P38 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells
P38 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells
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DOI：
10.1111/j.1365-2141.2007.06895.x
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发表时间：
2008-01-01
影响因子：
6.5
通讯作者：
Chang, Chung-Che
中科院分区：
文献类型：
--
作者：
Wen, Jianguo;Cheng, Haiyun Y.;Chang, Chung-Che
对三氧化二砷（ATO）治疗的抵抗在多发性骨髓瘤患者中相对常见（55-80%）。本研究发现，ATO在临床可达到的浓度（2-7 μ mol/l）激活骨髓瘤细胞系和原代骨髓瘤细胞中的p38丝裂原活化蛋白激酶（MAPK），这一发现以前在骨髓瘤细胞中没有得到充分记录。通过药理学抑制剂（SB 203580）抑制p38 MAPK活化或通过siRNA下调p38 MAPK显著增加ATO处理诱导的骨髓瘤细胞凋亡和/或生长抑制。ATO和p38 MAPK抑制剂的组合取消了白细胞介素-6增强的骨髓瘤细胞对ATO处理的保护作用。我们实验室开发的ATO耐药细胞系显示p38 MAPK活化增加。ATO和SB 203580组合引起的凋亡增加伴随着caspase-9和caspase-8的活化，表明涉及外源性和内源性凋亡途径。此外，ATO激活p38 MAPK与热休克蛋白27的磷酸化增加和表达上调有关。这些结果表明，ATO诱导的p38 MAPK活化在骨髓瘤细胞对ATO的耐药性中起重要作用，并且p38 MAPK抑制可以克服骨髓瘤患者对ATO治疗的耐药性。
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 mu mol/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.