Researcher:
Cingöz, Ahmet

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Ahmet

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Cingöz

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Cingöz, Ahmet

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2016 - 2019122020 - 20238

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    Directing chemiluminescent dioxetanes to mitochondria: a cationic luminophore enables in vitro and in vivo detection of cancer cells upon enzymatic activation
    (Elsevier B.V., 2023) Department of Chemistry; N/A; N/A; Department of Chemistry; N/A; N/A; N/A; N/A; N/A; Department of Chemistry; Gündüz, Hande; Acari, Alperen; Çetin, Sultan; Almammadov, Toghrul; Değirmenci, Nareg Pınarbaşı; Dırak, Musa; Cingöz, Ahmet; Kılıç, Eda; Önder, Tuğba Bağcı; Kölemen, Safacan; Researcher; Master Student; PhD Student; Researcher; PhD Student; PhD Student; Researcher; Master Student; Faculty Member; Faculty Member; Department of Chemistry; N/A; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/A; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/A; N/A; College of Sciences; Graduate School of Health Sciences; Graduate School of Sciences and Engineering; College of Sciences; Graduate School of Health Sciences; Graduate School of Sciences and Engineering; N/A; Graduate School of Sciences and Engineering; School of Medicine; College of Sciences; 224496; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 184359; 272051
    A mitochondrion targeted and leucine aminopeptidase (LAP) activatable 1,2-dioxatane based chemiluminescent probe (MCL) for detection of LAP activity in living cancer cells and tumor bearing mice was reported. MCL displayed a selective and sensitive turn-on response in aqueous solutions upon reacting with the LAP enzyme. In cell culture studies, a selective luminescence intensity increase was observed in cancer cell lines, suggesting that MCL can differentiate between cancer and normal cells and allows detection of varying endogenous LAP concentrations. Using fluorescence imaging with a commercial Mitotracker dye, MCL was also shown to localize mitochondria in cancer cell lines. Furthermore, MCL was used to image tumors in mice models. MCL marks not only the first ever example of a mitochondria targeted chemiluminescent probe, but also the first ever example of an organelle targeted 1,2-dioxetane derivative. © 2023 Elsevier B.V.
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    Mitoxantrone potentiates TRAIL-induced apoptosis in glioblastoma multiforme
    (Oxford Univ Press, 2016) Ayhan, Ceyda Açılan; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Şenbabaoğlu, Filiz; Cingöz, Ahmet; Kaya, Ezgi; Kazancıoğlu, Selena; Lack, Nathan Alan; Önder, Tuğba Bağcı; PhD Student; Researcher; PhD Student; Undergraduate Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; College of Sciences; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; 120842; 184359
    Glioblastoma multiforme (GBM) is the most aggressive and frequent type of primary brain tumor with dismal survival rates. As GBM cells suppress apoptosis and evade death, re-activating dormant apoptotic programs with pro-apoptotic ligands or small molecules might be a promising approach. As such, the tumor-selective killing capacity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential treatment option in GBM. However, many tumor cells are intrinsically resistant and/or acquire resistance to TRAIL. In this study, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in GBM. Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. One drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.
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    Quinacrine mediated sensitization of glioblastoma (GBM) cells to TRAIL through MMP-sensitive PEG hydrogel carriers
    (Wiley-V C H Verlag Gmbh, 2017) N/A; N/A; N/A; Department of Chemical and Biological Engineering; Erkoç, Pelin; Cingöz, Ahmet; Önder, Tuğba Bağcı; Kızılel, Seda; PhD Student; Researcher; Faculty Membe; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; School of Medicine; College of Engineering; N/A; N/A; 184359; 28376
