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.
- MeSH
- apoptóza účinky léků MeSH
- buňky HT-29 MeSH
- lidé MeSH
- měď aplikace a dávkování MeSH
- mitochondrie účinky léků MeSH
- myši MeSH
- nádorové proteiny biosyntéza MeSH
- nádory tračníku farmakoterapie patologie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky aplikace a dávkování MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- Schiffovy báze aplikace a dávkování MeSH
- signální transdukce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Autophagy plays an important role in cancer cells. Targeting autophagy in cancer can provide new opportunities for drug development. METHODS: In this study we tested four Schiff base Cu(II) complexes against human breast cancer cells (MCF-7) and human non-cancerous cells (HEK-293T). We have tested their cytotoxic effect by evaluating IC50 using MTT test. To detect morphological changes of the actin fibers we have used fluorescent microscopy. To determine the type of cell death we used electrophoretic analysis and western blot analysis (protein LC3). RESULTS: IC50 values of the complexes increased with time of their influence, indicating acquired resistance of MCF-7 to the complexes. Healthy cells HEK-293T were not sensitive to the Cu(II) complexes. Compared with the control cells (cells without Cu(II) complexes) which were without morphological changes of actin fibers, Cu(II) complexes induced condensation and asymmetric conformational changes in actin filaments. To examine the type of cell death induced by the Cu(II) complexes we treated MCF-7 cells with Cu(II) complexes (1, 10, 50 and 100μmol/L) during a 72h incubation period. By electrophoresis we have not detected any DNA fragmentation. To determine whether Cu(II) complexes induced autophagy or necrotic cell death we used the western blot analysis. MCF-7 cells influenced with tested Cu(II) complexes produced LC3 protein after their 72h incubation indicating autophagy in MCF-7 cancer cells. CONCLUSIONS: Tested Schiff base copper (II) complexes have antiproliferative activity against cancer cells but not against healthy cells. They have induced autophagy in the cancer cell line MCF-7.
- MeSH
- autofagie účinky léků fyziologie MeSH
- HEK293 buňky MeSH
- lidé MeSH
- měď farmakologie toxicita MeSH
- MFC-7 buňky MeSH
- myši MeSH
- proliferace buněk účinky léků fyziologie MeSH
- Schiffovy báze farmakologie toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Srdcovo-cievne ochorenia patria medzi vážne príčiny úmrtia ľudí. Ateroskleróza a oxidačne modifi kované lipoproteíny výraznou mierou prispievajú k patológii týchto ochorení. Významnú úlohu v antiaterogénnych procesoch hrajú HDL- -lipoproteíny a s nimi asociované enzýmy, najmä paraoxonáza. Živočíšne paraoxonázy (PON1, PON2 a PON3) sú rodinou významných hydroláz závislých od Ca2+ a aktívnych voči celému radu rôznych substrátov. Aj keď skutočný fyziologický substrát pre jednotlivé PON sa nepozná, v súčasnosti sa považujú za významné substráty laktóny, niektoré oxidované fosfolipidy, produkty oxidácie kyseliny arachidónovej a dokozahexaénovej ako aj laktóny odvodené od N-acetyl-homoserínu. Všetky PON sa pokladajú za enzýmy s významnou antiaterogénnou aktivitou. Ich aktivity sa stanovujú voči rôznym substrátom, pričom arylesterázová aktivita PON1 sa považuje za smerodatnejší ukazovateľ antiaterogénnej aktivity ako paraoxonázová aktivita PON1. Laktonázová aktivita je pravdepodobne bližšie k fyziologickému substrátu ako paraoxon, či fenylacetát.
Cardiovascular diseases (CV) are one of the most important mortal diseases. Atherosclerosis and oxidatively modifi - ed lipoproteins are main risk factors that contribute to the pathology of CV diseases. HDL as well as HDL-associated enzyme paraoxonase play an important role in the antiatherogenic processes. Mammalian paraoxonases (PON1, PON2 and PON3) are a unique family of calcium dependent hydrolases, with enzymatic activity towards a broad range of substrates. Although PONs physiological substrates have not been identifi ed yet, some studies suggest some lactones, or some specifi c oxidized phospholipids, or products of oxidation of arachidonic and docosahexaenoic acid as well as N-acyl-homoserine lactones to be suitable substrates for the enzyme. All three members of the PON family were shown to protect from atherosclerosis development. Their biological activities are determined towards different substrates and arylesterase activity is more decisive indicator of antiatherogenic activity than paraoxonase activity. However structure- -reactivity studies indicate that lactonase activity of PON1 is its native activity.
