Researcher:
Cevatemre, Buse

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Buse

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Cevatemre

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2019 - 201942020 - 20226

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    Unfolded protein response is involved in trans-platinum (ii) complex-induced apoptosis in prostate cancer cells via ros accumulation
    (2019) Karakaş, Didem; Oral, Arzu Y.; Yılmaz, Veysel T.; Ulukaya, Engin; Animal Laboratory; Cevatemre, Buse; Researcher; Animal Laboratory; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/A; N/A
    Background: Prostate cancer is one of the most common cancer types and it is the sixth leading cause of cancer-related death in men worldwide. Even though novel treatment modalities have been developed, it still a lifethreatening disease. Therefore novel compounds are needed to improve the overall survival. Methods: In our study, it was aimed to evaluate the anti-cancer activity of newly synthesized Platinum (II) [Pt(II)] complex on DU145, LNCaP and PC-3 prostate cancer cell lines. The cytotoxic activity of Pt(II) complex was tested by SRB and ATP cell viability assays. To detect the mode of cell death; fluorescent staining, flow cytometry and western blot analyses were performed. Results: The Pt(II) complex treatment resulted in a decrease in cell viability and increasing levels of apoptotic markers (pyknotic nuclei, annexin-V, caspase 3/7 activity) and a decrease in mitochondrial membrane potential in a dose dependent manner. Among cell types, tested PC-3 cells were found to be more sensitive to Pt(II) complex, demonstrating elevation of DNA damage in this cell line. In addition, Pt(II) complex induced Endoplasmic Reticulum (ER) stress by triggering ROS generation. More importantly, pre-treatment with NAC alleviated Pt(II) complex-mediated ER stress and cell death in PC-3. Conclusion: These findings suggest an upstream role of ROS production in Pt(II) complex-induced ER stressmediated apoptotic cell death. Considering the ROS-mediated apoptosis inducing the effect of Pt(II) complex, it warrants further evaluation as a novel metal-containing anticancer drug candidate.
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    A promising therapeutic combination for metastatic prostate cancer: chloroquine as autophagy inhibitor and palladium(II) barbiturate complex
    (Elsevier France-Editions Scientifiques Medicales Elsevier, 2020) Erkisa, Merve; Aydinlik, Seyma; Aztopal, Nazlihan; Akar, Remzi Okan; Celikler, Serap; Yilmaz, Veysel Turan; Ari, Ferda; Ulukaya, Engin; Animal Laboratory; Cevatemre, Buse; Researcher; Animal Laboratory; N/A; N/A
    Autophagy is a catabolic process for cells that can provide energy sources and allows cancer cells to evade cell death. Therefore, studies on the combination of autophagy inhibitors with drugs are increasing as a new treatment modality in cancer. Previously, we reported the anti-tumor activity of a Palladium (Pd)(II) complex against different types of cancer in vitro and in vivo. Chloroquine (CQ), the worldwide used anti-malarial drug, has recently been focused as a chemosensitizer in cancer treatment. The aim of this study was to investigate the efficacy of a combined treatment of these agents that work through different mechanisms to provide an effective treatment modality for metastatic prostate cancer that is certainly fatal. Metastatic prostate cancer cell lines (PC-3 and LNCaP) were treated with Pd (II) complex, CQ, and their combination. The combination enhanced apoptosis by increasing phosphatidylserine translocation and pro-apoptotic proteins. Apoptosis was confirmed by the use of apoptosis inhibitor. The formation of acidic vesicular organelles (AVOs) was observed by acridine orange staining in fluorescence microscopy. The Pd (II) complex increased AVOs formation in prostate cancer cells and CQ-pretreatment has potentiated this effect. Importantly, treatment with CQ suppressed the pro-survival function of autophagy, which might have contributed to enhanced cytotoxicity. In addition, PI3K/AKT/mTOR-related protein expressions were altered after the combination of treatments. Our results suggest that combination treatment enhances apoptotic cell death possibly via the inhibition of autophagy, and may therefore be regarded as a novel and better approach for the treatment of metastatic prostate cancer. (C) 2020 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.