    Overcoming drug resistance is a major challenge for cancer therapy. Tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) is a potent therapeutic as an activator of apoptosis, particularly in tumor but not in healthy cells. However, its efficacy is limited by the resistance of tumor cell populations to the therapeutic substance. Here, we have addressed this limitation through the development of a controlled release system, matrix-metalloproteinase (MMP)-sensitive and arg-gly-asp-ser (RGDS) peptide functionalized poly (ethylene-glycol) (PEG) particles which are synthesized via visible-light-induced water-in-water emulsion polymerization. Quinacrine (QC), a recently discovered TRAIL sensitizer drug, is loaded into the hydrogel carriers and the influence of this system on the apoptosis of a malignant type of brain cancer, glioblastoma multiforme (GBM), has been investigated in detail. The results suggest that MMP-sensitive particles are cytocompatible and superior to promote TRAIL-induced apoptosis in GBM cells when loaded with QC. Compared to QC and TRAIL alone, combination of QC-loaded PEG hydrogel and TRAIL demonstrates synergistic apoptotic inducing behavior. Furthermore, QC-loaded particles, but not QC or PEG-hydrogels alone, enhance apoptosis as is measured through expression of apoptosis-related genes. This system is promising to significantly improve the efficacy of chemotherapeutic drugs and suggests a combination treatment for GBM therapy.
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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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    Identification of mitoxantrone as a trail-sensitizing agent for glioblastoma multiforme
    (Taylor & Francis Inc, 2016) Ayhan, Ceyda Açılan; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Şenbabaoğlu, Filiz; Cingöz, Ahmet; Kaya, Ezgi; Kazancıoğlu, Selena; Lack, Nathan Alan; Önder, Tuğba Bağcı; PhD Student; Researcher; PhD Student; Undergraduate Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; College of Sciences; School of Medicine; School of Medicine; Koç University Hospital; N/A; N/A; N/A; N/A; 120842; 184359
    Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or develop resistance to TRAIL. Interestingly, many studies have identified several secondary agents that can overcome TRAIL resistance. To expand on these studies, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in a very malignant type of brain cancer, Glioblastoma Multiforme (GBM). Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. Cardiac glycosides constituted a large group of TRAIL-sensitizing compounds, and they were also effective on GBM cells as single agents. We then explored a second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.
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    Profiling of different GBM cell populations with varying apoptotic thresholds identifies IGFBP-2 as a novel mediator of trail resistance
    (Oxford Univ Press Inc, 2016) Gümüş, Zeynep Hülya; N/A; Department of Industrial Engineering; N/A; Cingöz, Ahmet; Gönen, Mehmet; Önder, Tuğba Bağcı; Researcher; Faculty Member; Faculty Member; Department of Industrial Engineering; Graduate School of Health Sciences / Animal Laboratory; College of Engineering; School of Medicine; N/A; 237468; 184359
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    An exploration of plastic deformation dependence of cell viability and adhesion in metallic implant materials
    (Elsevier, 2016) Gerstein, G.; Maier, H. J.; N/A; N/A; N/A; N/A; Department of Mechanical Engineering; Uzer, Benay; Toker, Sıdıka Mine; Cingöz, Ahmet; Önder, Tuğba Bağcı; Canadinç, Demircan; Researcher; PhD Student; Researcher; Faculty Member; Faculty Member; Department of Mechanical Engineering; N/A; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; School of Medicine; College of Engineering; N/A; 255504; N/A; 184359; 23433
    The relationship between cell viability and adhesion behavior, and micro-deformation mechanisms was investigated on austenitic 316L stainless steel samples, which were subjected to different amounts of plastic strains (5%, 15%, 25%, 35% and 60%) to promote a variety in the slip and twin activities in the microstructure. Confocal laser scanning microscopy (CLSM) and field emission scanning electron microscopy (FESEM) revealed that cells most favored the samples with the largest plastic deformation, such that they spread more and formed significant filopodial extensions. Specifically, brain tumor cells seeded on the 35% deformed samples exhibited the best adhesion performance, where a significant slip activity was prevalent, accompanied by considerable slip-twin interactions. Furthermore, maximum viability was exhibited by the cells seeded on the 60% deformed samples, which were particularly designed in a specific geometry that could endure greater strain values. Overall, the current findings open a new venue for the production of metallic implants with enhanced biocompatibility, such that the adhesion and viability of the cells surrounding an implant can be optimized by tailoring the surface relief of the material, which is dictated by the micro-deformation mechanism activities facilitated by plastic deformation imposed by machining.
