Huang Xue-Fei, Luo Shao-Kai, Xu Jie, Li Juan, Xu Duo-Rong, Wang Li-Hui, Yan Min, Wang Xian-Ren, Wan Xiang-Bo, Zheng Fei-Meng, Zeng Yi-Xin, Liu Quentin
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, 651 Dongfeng Road, Guangzhou, China.
Blood. 2008 Mar 1;111(5):2854-65. doi: 10.1182/blood-2007-07-099325. Epub 2007 Dec 26.
Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression of Aur-A was markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680-induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase among Aur-A-high VX-680-sensitive leukemia patients. VX-680-induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G(2)/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment.
此前，我们和其他人的研究表明，有丝分裂期极光激酶A（Aur-A）是准确进入有丝分裂和正确纺锤体组装所必需的。在本研究中，我们发现，从相当一部分初发急性髓系白血病（AML）患者获得的骨髓单个核细胞（BMMC）中，Aur-A的表达显著升高。用Aur-A激酶抑制剂VX-680靶向人原发性AML细胞，会导致细胞以剂量依赖性方式发生凋亡性死亡。重要的是，与Aur-A低表达的AML（P <.001）或正常BMMC（P <.001）相比，VX-680诱导的细胞死亡在Aur-A高表达的原发性白血病母细胞中优先更高，这表明在对VX-680敏感的Aur-A高表达白血病患者中靶向极光激酶可能存在药物治疗窗口。VX-680诱导AML细胞系发生细胞死亡，伴随着单极有丝分裂纺锤体的形成、G(2)/M期阻滞、磷酸化（p）-Akt-1减少，以及procaspase-3和聚（ADP）核糖聚合酶的蛋白水解切割增加。值得注意的是，VX-680增加了Bax/Bcl-2表达比率，这是AML中药物反应和生存的有利促凋亡预测指标。最后，VX-680增强了化疗药物依托泊苷（VP16）对AML细胞的细胞毒性作用。我们共同得出结论，极光激酶可能是AML的治疗靶点，且Aur-A高表达可能作为选择性治疗的鉴别标志物。