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    Structures and anticancer activity of chlorido platinum(II) saccharinate complexes with mono- and dialkylphenylphosphines
    (Elsevier Science Inc, 2019) İçsel, Ceyda; Yılmaz, Veysel T.; Aygün, Muhittin; Ulukaya, Engin; Animal Laboratory; Cevatemre, Buse; Researcher; Animal Laboratory; N/A; N/A
    cis-[PtCl(sac)(PPh2Me)(2)] (1), cis-[PtCl(sac)(PPhMe2)(2)] (2), trans-[PtCl(sac)(PPh2Et)(2)] (3) and trans- [PtCl(sac) (PPhEt2)(2)] (4) complexes (sac = saccharinate) were synthesized and characterized by elemental analysis and spectroscopic methods. The structures of 2-4 were determined by X-ray single-crystal diffraction. The interaction of the complexes with DNA was studied various biochemical, biophysical and molecular docking methods. Only the cis-configured complexes (1 and 2) showed nuclease activity and their binding affinity towards DNA was considerably higher than those of their trans-congeners (3 and 4). The chlorido ligand in the cis-configured complexes underwent aquation, making them more reactive towards DNA. Furthermore, 1 and 2 exhibited anticancer potency on breast (MCF-7) and colon (HCT116) cancer cells similar to cisplatin, whereas 3 and 4 were biologicallly inactive. Mechanistic studies on MCF-7 cells showed that higher nuclear uptake, cell cycle arrest at the S phase, dramatically increased DNA double-strand breaks, apoptosis induction, elevated levels of reactive oxygen species (ROS) and high mitochondrial membrane depolarization greatly contribute to the anticancer potency of 1 and 2.
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    Overcoming chemoresistance in triple negative breast cancer by bromodomain inhibition
    (Elsevier Sci Ltd, 2022) Philpott, M.; Cribbs, A.; Oppermann, U.; Onder, T. T.; Department of Molecular Biology and Genetics; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; Bayram, Özlem Yedier; Cingöz, Ahmet; Aksu, Ali Cenk; Değirmenci, Nareg Pınarbaşı; Esin, Beril; Kayabölen, Alişan; Cevatemre, Buse; Ayhan, Ceyda Açılan; Önder, Tuğba Bağcı; Researcher; Researcher; PhD Student; PhD Student; Master Student; PhD Student; Researcher; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; College of Engineering; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; N/A; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 219658; 184359
    Background: Triple negative breast cancer (TNBC) is an aggressive subtypeofbreastcancerwithpoorprognosis.TNBCcellsdonotexpress receptorsforestrogen,progesteroneorHer2,eliminatingthepossibilityof targetedtherapyapplications.Therefore,current treatmentoptionforTNBC is limitedwithsurgery followedbyconventional chemotherapy.However, acquiredresistancetochemotherapyisamajorchallengethatisassociated withrelapse,whichisdrivenbycoordinatedactionsofgeneticandepigenetic events. MaterialsandMethods:Weaimedtoelucidatetherolesoffullspectrum ofepigeneticmodifiersinmaintenanceandreversionofchemoresistancein TNBC.TogenerateinvitromodelsofchemoresistantTNBC,weexposed3 different TNBC cell lines to escalating doses of taxane (paclitaxel). Transcriptome analysis by RNA-sequencingwere performed to reveal changesthat regulatechemoresistance.Withourcustomepigenome-wide CRISPR-Cas9library(EpigeneticKnock-OutLibrary-EPIKOL)targetingall chromatinreaders,writers,erasersandassociatedproteins,wesystematicallyinterrogatedtherolesofepigeneticmodifiersinchemoresistantTNBC cells.Wealsoconductedmediumscalechemicalscreensutilizingepigenetic probelibrariesinchemoresistantcells. Results:RNAsequencingonpairedsensitiveandchemoresistancecell linesrevealedABCB1upregulationasamajordriverofresistance.Inhibition of themembersofMLLandSWI/SNFcomplexes, aswell as thegenes relatedwithhistoneubiquitinationandacetyl-mark readers re-sensitized chemoresistantcellstopaclitaxel.Amemberof thebromodomainprotein family,BRPF1,cameasacommonhit inourchemical screenaswellas geneticscreens.KnockoutofBRPF1or itschemical inhibitioncompletely abolishedpaclitaxel resistanceandmodulatedABCB1expression. Conclusions:ThroughEPIKOLscreensonchemoresistantTNBCcells coupledwithchemicalscreens,weidentifiednovelepigeneticmodifiersthat arecrucial formaintainingandovercomingdrug resistance.Collectively, thesefindingsprovideabasistodevelopcombinationtherapiestoefficiently killchemoresistantTNBC.
