Wen Jianguo, Cheng Haiyun Y, Feng Yongdong, Rice Lawrence, Liu Shangfeng, Mo Albert, Huang James, Zu Youli, Ballon Douglas J, Chang Chung-Che
Department of Pathology, The Methodist Hospital and The Methodist Hospital Research Institute, Houston, TX, USA.
Br J Haematol. 2008 Jan;140(2):169-80. doi: 10.1111/j.1365-2141.2007.06895.x.
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.
在多发性骨髓瘤患者中，对三氧化二砷（ATO）治疗产生耐药性的情况相对常见（55%-80%）。本研究发现，临床可达到的浓度（2-7 μmol/l）的ATO在骨髓瘤细胞系和原发性骨髓瘤细胞中均可激活p38丝裂原活化蛋白激酶（MAPK），这一发现此前在骨髓瘤细胞中尚未得到充分记录。用药物抑制剂（SB203580）抑制p38 MAPK激活或通过小干扰RNA（siRNA）下调p38 MAPK，均可显著增加ATO治疗诱导的骨髓瘤细胞凋亡和/或生长抑制。ATO与p38 MAPK抑制联合使用可消除白细胞介素-6对骨髓瘤细胞的增强保护作用，使其免受ATO治疗的影响。我们实验室建立的ATO耐药细胞系显示p38 MAPK激活增加。ATO与SB203580联合使用导致的凋亡增加伴随着半胱天冬酶-9和半胱天冬酶-8的激活，这表明外在和内在凋亡途径均参与其中。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激活在骨髓瘤细胞对ATO的耐药性中起重要作用，抑制p38 MAPK可能克服骨髓瘤患者对ATO治疗的耐药性。
