Du Yanzhi, Wang Kankan, Fang Hai, Li Junmin, Xiao Dakai, Zheng Peizheng, Chen Yulong, Fan Huiyong, Pan Xiaoling, Zhao Chunjun, Zhang Qinghua, Imbeaud Sandrine, Graudens Esther, Eveno Eric, Auffray Charles, Chen Saijuan, Chen Zhu, Zhang Ji
State Key Laboratory of Medical Genomics and Shanghai Institute of Ruijin Hospital, School of Medicine of Shanghai Jiao Tong University, Shanghai 200025, China.
Blood. 2006 Feb 15;107(4):1582-90. doi: 10.1182/blood-2005-06-2318. Epub 2005 Oct 25.
A treatment strategy that combines arsenic trioxide (ATO) with the tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) appears to induce markedly more cell apoptosis than imatinib mesylate alone in chronic myeloid leukemia (CML). To understand the mechanisms underlying the synergistic/additive action of these agents, we applied cDNA microarrays, component plane presentation integrated self-organizing map (CPP-SOM), and methods of protein biochemistry to study cell apoptosis induced by imatinib mesylate, ATO, and the combination of the 2 agents in the CML cell line K562. Numerous features with temporospatial relationships were revealed, indicating the coordinated regulation of molecular networks from various aspects of proapoptotic and apoptotic activities in CML. Imatinib mesylate appears to induce mainly the intrinsic pathway of cell apoptosis, whereas ATO induces the endoplasmic reticulum (ER) stress-mediated pathway of cell apoptosis, and the combination of the 2 agents seems to more effectively induce the intrinsic, extrinsic, and ER stress-mediated pathways of cell apoptosis, which results in a more effective and efficient induction of programmed cell death in K562 cells. This finding appears to be supported also by data derived from bone marrow cells of 2 patients with CML, one in chronic phase and the other in blast-crisis phase of the disease.
在慢性粒细胞白血病（CML）中，一种将三氧化二砷（ATO）与酪氨酸激酶抑制剂甲磺酸伊马替尼（STI571，格列卫）相结合的治疗策略，似乎比单独使用甲磺酸伊马替尼能诱导更多的细胞凋亡。为了了解这些药物协同/相加作用的潜在机制，我们应用cDNA微阵列、成分平面展示整合自组织映射（CPP-SOM）以及蛋白质生物化学方法，来研究甲磺酸伊马替尼、ATO以及这两种药物联合使用在CML细胞系K562中诱导的细胞凋亡。揭示了许多具有时空关系的特征，表明在CML中从促凋亡和凋亡活动的各个方面对分子网络进行了协调调控。甲磺酸伊马替尼似乎主要诱导细胞凋亡的内在途径，而ATO诱导内质网（ER）应激介导的细胞凋亡途径，并且这两种药物的联合使用似乎更有效地诱导细胞凋亡的内在、外在和ER应激介导途径，从而在K562细胞中更有效且高效地诱导程序性细胞死亡。来自2例CML患者骨髓细胞的数据似乎也支持了这一发现，其中1例处于疾病的慢性期，另1例处于急变期。