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    The mechanism for anticancer and apoptosis-inducing properties of Cu(II) complex with quercetin and 1,10-Phenanthroline
    (Wiley, 2022) Done, Gulseven; Ari, Ferda; Akgun, Oguzhan; Akgun, Halime; Genckal, Hasene Mutlu; Animal Laboratory; Cevatemre, Buse; Researcher; Animal Laboratory; N/A; N/A
    This article covers the anticancer activities and mechanisms of action of Cu(II) complexes of flavonoid-derived quercetin and 1,10-phenanthroline ligands. The antiproliferative activity of the complex and its ligands was evaluated by MTT, ATP, and SRB viability assays in human lung cancer cells (A549, H1299). Findings for apoptosis were determined by fluorescent staining, flow cytometry analysis, and the M30 antigen method. In addition, the mechanism of action of the complex was investigated by Annexin V staining, caspase 3/7 activity, ROS formation, and cell cycle analysis. The involvement of caspases, thus, apoptosis was confirmed by rescuing cell death by using a pan-caspase inhibitor (Z-VAD-FMK). Again, increased ROS levels in the cell showed that death may occur by apoptosis. For this reason, the accuracy of ROS-induced apoptosis in cells has been proven as a result of the application of N-acetylcysteine (NAC), which is a ROS inhibitor. The efficacy of the complex was compared with Cisplatin and ligands. The results showed that the Cu(II) flavonoid complex is cytotoxic on lung cancer cells and may have the potential to act as an effective metal-based anticancer drug with a lower IC50 over Cisplatin.
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    May iron(III) complexes containing phenanthroline derivatives as ligands be prospective anticancer agents?
    (Elsevier, 2019) Matos, Cristina P.; Adiguzel, Zelal; Yildizhan, Yasemin; Cevik, Ozge; Nunes, Patrique; Ferreira, Liliana P.; Carvalho, Maria Deus; Campos, Debora L.; Pavan, Fernando R.; Pesso, Joao Costa; Garcia, Maria Helena; Tomaz, Ana Isabel; Correia, Isabel; Animal Laboratory; N/A; N/A; Cevatemre, Buse; Önder, Tuğba Bağcı; Ayhan, Ceyda Açılan; Researcher; Faculty Member; Faculty Member; Animal Laboratory; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; School of Medicine; School of Medicine; N/A; 184359; 219658
    We report the design, synthesis and biological studies on a group of mixed ligand Fe(111) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L2-, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl) amine, and different aromatic bases NN = 2,21-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO3 (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FUR, UV-Vis, H-1 and C-13 NMR and fluorescence spectroscopies. [Fe(phen)Cl-3] and [Fe(amphen)Cl-3] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via M1T analysis all compounds 1-6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin VPAAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and gamma H2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTh activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies.
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    Cu(II) and V(IV)O complexes with tri- or tetradentate ligands based on (2-hydroxybenzyl)-L-alanines reveal promising anticancer therapeutic potential
    (Royal Soc Chemistry, 2021) Ribeiro, Nadia; Bulut, Ipek; Teixeira, Carlos; Yildizhan, Yasemin; Andre, Vania; Adao, Pedro; Pessoa, Joao Costa; Correia, Isabel; Animal Laboratory; N/A; Cevatemre, Buse; Ayhan, Ceyda Açılan; Researcher; Faculty Member; Animal Laboratory; N/A; School of Medicine; N/A; 219658
    Four new ligand precursors (H2L1-H2L4), derived from the Mannich condensation of two amino acids (L-Val and L-Phe) and two 3,5-disubstituted phenols (t-Bu or Me), and the corresponding oxidovanadium(IV) (1-4) and copper(II) (6-7) complexes are synthesized. Two other related compounds (H2L5 and H2L6), containing an additional 2-methyl-pyridine arm, and the corresponding (VO)-O-IV (5) and Cu-II (8-9) complexes were also obtained. All metal complexes are monomeric in the solid state, having a solvent molecule or a chloride ion in the coordination sphere. The in vitro cytotoxic activity of all compounds is evaluated against cancer cells from different origins. The IC50 values at 72 h are in the range of 6-15 mu M for HeLa cells, 4-17 mu M for A-549 cells and >25 mu M for MDA-MB-231 cells, except for [(VOL1)-O-IV(CH3OH)] (1) and [CuL6(H2O)] (9). With the exception of H2L6, overall, the metal complexes are more cytotoxic than the corresponding ligand precursors. Globally, the cellular viability data show that (i) the L-Phe derived compounds are more cytotoxic than the corresponding L-Val complexes; (ii) the presence of the bulkier t-Bu groups increases the cytotoxicity; (iii) the presence of a 2-methyl-pyridine arm increases considerably the cytotoxicity; and (iv) the Cu-II-complexes are more cytotoxic than the (VO)-O-IV-compounds. Complexes [(VOL3)-O-IV(CH3OH)] (3), [CuL3(H2O)] (7) and [CuL5(H2O)] (8) were further evaluated and their mechanism of action was determined to be apoptosis, evidenced by AnnexinV staining and the increase in caspase 3/7 activity. Compounds 3, 7 and 8 also exhibit DNA cleavage activity, involving the formation of reactive oxygen species and were able to induce genomic damage in cells as determined by COMET assay.
