Effect of Schiff base Cu(II) complexes on signaling pathways in HT-29 cells

• Published in: Molecular medicine reports Vol. 14; no. 5; pp. 4436 - 4444
• Main Authors: Koňariková, Katarína, Perdikaris, Georgios A, Gbelcová, Helena, Andrezálová, Lucia, Švéda, Martin, Ruml, Tomáš, Laubertová, Lucia, Žitňanová, Ingrid
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.11.2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic drugs; Antitumor agents; Antiviral agents; Apoptosis; Apoptosis - drug effects; BAX protein; Bcl-2 protein; Breast cancer; Cancer therapies; Care and treatment; Cell Proliferation - drug effects; Cellular signal transduction; Chemotherapy; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Colorectal cancer; Copper; Copper - administration & dosage; copper complexes; Cytochrome c; Cytotoxicity; Ethanol; Gene Expression Regulation, Neoplastic - drug effects; Health aspects; HT-29 cell line; HT29 Cells; Humans; Imidazole; Inflammation; Leukemia; Metabolism; Mice; Mitochondria; Mitochondria - drug effects; Neoplasm Proteins - biosynthesis; Proteins; Schiff base; Schiff bases; Schiff Bases - administration & dosage; Signal Transduction - drug effects; United States > US
• ISSN: 1791-2997; 1791-3004
• DOI: 10.3892/mmr.2016.5739

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.