P38 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells
Jianguo Wen1, Haiyun Y Cheng, Yongdong Feng
1Department of Pathology, The Methodist Hospital and The Methodist Hospital Research Institute, Houston, TX, USA.
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 mumol/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.
Insights
Arsenic trioxide resistance in multiple myeloma is common. Inhibiting p38 mitogen-activated protein kinase (MAPK) with ATO treatment increases cancer cell death, suggesting a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Resistance to arsenic trioxide (ATO) treatment affects 55-80% of multiple myeloma patients.
- The underlying mechanisms of ATO resistance in myeloma are not fully understood.
- Interleukin-6 (IL-6) can protect myeloma cells from ATO-induced apoptosis.
Purpose of the Study:
- To investigate the role of p38 mitogen-activated protein kinase (MAPK) in ATO resistance in multiple myeloma.
- To evaluate the efficacy of inhibiting p38 MAPK in overcoming ATO resistance.
Main Methods:
- Treatment of myeloma cell lines and primary cells with ATO at clinically relevant concentrations.
- Pharmacological inhibition of p38 MAPK using SB203580.
- Downregulation of p38 MAPK using siRNA.
- Assessment of apoptosis, cell growth inhibition, and activation of apoptotic pathways (caspase-9, caspase-8).
- Analysis of Heat shock protein 27 (HSP27) expression and phosphorylation.
Main Results:
- ATO activated p38 MAPK in myeloma cells at concentrations of 2-7 mumol/l.
- Inhibition of p38 MAPK significantly enhanced ATO-induced apoptosis and growth inhibition.
- Combined ATO and p38 MAPK inhibition abrogated IL-6-mediated protection against ATO.
- ATO-resistant myeloma cells exhibited increased p38 MAPK activation.
- Apoptosis induction by combined ATO and p38 MAPK inhibition involved both intrinsic and extrinsic pathways.
- ATO-induced p38 MAPK activation correlated with increased HSP27 phosphorylation and expression.
Conclusions:
- ATO-induced p38 MAPK activation is a key mechanism contributing to ATO resistance in multiple myeloma.
- Inhibition of p38 MAPK represents a promising strategy to overcome ATO resistance in myeloma patients.
- Targeting p38 MAPK may re-sensitize myeloma cells to ATO treatment.
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