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Öğe The improved killing of both androgen-dependent and independent prostate cancer cells by etoposide loaded SPIONs coupled with NIR irradiation(Royal Society of Chemistry, 2022) Onbaşlı, Kübra; Demirci, Gözde; Muti, Abdullah; Sennaroğlu, Alphan; Yağcı Acar, Havva; Erkısa Genel, Merve; Ulukaya, EnginEtoposide (Eto) is a toxic drug that shows promise in treating prostate cancer (PCa) but confers significant side effects, and has poor solubility and bioavailability. Nanoparticles are quite successful in overcoming such problems. Multifunctional nanoparticles that provide an opportunity to perform combination therapy have attracted great interest in recent years. Superparamagnetic iron oxide nanoparticles (SPIONs) are popular in various biomedical applications, including magnetic resonance imaging, drug delivery, magnetic hyperthermia and recently in photothermal therapy, combining imaging with therapy. Here, for the enhanced killing of PCa cells that are either androgen-dependent or not, the combination of SPION based Eto delivery and mild hyperthermia triggered by laser irradiation is proposed for the first time in the literature. For the encapsulation of Eto, highly stable, small, polyacrylic acid coated SPIONs were conjugated with bovine serum albumin (BSA) (Eto-BSA@PAA@SPION). Eto-BSA@PAA@SPION with 9% drug content produced better chemotherapeutic outcomes than free Eto on both androgen-dependent/castration sensitive LNCaP and androgen-independent/castration-resistant PC3 and DU145 PCa cells by enhancing drug internalization. Single and short irradiation of Eto-BSA@PAA@SPION treated cells at 808 nm improved the drug release and sensitized cells for Eto, hence, increasing the toxicity dramatically in all studied PCa cell lines. Caspase-mediated apoptosis, DNA damage, and ROS generation were detected in the treated cells, increasing with the Eto dose and laser treatment. The IC50 for Eto is reduced to 0.08 ?g mL-1, 0.13 ?g mL-1 and 2.8 ?g mL-1 with laser/Eto-BSA@PAA@SPION for LNCaP, DU145 and PC3 cells, respectively. These are the lowest IC50 values seen in the literature for Eto on these cell lines so far, suggesting that the demonstrated nanoparticles and treatment approaches have great potential to treat various PCa cells at low doses of the drug under mild laser treatment conditions.Öğe Preparation and characterization of palladium derivate-loaded micelle formulation in vitro as an innovative therapy option against non-small cell lung cancer cells(WILEY, 2021) Erkısa Genel, Merve; Arı, Ferda; Büyükköroğlu, Gülay; Senel, Bedriye; Yılmaz, Veysel Turan; Ulukaya, EnginNanoparticles have been used in cancer treatments to target tumor and reduce side effects. In this study, we aimed to increase the effectiveness of palladium(II) complex [PdCl(terpy)](sac)·2H2O, which previously showed anticancer potential, by preparing the nanoparticle formulation. An inhalable micellar dispersion containing a palladium(II) complex (PdNP) was prepared and its physicochemical characteristics were evaluated using in vitro tests. Morphology, size and surface charges of particle and loading/encapsulation efficiency of PdNP were analyzed by scanning electron microscopy, zeta sizer and inductively coupled plasma mass spectrometry while aerosol properties of PdNP were measured by the next generation impactor. A549 and H1299 non-small lung cancer cell types were used for cytotoxicity using SRB and ATP assays. Fluorescent staining and M30 antigen assay were carried out for cell death evaluation. Apoptosis was confirmed by flow cytometry analyses. SEM, particle size, and zeta potential results showed the particles have inhalable properties. The amount of the palladium(II) complex loaded into the particles was quantified which indicated high encapsulation efficiencies (97%). The micellar dispersion expected to reach the alveolar region and the brachial region was determined 35% and 47%, respectively. PdNP showed an anti-growth effect by increasing reactive oxygen species that is followed by the induction of mitochondria-dependent apoptosis that is evidenced by pyknotic nuclei and M30 antigen level increments and disruption of polarization of membrane in mitochondria (??m). The results show that PdNP might be a promising inhalable novel complex to be used in non-small cell lung cancer, which warrants animal studies in further.