Aurora B kinase inhibition in mitosis: Strategies for optimizing the use of Aurora kinase inhibitors such as AT9283
Aurora B kinase inhibition in mitosis: Strategies for optimizing the use of Aurora kinase inhibitors such as AT9283
复制标题
有丝分裂中的 Aurora B 激酶抑制：优化 Aurora 激酶抑制剂（例如 AT9283）使用的策略
作者：
J. Curry;H. Angove;L. Fazal;J. Lyons;M. Reule;N. Thompson;N. Wallis
极光激酶在调节有丝分裂中起关键作用，并且是有吸引力的肿瘤学靶点。AT 9283是一种多靶点激酶抑制剂，对Aurora A和B激酶具有强效活性，可抑制多种实体瘤细胞系的生长和存活，在小鼠异种移植模型中有效。AT 9283处理导致细胞和肿瘤样本中的核内复制和丝氨酸-10组蛋白H3磷酸化的消除，证实在这些模型中，它作为Aurora B激酶抑制剂发挥作用。体外研究表明，暴露于AT 9283一个完整的细胞周期可使整个p53检查点受损细胞（HCT 116）群体发生多核化和死亡，而处理p53检查点感受态细胞（HMEC，A549）相似的时间长度可导致4 N DNA可逆性细胞停滞。在同步化细胞群中的进一步研究表明，有丝分裂期间暴露于AT 9283对于最佳细胞毒性至关重要。因此，我们研究了利用这些特性优化Aurora激酶抑制剂在体内对p53检查点受损肿瘤的疗效和治疗指数的方法。在异种移植模型中，将Aurora B激酶抑制与紫杉醇（其在有丝分裂中阻止细胞）组合导致有希望的功效而没有额外的毒性。这些发现对优化Aurora激酶抑制剂在临床实践中的疗效具有重要意义。
Aurora kinases play a key role in regulating mitotic division and are attractive oncology targets. AT9283, a multi-targeted kinase inhibitor with potent activity against Aurora A and B kinases, inhibited growth and survival of multiple solid tumor cell lines and was efficacious in mouse xenograft models. AT9283-treatment resulted in endoreduplication and ablation of serine-10 histone H3 phosphorylation in both cells and tumor samples, confirming that in these models it acts as an Aurora B kinase inhibitor. In vitro studies demonstrated that exposure to AT9283 for one complete cell cycle committed an entire population of p53 checkpoint-compromised cells (HCT116) to multinucleation and death whereas treatment of p53 checkpoint-competent cells (HMEC, A549) for a similar length of time led to a reversible arrest of cells with 4N DNA. Further studies in synchronized cell populations suggested that exposure to AT9283 during mitosis was critical for optimal cytotoxicity. We therefore investigated ways in which these properties might be exploited to optimize the efficacy and therapeutic index of Aurora kinase inhibitors for p53 checkpoint compromised tumors in vivo. Combining Aurora B kinase inhibition with paclitaxel, which arrests cells in mitosis, in a xenograft model resulted in promising efficacy without additional toxicity. These findings have implications for optimizing the efficacy of Aurora kinase inhibitors in clinical practice.
影响因子：
4.8
作者：
Privette, Lisa M.;Weier, Jingly F.;Petty, Elizabeth M.
通讯作者：
Petty, Elizabeth M.