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    Combination of epigenetic enzyme inhibitors, gsk-j4 and belinostat, reveals high efficacy in idh1 mutant gliomas
    (N/A, 2020) Wakimoto, Hiroaki; Cahill, Daniel; Cribbs, Adam; Oppermann, Udo; N/A; Kayabölen, Alişan; Şahin, Gizem Nur; Şeker-Polat, Fidan; Cingöz, Ahmet; Işık, Bekir; Acar, Simge; Solaroğlu, İhsan; Önder, Tuğba Bağcı; PhD Student; PhD Student; PhD Student; Researcher; Undergraduate Student; Undergraduate Student; Faculty Member; Faculty Member; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; School of Medicine; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; N/A; N/A; 102059; 184359
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    TRAIL-conjugated silver nanoparticles sensitize glioblastoma cells to TRAIL by regulating CHK1 in the DNA repair pathway
    (Taylor & Francis, 2020) Altunbek, Mine; Kahraman, Mehmet; Culha, Mustafa; Sur, İlknur Erdem; Muslu, Kerem; Değirmenci, Nareg Pınarbaşı; Şeker-Polat, Fidan; Cingöz, Ahmet; Aydın, Serdar Onur; Solaroğlu, İhsan; Önder, Tuğba Bağcı; Faculty Member; Undergraduate Student; PhD Student; PhD Student; Researcher; Researcher; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; School of Medicine; 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; 361035; N/A; N/A; 321731; N/A; 102059; 184359
    Objectives: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers apoptosis in cancer cells, but not in normal cells. Resistance of glioblastoma cells to TRAIL is a major obstacle for successful clinical treatment of TRAIL. Thus, there is an essential requirement for novel approaches to sensitize TRAIL resistance. Silver nanoparticles (AgNPs) are one of the most promising nanomaterials that show immense antitumor potential via targeting various cellular and molecular processes; however, the effects of AgNPs on TRAIL sensitivity in cancer cells remain unclear. Therefore, we hypothesized that TRAIL-conjugated AgNPs (TRAIL-AgNPs) can overcome TRAIL resistance through inducing death receptor activation in glioblastoma cells, but not normal cells. Methods: In this study, the therapeutic effect of TRAIL-AgNPs is investigated by analyzing the cell viability, caspase activity, and CHK1 gene expression in T98 G TRAIL-Sensitive (TS) and T98 G TRAIL-Resistant (TR) glioblastoma cells. Results: It is found that TRAIL-AgNPs are more toxic compared to TRAIL and AgNPs treatments alone on TR cells. While TRAIL and AgNPs alone do not enhance the caspase activity, conjugation of TRAIL to AgNPs increases the caspase activity in TR cells. Moreover, the TRAIL-AgNPs-treated TR cells show less CHK1 expression compared to the TRAIL treatment. Conclusion: These results suggest that TRAIL sensitivity of TR cells can be enhanced by conjugation of TRAIL with AgNPs, which would be a novel therapeutic approach to sensitize TRAIL resistance.
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    Mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme
    (Elsevier, 2016) Ayhan, Ceyda Açılan; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Şenbabaoğlu, Fatih; Cingöz, Ahmet; Kaya, Ezgi; Kazancıoğlu, Selena; Lack, Nathan Alan; Önder, Tuğba Bağcı; Master Student; Researcher; PhD Student; Undergraduate Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; Graduate School of Health Sciences; College of Sciences; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; 120842; 184359
    Background: Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or develop resistance to TRAIL. Interestingly, many studies have identified several secondary agents that can overcome TRAIL resistance. To expand on these studies, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in a very malignant type of brain cancer, glioblastoma multiforme (GBM). Material and Methods: GBM cell lines U87MG, U373 and non-malignant cell lines BJ fibroblasts and Normal Human Astrocytes were used in in vitro experiments. 1,200 FDA approved drugs containing library was screened as single agents (5 uM) and/or TRAIL (25 ng/ml) in U87MG and U87MGR50. Cell viability was detected by an ATP-based assay after 24−48 hours. Chosen lead, Mitoxantrone was further studied by cell viability assays, proliferation by live cell imaging, apoptotic gene expression levels by qRT-PCR and death receptor and apoptotic protein expression levels by Western Blot. Results: Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. Cardiac glycosides constituted a large group of TRAIL-sensitizing compounds, and they were also effective on GBM cells as single agents. We then explored a second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Conclusions: Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.