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    Cytotoxic and apoptotic effects of the combination of palladium (II) 5,5-diethylbarbiturate complex with bis(2-pyridylmethyl)amine and curcumin on non small lung cancer cell lines
    (Pergamon-Elsevier Science Ltd, 2017) Tunç, Duygu; Dere, Egemen; Karakaş, Didem; Cevatemre, Buse; Yılmaz, Veysel Turan; Ulukaya, Engin
    Metal-based chemotherapeutics such as cisplatin are widely used treatment of lung cancer which is the major cause of cancer-related mortality worldwide. Recent studies demonstrated that novel metal-based compounds have strong cytotoxic activity in a similar way as cisplatin. Therefore, metal-based compounds have been synthesized and investigated in order to determine their cytotoxic activities. It has been also reported curcumin, which has been derived from turmeric plant, has powerful cytotoxic effect on various cancer cell lines. In the light of these data, it has been investigated the cytotoxic effects of combination of curcumin (0.78-100 mu M) and palladium (II) 5,5-diethylbarbiturate complex with bis(2-pyridylmethyl)amine [Pd(II) complex] (0.39-50 mu M) against non small lung cancer cell lines, A549 and H1299. It has been found that combination of Pd(II) complex and curcumin enhanced the cytotoxic activity and apoptotic cell death at 48 h, compared to single use of each agent, only in H1299 cell line (combination index <1). Apoptosis was evident by annexin v staining positivity, increased caspase 3/7 activity and the presence of pyknotic nuclei. Pro-apoptotic genes of TNFRSFIOA and HRK were found to be involved in apoptotic cell death. In conclusion, the application of this combination may be regarded as a novel and effective approach for the treatment of lung cancer due to its promising cytotoxic and apoptotic effect. (C) 2017 Elsevier Ltd. All rights reserved.
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    Evidence for heterogeneity in response to treatment in mammary tumors of dogs as happens in humans
    (NCI CPTAC Assay Portal, 2022) Turna, Özge; Üvez, Ayça; Baykal, Aslıhan; Develi, Elif Sedef; Dıramalı, Murat; Sönmez, Kıvılcım; Karakaş, Didem; Kaşıkçı, Güven; Armutak, Elif İlkay; Ulukaya, Engin
    Tumors are formed by various clones developed over a long time. This gives rise to a heterogeneous nature. This heterogeneity is the hardest challenge in the treatment of cancers because it is the main reason for drug resistance. This is a well-known fact in human cancer. Therefore, we have reasoned that if the tumor heterogeneity in canine mammary gland tumors (CMGTs) could be shown by an ex vivo assay, which will be used first time in veterinary oncology practice, this could be used further in clinics. To achieve this, twenty-six patients were included in the study. Tumor tissues were obtained from animals during routine surgery. Tumor cells were isolated and seeded ex vivo. The cells were exposed to anticancer drugs that are clinically used. Seven days after the treatment, chemosensitivity has luminometrically been assayed by ATP-tumor chemosensitivity assay (ATP-TCA). It has clearly been shown that all the tumor tissues have responded to treatment differently, implying that heterogeneity exists in mammary tumors. There has also been found that there was a weak to moderate statistically significant correlation between tumor size and drug index. However, there has been no correlation between drug index and metastasis to lymph nodes. Hyperplasic areas had relatively higher PCNA values. The results of our study demonstrate the heterogeneity in responses to in vitro drugs. Clinical trials based on test results and follow-up studies with large numbers of animals are needed to prove that such chemotherapeutic activity assessment tests can be clinically useful in predicting drug responses in CMGTs.
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    A trans-platinum(II) complex induces apoptosis in cancer stem cells of breast cancer
    (Pergamon-Elsevier Science Ltd, 2017) Aztopal, Nazlıhan; Karakaş, Didem; Cevatemre, Buse; Arı, Ferda; İçsel, Ceyda; Daidone, Maria G.; Ulukaya, Engin
    Recent accumulating evidence has supported the notion that tumors have hierarchically organized heterogeneous cell populations and a small subpopulation of cells, termed cancer stem cells (CSCs), are responsible for tumor initiation, maintenance as well as drug resistance. Therefore, targeting the CSCs along with the other cancer cells has been the most important topic during the last decade. In the present study, we evaluated the cytotoxic activity of trans-[PtCl2(2-hepy) 2] [2-hepy = 2-(2-hydroxyethyl) pyridine] complex and the mechanism of cell death in breast CSCs. Stemness markers, Oct-4 and Sox2, were determined in mammospheres by western blotting. Cytotoxicity was assessed using the ATP viability assay. Cell death was fluorescently visualized and further confirmed by flow cytometry as well as gene expression analysis. The Pt(II) complex significantly reduced the cell viability, prevented mammosphere formation and disrupted mammosphere structures in a dose-dependent manner (0100 lM). The mode of cell death was apoptosis and it was shown by the presence of caspase 3/7 activity, Annexin V-FITC positivity, decreased mitochondrial membrane potential and increased expressions of pro-apoptotic genes (TNFRSF10A and HRK). Interestingly, necroptosis was also observed by the evidence of increased MLKL expression. In conclusion, the Pt(II) complex seems to be a highly promising anticancer compound due to its promising cytotoxic activity on CSCs. Therefore, it deserves in vivo further studies for the proof-of-concept. (C) 2016 Elsevier Ltd. All rights reserved.