Koňariková Katarína, Perdikaris Georgios A, Gbelcova Helena, Andrezálová Lucia, Švéda Martin, Ruml Tomáš, Laubertová Lucia, Žitňanová Ingrid
Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, 813 72 Bratislava, Slovak Republic.
Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 813 72 Bratislava, Slovak Republic.
Mol Med Rep. 2016 Nov;14(5):4436-4444. doi: 10.3892/mmr.2016.5739. Epub 2016 Sep 14.
Schiff base copper (II) complexes are known for their anticancer, antifungal, antiviral and anti‑inflammatory activities. The aim of the current study was to investigate biological effects of Schiff base Cu (II) complexes (0.001‑100 µmol/l)‑[Cu2(sal‑D, L‑glu)2(isoquinoline)2]·2C2H5OH (1), [Cu(sal‑5‑met‑L‑glu)(H2O)].H2O (2), [Cu(ethanol)2(imidazole)4][Cu2(sal‑D, L-glu)2(imidazole)2] (3), [Cu(sal‑D,L‑glu)(2‑methylimidazole)] (4) on the human colon carcinoma cells HT‑29, the mouse noncancerous cell line NIH‑3T3 and the human noncancerous fibroblast cell line VH10. The results suggested that Cu (II) complexes exhibit cytotoxic effects against the HT‑29 cell line, while complexes 3 and 4 were the most effective. Subsequent to 72 h of incubation, apoptosis was observed in the HT‑29 cells induced by Cu (II) complexes 1 (0.1, 1, 10 and 50 µmol/l), 2 (1, 10, 50 and 100 µmol/l), 3 (0.01, 1, 10 and 50 µmol/l) and 4 (0.01, 0.1, 1 and 10 µmol/l). The apoptotic pathways activated by the Cu (II) complexes were identified. The results indicated that complexes 2, 3 and 4 were able to induce the mitochondria‑dependent pathway of apoptosis in HT‑29 cells, while complex 1 was obsered to activate the extrinsic pathway of apoptosis. The levels of the anti‑apoptotic protein Bcl‑2 were reduced and those of the pro‑apoptotic protein Bax increased following treatment with complexes 2, 3 and 4. Complex 1 had no effect on Bax protein expression. Complexes 2 and 3 induced elevation of cytochrome c (cyt c), while complex 4 induced a time‑dependent elevation of cyt c levels. No cyt c was detected in HT‑29 cells exposed to complex 1, suggesting that Cu (II) complexes activated the extrinsic pathway of apoptosis. The results from the current study in addition to previous studies suggest that Schiff base Cu (II) complexes have potential as novel anticancer drugs.
席夫碱铜（II）配合物以其抗癌、抗真菌、抗病毒和抗炎活性而闻名。本研究的目的是研究席夫碱铜（II）配合物（0.001 - 100 μmol/l）-[Cu2(sal-D,L-glu)2(isoquinoline)2]·2C2H5OH（1）、[Cu(sal-5-met-L-glu)(H2O)].H2O（2）、[Cu(ethanol)2(imidazole)4][Cu2(sal-D,L-glu)2(imidazole)2]（3）、[Cu(sal-D,L-glu)(2-methylimidazole)]（4）对人结肠癌细胞HT-29、小鼠非癌细胞系NIH-3T3和人非癌成纤维细胞系VH10的生物学效应。结果表明，铜（II）配合物对HT-29细胞系具有细胞毒性作用，其中配合物3和4最为有效。孵育72小时后，在由铜（II）配合物1（0.1、1、10和50 μmol/l）、2（1、10、50和100 μmol/l）、3（0.01、1、10和50 μmol/l）和4（0.01、0.1、1和10 μmol/l）诱导的HT-29细胞中观察到凋亡。确定了铜（II）配合物激活的凋亡途径。结果表明，配合物2、3和4能够诱导HT-29细胞中线粒体依赖性凋亡途径，而观察到配合物1激活凋亡的外源性途径。用配合物2、3和4处理后，抗凋亡蛋白Bcl-2水平降低，促凋亡蛋白Bax水平升高。配合物1对Bax蛋白表达无影响。配合物2和3诱导细胞色素c（cyt c）升高，而配合物4诱导cyt c水平随时间升高。在暴露于配合物1的HT-29细胞中未检测到cyt c，表明铜（II）配合物激活了凋亡的外源性途径。本研究结果以及先前的研究表明，席夫碱铜（II）配合物具有作为新型抗癌药物的潜力。
