Department of Biomedical Science , University of Sheffield , Sheffield S10 2TN , U.K.
Department of Chemistry , University of Sheffield , Sheffield S10 2TN , U.K.
J Am Chem Soc. 2019 Feb 20;141(7):2925-2937. doi: 10.1021/jacs.8b09999. Epub 2019 Feb 7.
Drug resistance to platinum chemotherapeutics targeting DNA often involves abrogation of apoptosis and has emerged as a significant challenge in modern, non-targeted chemotherapy. Consequently, there is great interest in the anti-cancer properties of metal complexes-particularly those that interact with DNA-and mechanisms of consequent cell death. Herein we compare a parent cytotoxic complex, [Ru(phen)(tpphz)] [phen = 1,10-phenanthroline, tpphz = tetrapyridyl[3,2- a:2',3'- c:3″,2″- h:2‴,3‴- j]phenazine], with a mononuclear analogue with a modified intercalating ligand, [Ru(phen)(taptp)] [taptp = 4,5,9,18-tetraazaphenanthreno[9,10- b] triphenylene], and two structurally related dinuclear, tpphz-bridged, heterometallic complexes, RuRe and RuPt. All three of these structural changes result in a switch from intercalation to groove-binding DNA interaction and concomitant reduction in cytotoxic potency, but no significant change in relative cytotoxicity toward platinum-resistant A2780CIS cancer cells, indicating that the DNA interaction mode is not critical for the mechanism of platinum resistance. All variants exhibited a light-switch effect, which for the first time was exploited to investigate timing of cell death by live-cell microscopy. Surprisingly, cell death occurred rapidly as a consequence of oncosis, characterized by loss of cytoplasmic volume control, absence of significant mitochondrial membrane potential loss, and lack of activation of apoptotic cell death markers. Importantly, a novel, quantitative proteomic analysis of the A2780 cell genome following exposure of the cells to either mononuclear complex reveals changes in protein expression associated with global cell responses to oxidative stress and DNA replication/repair cellular pathways. This combination of multiple targeting modalities and induction of a non-apoptotic death mechanism makes these complexes highly promising chemotherapeutic cytotoxicity leads.
针对 DNA 的铂类化疗药物耐药性通常涉及细胞凋亡的失活，这已成为现代非靶向化疗的重大挑战。因此，人们对金属配合物的抗癌特性，特别是那些与 DNA 相互作用的金属配合物，以及随之产生的细胞死亡机制非常感兴趣。在这里，我们比较了一个母体细胞毒性配合物[Ru(phen)(tpphz)]（phen=1,10-菲咯啉，tpphz=四吡啶[3,2-a:2',3'-c:3″,2″-h:2‴,3‴-j]吩嗪）和一个带有修饰的嵌入配体的单核类似物[Ru(phen)(taptp)]（taptp=4,5,9,18-四氮杂菲并[9,10-b]三联苯），以及两个结构相关的二核、tpphz 桥联、异金属配合物 RuRe 和 RuPt。所有这三种结构变化都导致从嵌入到沟结合 DNA 相互作用的转变，并伴随细胞毒性效力的降低，但对铂类耐药 A2780CIS 癌细胞的相对细胞毒性没有显著变化，表明 DNA 相互作用模式对铂类耐药机制并不关键。所有变体都表现出光开关效应，这是首次利用活细胞显微镜来研究细胞死亡的时间。令人惊讶的是，细胞死亡是由于肿瘤坏死引起的，其特征是细胞质体积控制丧失、线粒体膜电位显著丧失以及凋亡细胞死亡标志物的激活缺失。重要的是，对细胞暴露于单核配合物后 A2780 细胞基因组的新型定量蛋白质组学分析揭示了与氧化应激和 DNA 复制/修复细胞途径的细胞整体反应相关的蛋白质表达变化。这种多种靶向模式的组合和诱导非凋亡性死亡机制使这些配合物成为极具前景的化疗细胞毒性先导化合物。
