Modulating cell-to-cell variability and sensitivity to death ligands by co-drugging
Modulating cell-to-cell variability and sensitivity to death ligands by co-drugging
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DOI：
10.1088/1478-3975/10/3/035002
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发表时间：
2013-06-01
期刊：
影响因子：
2
通讯作者：
Sorger, Peter K.
中科院分区：
文献类型：
--
作者：
Flusberg, Deborah A.;Sorger, Peter K.
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）是一种有希望的抗癌治疗药物，但仅在一部分肿瘤细胞系中有效诱导凋亡。此外，即使在反应系的克隆群体中，也只有一部分细胞因响应于TRAIL而死亡，并且单个细胞在细胞死亡时间上表现出细胞与细胞之间的变异性。这些细胞群中的部分杀伤似乎不是由细胞之间的遗传差异引起的，而是由基因表达状态的差异、蛋白质水平的波动以及TRAIL诱导的死亡或存活途径被激活的程度引起的。在这项研究中，我们询问细胞间变异性如何在对TRAIL具有不同敏感性的细胞类型中表现出来，以及当细胞暴露于药物组合时它如何变化。我们发现，用TRAIL治疗后存活的单个细胞可以再生亲本群体的敏感性和死亡时间分布，这表明部分杀伤是细胞群体的稳定特性。我们还表明，细胞对细胞的变异性的时间和概率的细胞凋亡，在响应于治疗可以调整使用药物的组合，一起增加细胞凋亡的敏感性相比，单独使用一种药物治疗。在TRAIL的情况下，通过联合用药调节细胞间变异性似乎涉及线粒体外膜透化阈值的降低。
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) holds promise as an anti-cancer therapeutic but efficiently induces apoptosis in only a subset of tumor cell lines. Moreover, even in clonal populations of responsive lines, only a fraction of cells dies in response to TRAIL and individual cells exhibit cell-to-cell variability in the timing of cell death. Fractional killing in these cell populations appears to arise not from genetic differences among cells but rather from differences in gene expression states, fluctuations in protein levels and the extent to which TRAIL-induced death or survival pathways become activated. In this study, we ask how cell-to-cell variability manifests in cell types with different sensitivities to TRAIL, as well as how it changes when cells are exposed to combinations of drugs. We show that individual cells that survive treatment with TRAIL can regenerate the sensitivity and death-time distribution of the parental population, demonstrating that fractional killing is a stable property of cell populations. We also show that cell-to-cell variability in the timing and probability of apoptosis in response to treatment can be tuned using combinations of drugs that together increase apoptotic sensitivity compared to treatment with one drug alone. In the case of TRAIL, modulation of cell-to-cell variability by co-drugging appears to involve a reduction in the threshold for mitochondrial outer membrane permeabilization.