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Copper(i) complexes with phosphine derived from sparfloxacin. Part III: multifaceted cell death and preliminary study of liposomal formulation of selected copper(i) complexes†
Dalton Transactions ( IF 3.5 ) Pub Date : 2017-12-26 00:00:00 , DOI: 10.1039/c7dt03917d A. Kyzioł 1, 2, 3, 4 , A. Cierniak 2, 3, 5, 6, 7 , J. Gubernator 4, 8, 9, 10 , A. Markowski 4, 8, 9, 10 , M. Jeżowska-Bojczuk 1, 4, 9, 10 , U. K. Komarnicka 1, 4, 9, 10
Dalton Transactions ( IF 3.5 ) Pub Date : 2017-12-26 00:00:00 , DOI: 10.1039/c7dt03917d A. Kyzioł 1, 2, 3, 4 , A. Cierniak 2, 3, 5, 6, 7 , J. Gubernator 4, 8, 9, 10 , A. Markowski 4, 8, 9, 10 , M. Jeżowska-Bojczuk 1, 4, 9, 10 , U. K. Komarnicka 1, 4, 9, 10
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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.
中文翻译：
铜（i）与衍生自司帕沙星的膦形成复合物。第三部分：多方面的细胞死亡和所选铜（i）配合物脂质体制剂的初步研究†
碘化物或硫氰酸铜（I）配合物（1-PSf，2-PSf，3-PSf，4-PSf）与衍生自司帕沙星（HSf）的膦和2,9-二甲基-1,10-菲咯啉（dmp）或2,2'-联喹啉（bq）作为二亚胺辅助配体已在体外（MRC-5）和赘生性（MCF7）人类细胞系中得到证明。针对选定的dmp和bq配合物（1-PSf，3-PSf分别阐明以下内容：（i）在生物系统中产生活性氧（ROS）的效率（循环伏安法）；（ii）它们对线粒体膜电位的影响；（iii）激活胱天蛋白酶3和9的效力；（iv）对DNA降解程度的影响（彗星分析）。结论是，癌细胞的凋亡直接与caspase依赖的线粒体途径有关，并由ROS产生和不可逆的DNA片段化支持。最后，证明了包封在脂质体（1-PSf -L）内的所选铜（I）复合物在癌细胞内表现出增强的积累。这导致它对癌细胞具有更高的细胞毒性，治疗指数为约。60.活性肿瘤中选择性积聚的增加，同时增加铜（I）配合物脂质体制剂的生物利用度和降低的系统毒性，可以导致新的铜基疗法的发展及其在抗癌化学疗法中的成功实施。
更新日期：2017-12-26
中文翻译：
铜（i）与衍生自司帕沙星的膦形成复合物。第三部分：多方面的细胞死亡和所选铜（i）配合物脂质体制剂的初步研究†
碘化物或硫氰酸铜（I）配合物（1-PSf，2-PSf，3-PSf，4-PSf）与衍生自司帕沙星（HSf）的膦和2,9-二甲基-1,10-菲咯啉（dmp）或2,2'-联喹啉（bq）作为二亚胺辅助配体已在体外（MRC-5）和赘生性（MCF7）人类细胞系中得到证明。针对选定的dmp和bq配合物（1-PSf，3-PSf分别阐明以下内容：（i）在生物系统中产生活性氧（ROS）的效率（循环伏安法）；（ii）它们对线粒体膜电位的影响；（iii）激活胱天蛋白酶3和9的效力；（iv）对DNA降解程度的影响（彗星分析）。结论是，癌细胞的凋亡直接与caspase依赖的线粒体途径有关，并由ROS产生和不可逆的DNA片段化支持。最后，证明了包封在脂质体（1-PSf -L）内的所选铜（I）复合物在癌细胞内表现出增强的积累。这导致它对癌细胞具有更高的细胞毒性，治疗指数为约。60.活性肿瘤中选择性积聚的增加，同时增加铜（I）配合物脂质体制剂的生物利用度和降低的系统毒性，可以导致新的铜基疗法的发展及其在抗癌化学疗法中的成功实施。
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