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Bacterial Cytological Profiling Reveals the Mechanism of Action of Anticancer Metal Complexes.
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-06-30 , DOI: 10.1021/acs.molpharmaceut.8b00407
Yang Sun 1 , David K Heidary 1 , Zhihui Zhang 1 , Christopher I Richards 1 , Edith C Glazer 1
Affiliation  

Target identification and mechanistic studies of cytotoxic agents are challenging processes that are both time-consuming and costly. Here we describe an approach to mechanism of action studies for potential anticancer compounds by utilizing the simple prokaryotic system, E. coli, and we demonstrate its utility with the characterization of a ruthenium polypyridyl complex [Ru(bpy)2dmbpy2+]. Expression of the photoconvertible fluorescent protein Dendra2 facilitated both high throughput studies and single-cell imaging. This allowed for simultaneous ratiometric analysis of inhibition of protein production and phenotypic investigations. The profile of protein production, filament size and population, and nucleoid morphology revealed important differences between inorganic agents that damage DNA vs more selective inhibitors of transcription and translation. Trace metal analysis demonstrated that DNA is the preferred nucleic acid target of the ruthenium complex, but further studies in human cancer cells revealed altered cell signaling pathways compared to the commonly administrated anticancer agent cisplatin. This study demonstrates E. coli can be used to rapidly distinguish between compounds with disparate mechanisms of action and also for more subtle distinctions within in studies in mammalian cells.

中文翻译:

细菌细胞学分析揭示了抗癌金属配合物的作用机理。

细胞毒性剂的靶标鉴定和机理研究是既费时又昂贵的挑战性过程。在这里,我们描述了一种利用简单的原核系统大肠杆菌对潜在抗癌化合物进行作用机理研究的方法,并通过钌多吡啶基复合物[Ru(bpy)2dmbpy2 +]的表征证明了其实用性。光转换荧光蛋白Dendra2的表达促进了高通量研究和单细胞成像。这使得可以同时进行比例分析法来抑制蛋白质的产生并进行表型研究。蛋白质产量,细丝大小和数量的概况,核苷的形态揭示了破坏DNA的无机试剂与选择性的转录和翻译抑制剂之间的重要区别。痕量金属分析表明,DNA是钌配合物的首选核酸靶标,但在人类癌细胞中进行的进一步研究表明,与通常使用的抗癌药顺铂相比,细胞信号传导途径已改变。这项研究表明,大肠杆菌可用于快速区分具有不同作用机理的化合物,并且还可用于哺乳动物细胞研究中的更细微的区别。但是在人类癌细胞中的进一步研究表明,与通常使用的抗癌药顺铂相比,细胞信号传导途径发生了变化。这项研究表明,大肠杆菌可用于快速区分具有不同作用机理的化合物,并且还可用于哺乳动物细胞研究中的更细微的区别。但是在人类癌细胞中的进一步研究表明,与通常使用的抗癌药顺铂相比,细胞信号传导途径发生了变化。这项研究表明,大肠杆菌可用于快速区分具有不同作用机理的化合物,并且还可用于哺乳动物细胞研究中的更细微的区别。
更新日期:2018-06-04
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