Cell type variation in responses to antimitotic drugs that target microtubules and kinesin-5
Cell type variation in responses to antimitotic drugs that target microtubules and kinesin-5
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DOI：
10.1158/0008-5472.can-07-6699
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发表时间：
2008-05-01
期刊：
影响因子：
11.2
通讯作者：
Mitchison, Tim
中科院分区：
文献类型：
--
作者：
Shi, Jue;Orth, James D.;Mitchison, Tim
为了改善癌症化疗，我们需要了解决定癌症和正常细胞药物敏感性的机制。在这里，我们在表型和分子水平上对三种抗有丝分裂药物的11种细胞系进行了研究：紫杉醇，诺考达唑和驱动蛋白-5抑制剂（也称为KSP，Eg 5，Kif 11）。使用自动化显微镜与有丝分裂和细胞凋亡的标记物（高含量筛选），我们发现，有丝分裂阻滞反应显示相对较小的变化之间的细胞类型，而经历细胞凋亡的趋势显示大的变化。我们没有发现有丝分裂阻滞和细胞凋亡之间的相关性。细胞凋亡依赖于进入有丝分裂，发生在有丝分裂内和退出后。对三种药物的反应强烈相关，尽管紫杉醇在相似的有丝分裂阻滞水平下在一些细胞系中引起更多的凋亡。分子生物学研究表明，细胞凋亡的敏感性与药物反应过程中抗凋亡蛋白XIAP的丢失相关，但与其反应前水平无关，并且在一定程度上也与p38和c-Jun NH 2激酶通路的激活相关。我们的结论是，在药物幼稚细胞系的抗有丝分裂药物的敏感性的变化是由凋亡信号的差异比有丝分裂纺锤体或纺锤体组装检查点蛋白的差异，并与不同的机制，抗有丝分裂药物触发非常相似，但不相同，反应。
To improve cancer chemotherapy, we need to understand the mechanisms that determine drug sensitivity in cancer and normal cells. Here, we investigate this question across a panel of 11 cell lines at a phenotypic and molecular level for three antimitotic drugs: paclitaxel, nocodazole, and an inhibitor of kinesin-5 (also known as KSP, Eg5, Kif11). Using automated microscopy with markers for mitosis and apoptosis (high content screening), we find that the mitotic arrest response shows relatively little variation between cell types, whereas the tendency to undergo apoptosis shows large variation. We found no correlation between levels of mitotic arrest and apoptosis. Apoptosis depended on entry into mitosis and occurred both from within mitosis and after exit. Response to the three drugs strongly correlated, although paclitaxel caused more apoptosis in some cell lines at similar levels of mitotic arrest. Molecular investigations showed that sensitivity to apoptosis correlated with loss of an antiapoptotic protein, XIAP, during the drug response, but not its preresponse levels, and to some extent also correlated with activation of the p38 and c-Jun NH2 kinase pathways. We conclude that variation in sensitivity to antimitotic drugs in drug-naive cell lines is governed more by differences in apoptotic signaling than by differences in mitotic spindle or spindle assembly checkpoint proteins and that antimitotics with different mechanisms trigger very similar, but not identical, responses.