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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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    Enhanced cytotoxic activity of doxorubicin through the inhibition of autophagy in triple negative breast cancer cell line
    (Elsevier Science Bv, 2017) Aydınlık, Şeyma; Erkısa, Merve; Cevatemre, Buse; Sarımahmut, Mehmet; Dere, Egemen; Arı, Ferda; Ulukaya, Engin
    Background: The outcome of triple negative breast cancer is still poor and requires improvement with better therapy options. Autophagy has recently been shown to play a role in anticancer drug resistance. Therefore, we investigated if the effectiveness of doxorubicin was augmented by the inhibition of autophagy. Methods: MDA-MB-231 was used as a model cell line for triple negative breast cancer and 3-methyladenine was used as an inhibitor of autophagy. Cells were treated with 0.46-1.84 mu M doxorubicin and 2.5-10 mu M 3-methyladenine for 48 h. Cell death mode was examined with M30 and M65 ELISA assays. ROS level and LDH activity was examined and the cellular acidic compartment of cells was monitored by acridine orange staining. The expression of various autophagy and apoptosis related proteins/genes were evaluated with Western blotting and RT-qPCR respectively. Results: Synergism was observed between the compounds (CI value < 1.0). RT-qPCR analysis revealed that the combination resulted in a down-regulation of autophagy-related genes. Moreover, the combination resulted in a different cell death modality, upregulating necroptosis-related genes. This suggests that the mode of cell death may switch from apoptosis to necroptosis, which is a more severe form of cell death, when autophagy is inhibited. These results were further confirmed at protein level by Western blotting. Conclusion: Inhibition of autophagy seems to sensitize triple negative breast cancer cells to doxorubicin, warranting further in vivo studies for the proof of this concept. General significance: Autophagy has a key role in drug resistance in MDA-MB-231 cells. Therefore combinatorial approaches may effectively overcome resistance. (C) 2016 Elsevier B.V. All rights reserved.
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    Identification of microenvironmental regulation and therapeutic targeting of oncogenic eEF2K in pancreatic cancer
    (Wiley, 2019) Karakaş Zeybek, Didem; Kahraman, Nermin; Bayraktar, Recep; Kabil, Nashwa; Ulukaya, Engin; Dere, Egemen; Berestein, Gabriel Lopez; Özpolat, Bülent
    Eukaryotic elongation factor 2 kinase (eEF2K) is overexpressed in cancer cells and its overexpression is correlated with poor prognosis in several types of cancer. It has been known that pancreatic cancer (PaCa) has a unique tumor microenvironment (TME) which contributes all stages of tumorigenesis. In this study, the effects of interaction between PaCa cells and macrophages on eEF2K levels and aggressive tumor behaviours were investigated.
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    Identification of microenvironmental regulation and therapeutic targeting of ongenic EF-2 kinase in pancreatic cancer
    (Science Direct, 2018) Karakaş Zeybek, Didem; Kahraman, Nermin; Bayraktar, Recep; Kabil, Nashwa; Ulukaya, Engin; Dere, Egemen; Lopez-Berestein, Gabriel; Özpolat, Bülent
    Introduction Pancreatic cancer (PaCa) is one of the most aggressive and deadliest cancer with 6 months average survival rate. Recent studies indicate that the tumour microenvironment (TME) plays an important role in all stages of tumorigenesis in PaCa. Therefore, both tumour cells and their TME should be targeted for an effective treatment. Eukaryotic elongation factor 2 kinase (EF2K) is an enzyme which is overexpressed in cancer cells and plays a key role in cancer cell survival under stress conditions. There is no study that have shown the relationship between EF2K and TME. Thus, we investigated that the effects of EF2K expression on PaCa cell line (PANC1) and the TME.
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    Induction of autophagy enhances apoptotic cell death via epidermal growth factor receptor inhibition by canertinib in cervical cancer cells
    (Elsevier, 2019) Aydınlık, Şeyma; Dere, Egemen; Ulukaya, Engin
    Background: It has been known epidermal growth factor receptor (EGFR) frequently overexpressed in cervical cancer. High levels of EGFR expression in their tumors leads to a poor prognosis and inhibition frequently induces autophagy in cancer cells. This study aimed to investigate whether EGFR inhibition by canertinib induces autophagy and this induction influence the effect of Palladium (Pd) (II) complex and 5-fluorouracil (5-FU) especially in nontoxic doses. Methods: Cytotoxicity was evaluated by using SRB assay. Apoptosis, autophagy, and EGFR key markers were determined by flow cytometry, fluorescence staining, and immunoblotting. Colony formation, invasion, and wound healing assays were performed to investigate cell proliferation, invasion, and migration, respectively. Results: Blocking EGFR by the pan-ErbB tyrosine kinase inhibitor canertinib inhibited cell growth of HeLa cervical cancer cells in combination with Pd(II) complex and 5-FU. Combination of canertinib and Pd(II) complex promotes autophagy and apoptosis of HeLa cancer cells via blockade of the PI3K/AKT and MAPK/ERK pathway, which leads to cervical cancer cell death. ROS accumulation and DNA damage were increased after combinatorial treatment which causes depolarization of the mitochondrial inner membrane and leads to apoptotic cell death. Canertinib combined with Pd(II) complex leads to inhibition of migration and invasion. Conclusion: Inhibition of EGFR signaling by canertinib in combination with Pd(II) complex promotes apoptosis and autophagy via blockade of the PI3K/AKT and MAPK/ERK. General significance: The cytotoxic activity of Pd(II) complex and 5-FU on HeLa cells is mediated by EGFR inhibition and autophagy induction, leading to activation of mitochondrial apoptotic cell death.