Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 38, 1090, Vienna, Austria.
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090, Vienna, Austria.
Chemistry. 2020 Dec 1;26(67):15528-15537. doi: 10.1002/chem.202003495. Epub 2020 Nov 3.
The organometallic Au bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene) ] (AuTMX ) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX in the cellular context using mass spectrometry-based methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal-based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX by alterations in the nucleolus, telomeres, actin stress-fibres and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.
先前的研究表明，有机金属 Au 双-N-杂环卡宾配合物 [Au(9-甲基咖啡酰亚胺) ]（AuTMX）能够选择性地、有效地稳定端粒 DNA G-四链体（G4）结构。本研究使用基于质谱的方法，包括在 A2780 卵巢癌细胞中的 shotgun 蛋白质组学，深入研究了 AuTMX 在细胞环境中的分子反应性和作用模式。与其他基于金属的抗癌药物不同，这种有机金化合物与生物亲核试剂形成配位键的倾向较小，预计主要通过非共价相互作用发挥其药物作用。经处理的癌细胞的总蛋白表达变化通过核仁、端粒、肌动蛋白应激纤维和应激反应的改变揭示了 AuTMX 的多模式作用模式，这些变化得到了药理学测定、荧光显微镜和细胞积累实验的进一步支持。蛋白质组学数据可通过 ProteomeXchange 以标识符 PXD020560 获得。
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