Öğe Water-soluble silver(I) complexes with N-donor benzimidazole ligands containing an imidazolium core: stability and preliminary biological studies(Royal Society of Chemistry, 2021) Karataş, Mert Olgun; Özdemir, Namık; Sarıman, Melda; Günal, Selami; Ulukaya, Engin; Özdemir, İsmailHerein, we report the synthesis, characterisation and preliminary biological evaluation of two novel silver(I) complexes of type [AgL2](NO3)3 (3 and 4) with ionic N-donor benzimidazoles. The complexes have been synthesized by the reaction of 1.5 equivalents of silver nitrate and N-donor benzimidazoles containing an imidazolium core at the 2-position (1 and 2) in ethanol. The X-ray analysis of 4 shows that it has two free imidazolium cores and the charge is balanced with three nitrate anions. A study by the combination of NMR, IR, LC-MS and elemental analysis techniques also suggests that the complexes have this structure both in the solid-state and solution. The complexes are highly soluble and stable in water. Cytotoxicity evaluation against four cancerous human cells and one non-cancerous human cell revealed that the complexes have no significant anti-growth effect. However, the complexes showed a remarkable antimicrobial effect at normalized minimum inhibitory concentrations (normalized MICs) in the range of 33–268 ?M against a panel of microorganisms consisting of Gram-negative and Gram-positive bacteria, and fungi.Öğe Palladium (II) complex and thalidomide intercept angiogenic signaling via targeting FAK/Src and Erk/Akt/PLC gamma dependent autophagy pathways in human umbilical vein endothelial cells(Elsevier, 2021) Aydınlık, Şeyma; Üvez, Ayça; Kıyan, Hülya Tuba; Gürel-Gürevin, Ebru; Yılmaz, Veysel Turan; Ulukaya, EnginThe current study assessed the effects of the thalidomide and palladium (II) saccharinate complex of terpyridine on the suppression of angiogenesis-mediated cell proliferation. The viability was assessed after treatment with palladium (II) complex (1.56–100 ?M) and thalidomide (0.1-400 µM) alone by using ATP assay for 48h. Palladium (II) complex was found to inhibit growth statistically significant in a dose-dependent manner in HUVECs and promoted PARP-1 cleavage through the production of ROS. On the other hand, thalidomide did not cause any significant change in cell viability. Moreover, cell death was observed to be manifested as late apoptosis due to Annexin V/SYTOX staining after palladium (II) complex treatment however, thalidomide did not demonstrate similar results. Thalidomide and palladium (II) complex also suppressed HUVEC migration and capillary-like structure tube formation in vitro in a time-dependent manner. Palladium (II) complex (5 mg/ml) treatment showed a strong antiangiogenic effect similar to positive control thalidomide (5mg/ml) and successfully disrupted the vasculature and reduced the thickness of the vessels compared to control (agar). Furthermore, suppression of autophagy enhanced the cell death and antiangiogenic effect of thalidomide and palladium (II) complex. We also showed that being treated with thalidomide and palladium (II) complex inhibited phosphorylation of the signaling regulators downstream of the VEGFR2. These results provide evidence for the regulation of endothelial cell functions that are relevant to angiogenesis through the suppression of the FAK/Src/Akt/ERK1/2 signaling pathway. Our results also indicate that PLC-?1 phosphorylation leads to activation of p-Akt and p-Erk1/2 which cause stimulation on cell proliferation at lower doses. Hence, we demonstrated that palladium (II) and thalidomide can induce cell death via the Erk/Akt/PLC? signaling pathway and that this pathway might be a novel mechanism.