A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia
A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia
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DOI：
10.1158/1535-7163.mct-07-0067
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发表时间：
2007-06-01
影响因子：
5.7
通讯作者：
Taguchi, Hirokuni
中科院分区：
文献类型：
--
作者：
Ikezoe, Takayuki;Yang, Jing;Taguchi, Hirokuni
在有丝分裂过程中，极光激酶在染色体排列、分离和细胞分裂中起重要作用。这些激酶的异常表达发生在实体瘤中，并与非整倍体和癌变有关。我们在本研究中发现，极光激酶A和B在多种类型的人类白血病细胞系（n = 15，例如，PALL-1, PALL-2, HL-60, NB4， MV4-11等）中表达异常，并且在急性髓性白血病个体新鲜分离的白血病细胞（n = 44）中与健康志愿者的骨髓单核细胞（n = 11）相比，通过实时荧光定量PCR检测，极光激酶A和B在急性髓性白血病个体（n = 11）中表达异常。ZM447439是一种新型的选择性极光激酶抑制剂。通过胸苷摄取、细胞周期分析和膜联蛋白V染色分别检测到该化合物诱导生长抑制，引起4N/8N DNA含量的细胞积累，并介导人白血病细胞凋亡。特别是在PALL-1和PALL-2细胞中发生了深刻的生长抑制，PALL-1和PALL-2细胞具有野生型p53基因。相比之下，ZM447439不抑制从健康正常志愿者身上获得的髓系干细胞的克隆生长。综上所述，抑制极光激酶可能是一种有希望的治疗白血病的策略。
The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases occurs in solid tumors and is associated with aneuploidy and carcinogenesis. We found in this study that Aurora kinase A and B were aberrantly expressed in a variety of types of human leukemia cell lines (n = 15, e.g., PALL-1, PALL-2, HL-60, NB4, MV4-11, etc.), as well as freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n = 44) compared with bone marrow mononuclear cells from healthy volunteers (n = 11), as measured by real-time PCR. ZM447439 is a novel selective Aurora kinase inhibitor. The compound induced growth inhibition, caused accumulation of cells with 4N/8N DNA content, and mediated apoptosis of human leukemia cells as measured by thymidine uptake, cell cycle analysis, and annexin V staining, respectively. Especially profound growth inhibition occurred with the PALL-1 and PALL-2 cells, which possess wild-type p53 gene. In contrast, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy normal volunteers. Taken together, inhibition of Aurora kinases may be a promising treatment strategy for individuals with leukemia.