Selective inhibition of Aurora A and B kinases effectively induces cell cycle arrest in t(8;21) acute myeloid leukemia
Selective inhibition of Aurora A and B kinases effectively induces cell cycle arrest in t(8;21) acute myeloid leukemia
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选择性抑制 Aurora A 和 B 激酶可有效诱导 t(8;21) 急性髓系白血病细胞周期停滞
DOI：
10.1016/j.biopha.2019.109113
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发表时间：
2019-09-01
影响因子：
7.5
通讯作者：
Xu, Kailin
中科院分区：
文献类型：
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作者：
Qi, Jialei;Gao, Xiang;Xu, Kailin
融合基因AML1-ETO在t（8;21）急性髓性白血病中最初会失调各种细胞周期分子。极光激酶在治疗肿瘤方面显示出巨大的希望。然而，极光激酶（AURK） A和B抑制在t(8;21) AML中的疗效尚不清楚。我们发现AURK-A抑制剂Alisertib和AURK-B抑制剂Barasertib强烈抑制t(8; 21) AML细胞的生长和增殖。药物暴露14 d后，细胞集落的数量和大小明显减少。细胞周期分布被阻断在G2/M期，呈剂量依赖性和时间依赖性。p53家族和cdc2-p34的表达也发生了显著变化。值得注意的是，我们发现t(8;21) AML细胞对Aurora B抑制更敏感。在每组实验中，Barasertib用更少的时间或更低的浓度达到相似的效果。综上所述，我们的数据突出了Aurora激酶作为治疗t(8;21) AML的有希望的细胞周期靶点的潜在作用，从而为指导相关临床试验提供了理论依据。
The fusion gene AML1-ETO initially dysregulates various cell cycle molecules in t(8;21) acute myeloid leukemia. Aurora kinases have shown great promise in treating tumors. However, the efficacy of Aurora kinase (AURK) A and B inhibition in t(8;21) AML remains unclear. We found that AURK-A inhibitor Alisertib and AURK-B inhibitor Barasertib strongly inhibited the growth and proliferation of t(8; 21) AML cells. The quantity and size of cell colonies were markedly decreased after a 14-d drug exposure. The cell cycle distribution was blocked at the G2/M phase in both dose- and time-dependent manner. The expression of p53 family and cdc2-p34 significantly changed as well. Notably, we found that t(8;21) AML cells are more sensitive to Aurora B inhibition. In each set of experiments, Barasertib took less time or a lower concentration to achieve similar efficacy. Taken together, our data highlighted the potential role of Aurora kinases as promising cell cycle targets for the treatment of t(8;21) AML and hereby provided a theoretical basis to guide relevant clinical trials.