文章：

极光激酶抑制剂作为抗癌剂

Aurora-kinase inhibitors as anticancer agents

原文发布日期：2004-12-01

DOI: 10.1038/nrc1502

类型: Review Article

开放获取: 否

要点：

1. Human tumour cells are typically aneuploid, with both changes in chromosome number and structure, due to chromosome instability. One source of this instability is mitosis, during which errors in chromosome segregation can lead to gains or losses of chromosomes.
2. Members of the Aurora family of protein kinases are required for multiple aspects of mitosis. Aurora-A localizes to centrosomes/spindle poles and is required for spindle assembly, whereas Aurora-B is a chromosome passenger protein required for phosphorylation of histone H3, chromosome segregation and cytokinesis.
3. Aurora-A and -B are both overexpressed in a wide range of different human tumours. Aurora-A has also been shown to be an oncogene in in vitro transformation assays.
4. Three Aurora-kinase inhibitors have recently been described — ZM447439, Hesperadin and VX-680. All three induce similar phenotypes in cell-based assays and, interestingly, VX-680 shows antitumour activity in rodent xenograft models.
5. In mitosis, ZM447439 and Hesperadin both inhibit chromosome alignment and spindle-checkpoint function. RNAi-based experiments and overexpression of Aurora-kinase mutants indicate that these phenotypes seem to be due to inhibition of Aurora-B, not Aurora-A.
6. These drugs are not 'antimitotic' agents in that they do not directly inhibit cell-cycle progression. Rather, following an aberrant mitosis, activation of the p53-dependent post-mitotic checkpoint induces 'pseudo G1' cell-cycle arrest.
7. Although Aurora-A has received most of the attention so far in terms of a link with human cancer, Aurora-B might be the more suitable anticancer drug target, simply because inhibition of Aurora-B rapidly results in a catastrophic mitosis, which leads to cell death.

要点翻译：

1. 人类肿瘤细胞通常呈现非整倍体，这是由于染色体不稳定性导致的染色体数量和结构改变。这种不稳定的一个来源是有丝分裂，在此过程中染色体分离错误可能导致染色体的增加或减少。
2. Aurora蛋白激酶家族成员参与有丝分裂的多个环节。Aurora-A定位于中心体/纺锤体极，是纺锤体组装所必需的；而Aurora-B作为染色体乘客蛋白，负责组蛋白H3的磷酸化、染色体分离和胞质分裂。
3. Aurora-A和-B在多种人类肿瘤中均过度表达。体外转化实验也证实Aurora-A具有癌基因功能。
4. 近期已有三种Aurora激酶抑制剂的报道——ZM447439、Hesperadin和VX-680。在细胞实验中三者均能诱导相似的表型，值得注意的是VX-680在啮齿类动物移植瘤模型中显示出抗肿瘤活性。
5. 在有丝分裂过程中，ZM447439和Hesperadin均能抑制染色体排列和纺锤体检查点功能。基于RNAi的实验及Aurora激酶突变体的过表达表明，这些表型源于对Aurora-B而非Aurora-A的抑制。
6. 这些药物并非"抗有丝分裂"制剂，因为它们不直接抑制细胞周期进程。而是在异常有丝分裂后，p53依赖性有丝分裂后检查点的激活诱导了"伪G1期"细胞周期停滞。
7. 尽管目前Aurora-A因与人类癌症的关联性获得更多关注，但Aurora-B可能是更理想的抗癌药物靶点，因为抑制Aurora-B能迅速引发灾难性有丝分裂，从而导致细胞死亡。

英文摘要：

Errors in mitosis can provide a source of the genomic instability that is typically associated with tumorigenesis. Many mitotic regulators are aberrantly expressed in tumour cells. These proteins could therefore make useful therapeutic targets. The kinases Aurora-A, -B and -C represent a family of such targets and several small-molecule inhibitors have been shown to block their function. Not only have these inhibitors advanced our understanding of mitosis, but, importantly, their in vivo antitumour activity has recently been reported. What have these studies taught us about the therapeutic potential of inhibiting this family of kinases?

摘要翻译： 

有丝分裂中的错误可能成为基因组不稳定性的来源，而基因组不稳定性通常与肿瘤发生相关。许多有丝分裂调控蛋白在肿瘤细胞中异常表达，因此这些蛋白可能成为有用的治疗靶点。Aurora-A、-B和-C激酶就是这样一个靶点家族，已有多种小分子抑制剂被证实可阻断其功能。这些抑制剂不仅促进了我们对于有丝分裂的理解，更重要的是，它们在体内抗肿瘤活性最近已被报道。这些研究让我们对这一激酶家族抑制治疗的潜力有何认识？

原文链接：

Aurora-kinase inhibitors as anticancer agents