Öğe A brief reconnoitre about effects of MMP9 on aortic dissection(DergiPark, 2021) Salman Yaylaz, Burcu; Sarıman, Melda; Ekmekçi, Ahmet; Ergül, Emel; Uluganyan, Mahmut; Çosan, Fulya; Totuk Gedar, Özgün Melike; Abacı, NeslihanObjective: Matrix metalloproteinases (MMPs) are the extracellular ma-trix regulators that frequently investigate cardiovascular diseases and cancer metastasis. Our study aimed to examine specific polymorphisms in the MMP9 gene in our patients with aortic dissection and compare the effect of MMP9 on aortic dissection with expression datasets. Materials and Methods: Q279R and P574R polymorphisms were analyzed in 44 aortic dissection patients and 40 healthy donors via polymerase chain reaction-restriction fragment length polymorphism. (PCR-RFLP) methods. Q279R and P574R prevalence was statistically compared with the medical data of the patients. Additionally, we col-lected datasets of aortic dissection from NCBI GEO to reanalyze GEO2R and RStudio to see metalloproteinase activity on samples. Later, enrich-ment analysis was processed on widely used databases. Results: Genotypic distribution of alleles was similar in the two study groups. In addition to this, female CG carriers had a higher risk of de-veloping aortic dissection than those of males. As the results of the protein-protein interaction analysis of MMP9 and patients’ clinical data, hypertension was found to be the significant outcome of P574R varia-tion in the patients. In array analysis, MMP9 expression did not change critically, but TIMPs had been downregulated in many samples. Also, MMP9 targeted miRNA expression levels were detected as low in aortic tissue and blood. Conclusion: Q279R and P574R are two polymorphisms that do not di-rectly affect MMP9 protein structure. Consequently, studied polymor-phisms and performed meta-analysis show that MMP9 does not spark off the phenotype but sets the stage for aortic dissection development as seen in the statistical results. Furthermore, enrichment analysis on datasets shows MMP9 was not a primary reason for vascular remodeling.Öğe Kalsitriol ve doksorubisin kombinasyonunun MCF7 üzerine olası anti kanser etkilerinin araştırılması(DergiPark, 2018) Bildiren, Özge; Cevatemre, Buse; Ay, Ebru Nur; Özen, Güneş; Hepokur, Ceylan; Erkısa Genel, Merve; Ulukaya, EnginAmaç: Bu çalışmada amacımız, belirli bir dozun üzerinde kardiyak yan etkileri oldukça fazla olan ve meme kanseri tedavisinde kullanılan kemoterapötiklerden doksorubisinin, tedavide kullanım miktarlarını azaltmayı ve etkinliğini arttırmayı sağlayan bir maddeyi saptamaktı. Etken madde olarak anti proliferatif etkisi olduğu düşünülen vitamin D analoglarından biri olan kalsitriol seçilmiş ve doksorubisin ile kombine tedavisinin, insan meme kanseri hücre hattı MCF-7 üzerine sitotoksik etkisinin saptanması amaçlanmıştır. Gereç ve Yöntem: MCF-7 insan meme kanseri hücre hattı kalsitriol ile muamele edilerek, gerçek zamanlı olarak, x-CELLigence cihazında 72 saat inkübasyona bırakıldı ve kalsitriolün anti-proliferatif optimum doz tespiti zamana bağlı hücre indeksi grafiği The xCELLigence Real-Time Cell Analysis (RTCA) software programı kullanılarak yapıldı. Kalsitriol optimum dozu ve doksorubisinin farklı dozlarının kombinasyonu MCF-7 hücre kültürü ile muamele edilerek sitotoksisite tayini için Sulforhodamine-B (SRB) uygulaması ve spektrofotometrik ölçüm uygulandı. Spektrofotometrik ölçüm sonuçları anlamlılık sonuçları için Student’s t-Testi ile değerlendirildi. Bulgular: MCF-7 hücrelerinin antiproliferative optimum kalsitriol doz tespiti zamana bağlı hücre indeksi grafiği RTCA software programı kullanılarak yapılmıştır. Sitotoksisite tayini için uygulanan SRB yöntemi sonucu elde edilen spektrofotometrik ölçüm sonuçları GraphPad Prism programı kullanılarak Student’s t-testi ile istatistiksel olarak değerlendirilmiştir. Kalsitriol optimum dozu 250 nM tespit edilmiştir. Doksorubisinin farklı dozları (1,84 µM-0,92 µM), kalsitriol (250 nM) ve kalsitriol olmaksızın MCF-7 hücre hattı ile sitotoksik etki saptaması için muamele edilmiştir. 