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    Cytotoxic platinum(II) complexes derived from saccharinate and phosphine ligands: synthesis, structures, DNA cleavage, and oxidative stress-induced apoptosis
    (Springer, 2020) İçsel, Ceyda; Yılmaz, Veysel T.; Aygün, Muhittin; Ulukaya, Engin; Animal Laboratory; Cevatemre, Buse; Researcher; Animal Laboratory; N/A; N/A
    A series of the structurally related platinum(II) saccharinate (sac) complexes with alkylphenylphosphines, namely cis-[Pt(sac)(2)(PPh2Me)(2)]center dot DMSO (1), cis-[Pt(sac)(2)(PPhMe2)(2)] (2), cis-[Pt(sac)(2)(PPh2Et)(2)] (3), and cis-[Pt(sac)(2)(PPhEt2)(2)]center dot 2DMSO (4), were synthesized and fully characterized; their structures were determined by X-ray crystallography. All the complexes were investigated for their anticancer potentials on three human cancer cells including A549 (lung), MCF-7 (breast), and HCT116 (colon) in addition to a noncancerous human bronchial epithelial cells (BEAS-2B). Specifically, 1 and 3 showed significant cytotoxic effects against MCF-7 and HCT116 cell lines in comparison to cisplatin, and were considered as the most potent ones in the series. The cytotoxic complexes were found to cleave DNA efficiently. In addition, the binding interactions of the complexes with DNA were confirmed by enzyme inhibition and molecular docking studies. Complexes 1 and 3 were capable of inducing apoptosis and arrested the cell cycle at the DNA synthesis (S) phase in MCF-7 cells. Furthermore, 1 and 3 caused the excessive generation of reactive oxygen species (ROS), leading to mitochondrial dysfunction and double-strand DNA breaks.
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    PublicationOpen Access
    Experimental data on novel Fe(III)-complexes containing phenanthroline derivatives for their anticancer properties
    (Elsevier, 2019) Matos, Cristina P.; Adıgüzel, Zelal; Yıldızhan, Yasemin; Çevik, Özge; Nunes, Patrique; Ferreira, Liliana P.; Carvalho, Maria Deus; Campos, Debora L.; Pavan, Fernando R.; Pessoa, Joao Costa; Garcia, Maria Helena; Tomaz, Ana Isabel; Correia, Isabel; Department of Molecular Biology and Genetics; Cevatemre, Buse; Önder, Tuğba Bağcı; Ayhan, Ceyda Açılan; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; N/A; 184359; N/A
    This dataset is related to the research article entitled “May iron(III) complexes containing phenanthroline derivatives as ligands be prospective anticancer agents?” [1]. It includes the characterization by UV–Vis absorption spectroscopy and magnetic techniques of a group of mixed ligand Fe(III) complexes bearing a tripodal aminophenolate ligand L2−, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases (NN = 2,2′-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline), as well as [Fe(L)(EtOH)]NO3 (6), [Fe(phen)Cl3] (7) and [Fe(amphen)Cl3] (8). Data on their hydrolytic stability in physiological buffers is shown, as well as on their interaction with calf thymus DNA by spectroscopic tools. Additionally, the anticancer efficacy and the cellular death mechanisms activated in response to these drugs in HeLa, H1299 and MDA-MB-231 cells are provided.
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    PublicationOpen Access
    Pyruvate dehydrogenase contributes to drug resistance of lung cancer cells through epithelial mesenchymal transition
    (Frontiers, 2022) Ulukaya, Engin; Dere, Egemen; Ayhan, Ceyda Açılan; Cevatemre, Buse; Dilege, Şükrü; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 219658; N/A; 122573
    Recently, there has been a growing interest on the role of mitochondria in metastatic cascade. Several reports have shown the preferential utilization of glycolytic pathway instead of mitochondrial respiration for energy production and the pyruvate dehydrogenase (PDH) has been considered to be a contributor to this switch in some cancers. Since epithelial mesenchymal transition (EMT) is proposed to be one of the significant mediators of metastasis, the molecular connections between cancer cell metabolism and EMT may reveal underlying mechanisms and improve our understanding on metastasis. In order to explore a potential role for PDH inhibition on EMT and associated drug resistance, we took both pharmacological and genetic approaches, and selectively inhibited or knocked down PDHA1 by using Cpi613 and shPDHA1, respectively. We found that both approaches triggered morphological changes and characteristics of EMT (increase in mesenchymal markers). This change was accompanied by enhanced wound healing and an increase in migration. Interestingly, cells were more resistant to many of the clinically used chemotherapeutics following PDH inhibition or PDHA1 knockdown. Furthermore, the TGF?RI (known as a major inducer of the EMT) inhibitor (SB-431542) together with the PDHi, was effective in reversing EMT. In conclusion, interfering with PDH induced EMT, and more importantly resulted in chemoresistance. Therefore, our study demonstrates the need for careful consideration of PDH-targeting approaches in cancer treatment.