistant cell line developed in our laboratory showed an increase in p38 MAPK activation. The increase of apoptosis by the combination of ATO and SB203580 was accompanied by the activation of caspase-9 and caspase-8 suggesting that both extrinsic and intrinsic apoptotic pathways are involved. Additionally, the p38 MAPK activation by ATO was associated with increased phosphorylation and upregulated expression of Heat shock protein 27. These results suggest that ATO-induced p38 MAPK activation plays an important role in the resistance to ATO in myeloma cells and that p38 MAPK inhibition may overcome resistance to ATO treatment in myeloma patients.

Original languageEnglish (US)
Pages (from-to)169-180
Number of pages12
JournalBritish Journal of Haematology
Volume140
Issue number2
DOIs
StatePublished - Jan 2008

Keywords

  • Arsenic trioxide
  • Myeloma
  • p38 MAPK
  • Resistance

ASJC Scopus subject areas

  • Hematology

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