0,46 µM doksorubisin ve optimum kalsitriol kombinasyonunun sitotoksik açıdan diğer dozlara göre anlamlı olduğu (p=0,0087) fakat doksorubisin kullanımında doz azaltımını sağlayacak kadar etkin olmadığı saptanmıştır. Sonuç: Doksorubisinin, kalsitriol ile kombine kullanımının günümüzde kullanılan dozlar üzerinde azaltıcı yönde anlamlı bir etkisinin olmadığını saptanmıştır. Vitamin D ve doksorubisin birlikte kullanımının meme kanserinde fayda sağlamayacağını söylemek için ise henüz erkendir. İlerleyen çalışmalarda vitamin D’nin farklı analogları ile çeşitli çalışmalar yapılabilir.Öğe Synergistic interactions between resveratrol and doxorubicin inhibit angiogenesis both in vitro and in vivo(POLSKA AKAD NAUK, 2020) Uvez, A.; Aydınlık, S.; Esener, O. B. B.; Erkısa Genel, Merve; Karakuş, D.; Armutak, E.Resveratrol is a polyphenolic compound which is found in many nutrients including grapes, peanuts, raspberries, and apples. Anti-proliferative, anti-angiogenic and apoptotic effects of resveratrol have been shown on various cancer cells. Doxorubicin is considered as one of the most effective anticancer agents and reveals its antitumor activity by induction of apoptosis and inhibition of angiogenesis. Our study reports for the first time the potent ability of resveratrol in combination with doxorubicin to inhibit angiogenesis in vitro and in vivo. The cytotoxic effect of resveratrol (1.56-100 mu M), doxorubicin (0.01-0.92 mu M) and their combination were analyzed in the human umbilical vein endothelial cells (HUVECs) by ATP assay. In vitro angiogenesis was evaluated using tube formation assay in HUVECs. In vivo anti-angiogenic activity was assessed in a chick chorioallantoic membrane (CAM) model using fertilized chicken eggs. All test groups were compared to thalidomide as a positive control, three concentrations of resveratrol (10-5-2.5 mu g/pellet) and a 2 mu g/pellet concentration of doxorubicin was examined. All data were evaluated statistically. Resveratrol and doxorubicin alone displayed inhibitory effects on angiogenesis and cell viability at higher doses. However, the combination of resveratrol and doxorubicin exhibited a significant dose-dependent inhibition of CAM angiogenesis in vivo as well as proliferation and tube formation in HUVECs compared to the positive control (+/-)-thalidomide. Our results suggest that resveratrol in combination with doxorubicin is a novel strategy in the prevention and treatment of angiogenesisÖğe Palladium (II) complex enhances ROS-dependent apoptotic effects via autophagy inhibition and disruption of multiple signaling pathways in colorectal cancer cells(2021) Aydınlık, Şeyma; Erkısa Genel, Merve; Arı, Ferda; Çelikler, Serap; Ulukaya, EnginBackground: Inhibition of autophagy is reported to be a therapeutically effective strategy in overcoming the resistance that is a deadly outcome in cancer. One of the most common reasons for chemo-resistance to treatment is the patients with tumors exhibiting a KRAS mutation which occurs in approximately 40% of colorectal cancer patients. Objective: Hence, we assessed whether a palladium (Pd)(II) complex is a promising anticancer complex, compared to 5-fluorouracil in KRAS wt HT-29 and KRAS mutant HCT-15 cells. Methods: HCT-15 and HT-29 cells were used for colorectal cancer and chloroquine (CQ) was used as an inhibitor of autophagy. In this context, cells were treated with Pd(II) complex and 5-FU in combination with CQ for 48 h and cell viability was measured by SRB assay. Cell death mode was examined with M30 and M65 ELISA assays, annexin V/propidium iodide. Autophagy was determined by acridine orange (AO) staining. Furthermore, the expression of various autophagy and apoptosis related proteins were evaluated with Western