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    Cytotoxic activity and apoptosis induction by a series Ag(I)-NHC complexes on human breast cancer cells and non-tumorigenic epithelial cell line
    (Elsevier, 2021) Kutlu, Turkan; Yildirim, Isil; Karabiyik, Hande; Kilincli, Ayten; Tekedereli, Ibrahim; Gok, Yetkin; Dikmen, Miris
    The main problems encountered in treatment with anticancer drugs, undesired side effects, and toxicity. One of the most important parameters in cell transport is the lipophilic and solubility property of the drug. Enough with the potential effects, side effects with minimal demand for new anti-cancer compounds, mechanisms of action of the compound can meet because of increased efforts to be clarified. In this case, scientists were encouraged to do new research. In particular, the organometallic compounds are one of the topics focused lately. Ag(I)-NHC complexes are one of the most important classes of organometallic compounds. Although the anticancer activity of Ag(I)-NHC complexes have been known recently times, the anticancer effects of 2-morpholino ethyl substituted benzimidazolium derivative, lipophilic, and solubility properties. Ag(I)-NHC complexes have not unknown yet. Therefore, we aimed to investigate of cytotoxic effect and apoptosis mechanism on breast cancer cell lines (MCF7), breast adenocarcinoma cell lines (MDA-MB-231), and non-tumorigenic epithelium cell lines (MCF 10A) of new Ag(I)-NHC complexes that derivative from morpholine-linked benzimidazole, were synthesized and antimicrobial activity was determined in our previous study. The cytotoxicity was determined by the MTS method, and the apoptosis mechanisms were determined the cell cycle, Annexin V, and caspase-3 analysis. A new benzimidazolium salt bearing morpholino ethyl substituent (2) was synthesized. This benzimidazolium salt was characterized by NMR and FT-IR spectroscopic method and elemental analysis technique. Also, the structure of the new benzimidazolium salt was confirmed by single-crystal X-ray diffraction. Ag(I)-NHC complexes inhibited the growth of MCF7 and MDA-MB-231 cells depending on the dosage and time. The complexes 3a and 3b exhibited a significant difference p < 0.05; p < 0.001; and p < 0.001 level depend on depending on the increase in concentration on cancer cells. All compound induced by apoptosis was associated with stopping the cell cycle in phase G1 and the caspase-3 activity exhibited. The complex 3c was the lowest number of caspase-activating cells (2.1%) compared with both the control and other complexes in MDA-MB-231 cells. But the complex 3a was the highest number of caspase-activating cells (% 9.6). These findings have shown that these new Ag(I)-NHC complexes can be important new anticancer agents for breast cancer treatments. (C) 2020 Elsevier B.V. All rights reserved.
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    The Cytotoxicity Profile, Apoptosis Mechanism, and Molecular Docking Studies of a Series of Benzimidazolium Derivative Morpholine-Substituted Ag(I) Heterocyclic Carbene Complexes
    (Springer, 2023) Kutlu, Tuerkan; Yildirim, Isil; Dikmen, Miris; Tok, Tugba Taskin; Aktas, Aydin; Gok, Yetkin
    The main problems experienced in treatment with anticancer drugs are undesirable side effects, and toxicity. Minimal side effects for new anticancer compounds may be met due to enhanced efforts to clarify the compound's mechanisms of action. Therefore, we aimed to investigate whether or the cytotoxic effect and apoptosis mechanism of a series Ag(I)NHC complexes on non-small cell lung cancer cell line (A549) and normal lung fibroblast cell line (CCD-19Lu) in this study. The cytotoxicity was determined by using the MTT method, and apoptotic effects were detected by cell cycle, annexin-V/propidium iodide (PI) staining and cell cycle, caspase-3, mitochondrial membrane potential analysis. Molecular docking studies were performed using in silico ADMET analysis, and molecular docking information on the compounds was gained using the DS 3.5 software subprotocol. All the time, the cytotoxic effect of silver compounds was monitored for 24 h in comparison to cisplatin. The apoptotic effect of these compounds increased in cancer cells as compared to normal cells. Complex 3b exhibited the highest cytotoxic activity on cancer cell in 24 and 72 h, but complex 3a exhibited the highest cytotoxic activity on cancer cell s in 48 h. Moreover, all Ag(I)NHC complexes exhibited significant statistical difference depending on the increase in concentration on cancer cells, and all compounds induced apoptosis associated with distributing of membrane polarization and stopping the cell cycle in phase G1 and the caspase-3 activity. Caspase-3 activity of the new Ag(I)NHC compounds showed 8.3 to 17.6-fold increase compared the untreated cells. The loss of mitochondrial membrane potential indicated that JC-1 assay results were 16.9 to17.2-fold higher than normal cells in Ag(I)NHC compounds and 11.3-fold higher her in cisplatin. In addition, molecular docking studies were executed on the Ag(I)NHC complexes, and cisplatin estimate that the binding modes towards the EGFR kinase. Because epidermal growth factor receptor (EGFR) is expressed highly in a great number of epithelial tumors. These findings suggested that Ag(I)NHC complexes exhibited anticancer activity and may be considered to have a new therapeutic potential for human non-small cell lung cancer cell treatment.