PDF(Pubmed)
Abstract：
Ruthenium polypyridyl complexes are promising anticancer candidates, while their cellular targets have rarely been identified, which limits their clinical application. Herein, we design a series of Ru(II) polypyridyl complexes containing bioactive β-carboline derivatives as ligands for anticancer evaluation, among which Ru5 shows suitable lipophilicity, high aqueous solubility, relatively high anticancer activity and cancer cell selectivity. The subsequent utilization of a photo-clickable probe, Ru5a, serves to validate the significance of ATP synthase as a crucial target for Ru5 through photoaffinity-based protein profiling. Ru5 accumulates in mitochondria, impairs mitochondrial functions and induces mitophagy and ferroptosis. Combined analysis of mitochondrial proteomics and RNA-sequencing shows that Ru5 significantly downregulates the expression of the chloride channel protein, and influences genes related to ferroptosis and epithelial-to-mesenchymal transition. Finally, we prove that Ru5 exhibits higher anticancer efficacy than cisplatin in vivo. We firstly identify the molecular targets of ruthenium polypyridyl complexes using a photo-click proteomic method coupled with a multiomics approach, which provides an innovative strategy to elucidate the anticancer mechanisms of metallo-anticancer candidates.
摘要：
钌多吡啶配合物是有前途的抗癌候选物，虽然它们的细胞靶标很少被识别，这限制了它们的临床应用。在这里，我们设计了一系列含有生物活性β-咔啉衍生物的Ru(II)多吡啶配合物作为抗癌评价配体,其中Ru5显示出合适的亲脂性，高水溶性，相对较高的抗癌活性和癌细胞选择性。随后使用光可点击的探针，Ru5a,通过基于光亲和力的蛋白质谱分析，用于验证ATP合酶作为Ru5的关键靶标的重要性。Ru5在线粒体中积累，损害线粒体功能并诱导线粒体自噬和铁凋亡。线粒体蛋白质组学和RNA测序的联合分析表明，Ru5显著下调氯通道蛋白的表达，并影响与铁凋亡和上皮间质转化相关的基因。最后,我们证明Ru5在体内表现出比顺铂更高的抗癌功效。我们首先使用光点击蛋白质组学方法结合多组学方法鉴定钌多吡啶复合物的分子靶标，这为阐明金属抗癌候选物的抗癌机制提供了创新策略。
