Kinetic Heterogeneity of Cancer Cell Fractional Killing
Kinetic Heterogeneity of Cancer Cell Fractional Killing
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DOI：
10.1016/j.celrep.2020.107845
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发表时间：
2020-07-07
期刊：
影响因子：
8.8
通讯作者：
Dixon, Scott J.
中科院分区：
文献类型：
--
作者：
Inde, Zintis;Forcina, Giovanni C.;Dixon, Scott J.
致命药物可以诱导癌细胞群体中的不完全细胞死亡，这种现象被称为部分杀伤。在这里，我们表明，高通量的人口水平的延时成像可用于量化分数杀死数百种不同的药物治疗并行响应。我们发现，稳定的中等水平的部分杀伤是罕见的，许多药物治疗导致完全或接近完全根除所有细胞，如果给予足够的时间。随着时间的推移，部分杀伤的动力学随着药物、药物剂量和遗传背景的变化而变化。在分子水平上，抗凋亡蛋白MCL1是响应MAPK通路抑制剂而不是其他致死刺激的部分杀伤动力学的重要决定因素。这些研究表明，分数杀伤是由不同的致命刺激特异性机制。
Lethal drugs can induce incomplete cell death in a population of cancer cells, a phenomenon referred to as fractional killing. Here, we show that high-throughput population-level time-lapse imaging can be used to quantify fractional killing in response to hundreds of different drug treatments in parallel. We find that stable intermediate levels of fractional killing are uncommon, with many drug treatments resulting in complete or near-complete eradication of all cells, if given enough time. The kinetics of fractional killing over time vary substantially as a function of drug, drug dose, and genetic background. At the molecular level, the antiapoptotic protein MCL1 is an important determinant of the kinetics of fractional killing in response to MAPK pathway inhibitors but not other lethal stimuli. These studies suggest that fractional killing is governed by diverse lethal stimulus-specific mechanisms.