Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Kraków, Poland.
Dalton Trans. 2018 Feb 6;47(6):1981-1992. doi: 10.1039/c7dt03917d.
The cytotoxic effect of iodide or thiocyanate copper(i) complexes (1-PSf, 2-PSf, 3-PSf, 4-PSf) with phosphine derived from sparfloxacin (HSf) and 2,9-dimethyl-1,10-phenanthroline (dmp) or 2,2'-biquinoline (bq) as diimine auxiliary ligands was proved in vitro on somatic (MRC-5) and neoplastic (MCF7) human cell lines. Differences in mode of action were investigated in-depth for the selected dmp and bq complexes (1-PSf, 3-PSf, respectively) by elucidation of the following: (i) the efficiency to produce reactive oxygen species (ROS) in biological systems (cyclic voltammetry); (ii) their impact on mitochondrial membrane potential; (iii) potency for the activation of caspases 3 and 9; (iv) influence on the degree of DNA degradation (comet assay). It was concluded that the apoptosis of cancer cells is directly connected to the caspase-dependent mitochondrial pathway and supported by ROS production along with irreversible DNA fragmentation. Finally, it was demonstrated that the selected copper(i) complex encapsulated inside liposomes (1-PSf-L) exhibited enhanced accumulation inside cancer cells. This resulted in its higher cytotoxicity against cancer cells with therapeutic index of ca. 60. Increased selective accumulation in active neoplasm with simultaneous enhanced bioavailability and reduced systemic toxicity of liposomal formulation of copper(i) complexes can result in the development of new copper-based therapeutics and their successful implementation in anticancer chemotherapy.
碘化物或硫氰酸根铜（I）配合物（1-PSf、2-PSf、3-PSf、4-PSf）与来源于司帕沙星（HSf）和 2,9-二甲基-1,10-菲咯啉（dmp）或 2,2'-联喹啉（bq）的膦作为二亚胺辅助配体的细胞毒性作用在体外对体细胞（MRC-5）和肿瘤细胞系（MCF7）进行了证明。通过阐明以下内容，深入研究了所选 dmp 和 bq 配合物（分别为 1-PSf 和 3-PSf）的作用方式：（i）在生物体系中产生活性氧物种（ROS）的效率（循环伏安法）；（ii）它们对线粒体膜电位的影响；（iii）激活 caspase 3 和 9 的能力；（iv）对 DNA 降解程度的影响（彗星试验）。结论是癌细胞的凋亡与 caspase 依赖性线粒体途径直接相关，并通过 ROS 产生和不可逆的 DNA 片段化得到支持。最后，证明了包封在脂质体中的选定铜（I）配合物（1-PSf-L）在癌细胞内的积累增强。这导致其对癌细胞的细胞毒性增加，治疗指数约为 60。通过增加在活性肿瘤中的选择性积累，同时提高脂质体制剂的生物利用度和降低系统毒性，可能会开发出新的基于铜的治疗方法，并成功将其应用于癌症化疗中。
