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Cu(ii) phenanthroline-phenazine complexes dysregulate mitochondrial function and stimulate apoptosis.
Metallomics ( IF 3.4 ) Pub Date : 2019-10-18 , DOI: 10.1039/c9mt00187e
Garret Rochford 1 , Zara Molphy , Kevin Kavanagh , Malachy McCann , Michael Devereux , Andrew Kellett , Orla Howe
Affiliation  

Herein we report an in-depth study on the cytotoxic mechanism of action of four developmental cytotoxic copper(II) complexes: [Cu(phen)2]2+ (Cu-Phen); [Cu(DPQ)(Phen)]2+ (Cu-DPQ-Phen); [Cu(DPPZ)(Phen)]2+; and [Cu(DPPN)(Phen)]2+ (where Phen = 1,10-phenanthroline, DPQ = dipyrido[3,2-f:2′,3′-h]quinoxaline, DPPZ = dipyrido[3,2-a:2′,3′-c]phenazine, and DPPN = benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine). This complex class is known for its DNA intercalative properties and recent evidence—derived from an in vivo proteomic study—supports the potential targeting of mitochondrial function. Therefore, we focused on mitochondrial-mediated apoptosis related to cytotoxic activity and the potential impact these agents have on mitochondrial function. The Cu(II) complexes demonstrated superior activity regardless of aromatic extension within the phenazine ligand to the previously demonstrated activity of cisplatin. Unique toxicity mechanisms were also identified in prior demonstrated cisplatin sensitive and resistant cell lines. Double strand breaks in genomic DNA, quantified by γH2AX foci formation, were then coupled with apoptotic gene expression to elucidate the mechanisms of cell death. These results indicate that while DNA damage-induced apoptosis by BAX, XIAP and caspase-9 and -3 expression is moderate for the Cu(II) complexes when compared to cisplatin, protein targets independent of DNA exert a multimodal mechanistic effect. Significantly, mitochondrial gene expression of oxidative stress, protease expression, and fission/fusion processes—upregulated HMOX, DRP1 and LON, respectively—indicated an increased oxidative damage associated with compromised mitochondrial health upon exposure to these agents. These data support a unique mode of action by these complexes and provide valuable evidence of the developmental potential of these therapeutic inorganic complexes.

中文翻译:

铜(ii)菲咯啉-吩嗪复合物失调线粒体功能并刺激细胞凋亡。

在本文中,我们报告了对四种发育性细胞毒性铜(II)配合物:[Cu(phen)2 ] 2+(Cu-Phen)的作用的细胞毒性机理的深入研究。[Cu(DPQ)(Phen)] 2+(Cu-DPQ-Phen);[Cu(DPPZ)(Phen)] 2+;和[Cu(DPPN)(Phen)] 2+(其中Phen = 1,10-菲咯啉,DPQ =二吡咯并[3,2- f:2',3'- h ]喹喔啉,DPPZ =二吡咯并[3,2- a:2',3'- c ]吩嗪,而DPPN =苯并[ i ] dipyrido [3,2- a:2',3'- c ]吩嗪)。这种复杂的类因其DNA插入性和最近的证据而闻名-源自体内蛋白质组学研究-支持线粒体功能的潜在靶向。因此,我们集中于与细胞毒性活性相关的线粒体介导的细胞凋亡以及这些药物对线粒体功能的潜在影响。Cu(II)配合物显示出卓越的活性,而与吩嗪配体相比,吩嗪配体中的芳香族延伸都没有。在先前证明的顺铂敏感性和耐药性细胞系中也鉴定出独特的毒性机制。然后,通过γH2AX灶形成定量的基因组DNA中的双链断裂与凋亡基因表达相结合,以阐明细胞死亡的机制。这些结果表明,虽然由DNA损伤诱导的细胞凋亡BAXXIAP与顺铂相比,Cu(II)配合物的caspase-9-3表达适中,独立于DNA的蛋白质靶标发挥了多峰机制的作用。值得注意的是,氧化应激的线粒体基因表达,蛋白酶表达和裂变/融合过程(分别上调HMOXDRP1LON)表明,接触这些物质后,与线粒体健康受损相关的氧化损伤增加。这些数据支持了这些配合物的独特作用方式,并提供了这些治疗性无机配合物发展潜力的宝贵证据。
更新日期:2019-10-18
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