Dreier Megan R, Grabovich Aaron Z, Katusin Jamie D, Taylor William R
Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA.
Exp Cell Res. 2009 Apr 15;315(7):1085-99. doi: 10.1016/j.yexcr.2009.02.008. Epub 2009 Feb 20.
Aurora kinases are essential for mitosis and are candidate targets of novel chemotherapeutic agents. The inhibitors ZM447439, MK-0457 (VX-680) as well as Hesperadin have been used to dissect the roles of Aurora kinases in the cell cycle and have been tested clinically for the treatment of cancer. Here we have carried out a detailed kinetic analysis of two isogenic cell lines differing in p53 function and have compared the effects of ZM447439 and VE-465 (related to MK-0457). We find that p53 is needed for efficient cell cycle arrest when Aurora kinases are inhibited by either ZM447439 or VE-465. However, the p53-induced cell cycle block is neither immediate nor absolute. ZM447439 induced the localized accumulation of gammaH2A.X indicating that p53 induction by this drug occurs in response to DNA damage. Our analysis of the long-term effects of ZM447439 indicates that cells can evade killing by the drug, but not via a classical drug-resistance mechanism. Several mechanisms to explain how cells may evade killing by Aurora kinase inhibitors are described.
极光激酶对有丝分裂至关重要，是新型化疗药物的候选靶点。抑制剂ZM447439、MK - 0457（VX - 680）以及海鞘素已被用于剖析极光激酶在细胞周期中的作用，并已进行癌症治疗的临床测试。在此，我们对两种p53功能不同的同基因细胞系进行了详细的动力学分析，并比较了ZM447439和VE - 465（与MK - 0457相关）的作用。我们发现，当极光激酶被ZM447439或VE - 465抑制时，有效的细胞周期停滞需要p53。然而，p53诱导的细胞周期阻滞既不是即时的也不是绝对的。ZM447439诱导了γH2A.X的局部积累，表明该药物诱导p53是对DNA损伤的反应。我们对ZM447439长期作用的分析表明，细胞可以逃避该药物的杀伤，但不是通过经典的耐药机制。本文描述了几种解释细胞如何逃避极光激酶抑制剂杀伤的机制。
