Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells
Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells
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DOI：
10.1158/1535-7163.mct-07-2051
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发表时间：
2008-05-01
影响因子：
5.7
通讯作者：
Cortese, Riccardo
中科院分区：
文献类型：
--
作者：
D'Alise, Anna Morena;Amabile, Giovanni;Cortese, Riccardo
这个小合成分子的演示。reversine [2-(4-morpholinoanilino)- n (6)-cyclohexyladenine]促进了承诺细胞向多能祖细胞型的去分化，这给利用这种小化学工具生成干细胞带来了希望。在这里，我们发现逆转录导致细胞质分裂失败并诱导多倍体化。这些逆转作用是由于抑制极光A和B，这两个相关的激酶涉及有丝分裂的几个方面，并且在人类肿瘤中经常被放大和过度表达。逆转录酶抑制组蛋白H3的磷酸化，这是Aurora激酶的直接下游靶点。与最近进入癌症治疗II期临床试验的Aurora激酶抑制剂VX-680类似，reversine抑制急性髓系白血病患者白血病细胞的集落形成，但对健康供体细胞的毒性明显低于VX-680。逆转录酶-极光B激酶复合物的晶体结构表明，逆转录酶是一类新型的atp竞争性极光激酶抑制剂。因此，尽管我们的研究对逆转录酶在再生医学中的应用提出了严重的质疑，但它们支持逆转录酶可能是癌症化疗中一种有用的药物的范式。
The demonstration that the small synthetic molecule. reversine [2-(4-morpholinoanilino)-N(6)-cyclohexyladenine] promotes the dedifferentiation of committed cells into multipotent progenitor-type cells has raised hopes on the exploitation of this small chemical tool for the generation of stem cells. Here, we show that reversine causes a failure in cytokinesis and induces polyploidization. These effects of reversine are due to the inhibition of Aurora A and B, two related kinases that are implicated in several aspects of mitosis and that are frequently amplified and overexpressed in human tumors. Reversine inhibits the phosphorylation of histone H3, a direct downstream target of Aurora kinases. Similarly to the Aurora kinase inhibitor VX-680, which has recently entered phase II clinical trials for cancer treatment, reversine inhibited colony formation of leukemic cells from patients with acute myeloid leukemia but was significantly less toxic than VX-680 on cells from healthy donors. The crystal structure of the reversine-Aurora B kinase complex shows that reversine is a novel class of ATP-competitive Aurora kinase inhibitors. Thus, although our studies raise serious doubts on the application of reversine in regenerative medicine, they support the paradigm that reversine might be a useful agent in cancer chemotherapy.