blotting.Luminex assay and reactive oxygen species (ROS) level were examined. Results: Cell viability was decreased in a dose dependent matter and CQ enhances cytotoxic effect in Pd(II) and 5-FU treated cells in colorectal cancer cells. Our data showed that inhibition of autophagic flux significantly increase intrinsic apoptosis through the activation of ROS. We showed that combinatorial treatment with CQ induces apoptosis via the caspase-dependent mitochondrial pathway. Luminex analysis revealed that the combination resulted in a down-regulation of a NF-?B/AKT/CREB signaling pathways in both cell line, however, decreased Erk1/2 protein expression was only observed after treated with CQ combination in HCT-15 cells. Conclusion: We suggest that inhibition of autophagy along with Pd(II) and 5-FU treatment has a synergistic effect in KRAS-mutant colorectal cancer cells. Autophagy inhibition by CQ promotes apoptosis via blockade of the NF-?B/AKT/CREB and activation of ROS.Öğe Etoposide loaded SPION-PNIPAM nanoparticles improve the in vitro therapeutic outcome on metastatic prostate cancer cells via enhanced apoptosis(2020) Erkısa Genel, Merve; Arı, Ferda; Ülkü, İrem; Khodadust, Rouhollah; Yar, Yasemin; Acar, Havva Yağcı; Ulukaya, EnginProstate cancer is among the leading causes of death worldwide because its metastatic form is a deadly disease. Therefore, the development of new chemotherapeutics is of immense importance. Nanoparticle technology seems to provide diverse options in this regard. Therefore, poly(N-isopropylacrylamide) (PNIPAM) coated superparamagnetic iron oxide nanoparticles (SPION) loaded with etoposide were prepared in small sizes (57 nm) and with 3.5% drug content to improve the efficiency of etoposide in prostate cancer therapy. Sustained release of the drug was achieved, which found to be sensitive to low pH and high temperature. The anti-growth activity of SPION-PNIPAM-Etoposide formulation against metastatic prostate cancer cells (PC-3, LNCaP) were investigated by SRB assay, then confirmed by ATP assay. Mode of cell death was evaluated by using flow cytometry analyses. A significant improvement of nanoformulated drug was observed at 5-10 ?g/ml doses of the drug in both cell lines. More importantly, this formulation enhanced the cytotoxic effect of etoposide on PC-3 cells, which is considered more resistant to etoposide than LNCaP, and reduced the IC 50 by 55% reaching to 4.5 ?g drug/ml, which is a very significant improvement in the literature. It was clearly shown that nanoformulated drug provided about 3 fold increases in caspase-dependent early apoptotic cells in PC-3 cells. The novel formulation seems to successfully cause cell death of especially PC-3 metastatic prostate cancer cells. It should therefore be taken into consideration for further animal studies as a novel potent anticancer agent.Öğe Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells(Elsevier Ireland Ltd, 2018) Aztopal, Nazlıhan; Erkısa Genel, Merve; Ertürk, Elif; Ulukaya, Engin; Tokullugil, Asuman Hatice; Arı, FerdaCancer stem-like cells (CSCs) are a cell subpopulation that can reinitiate tumors, resist chemotherapy, give rise to metastases and lead to disease relapse because of an acquired resistance to apoptosis. Especially, epigenetic alterations play a crucial role in the regulation of stemness and also have been implicated in the development of drug resistance. Hence, in the present study, we examined the cytotoxic and apoptotic activity of valproic acid (VPA) as an inhibitor of histone deacetylases (HDACs) against breast CSCs (BCSCs). Increased expression of stemness markers were determined by western blotting in mammospheres (MCF-7s, a cancer stem cell-enriched population) propagated from parental MCF-7 cells. Anti-growth activity of VPA was determined via ATP viability assay. The sphere formation assay (SFA) was performed to assess the inhibitory effect of VPA on the self-renewal capacity of MCF-7s cells. Acetylation of histon H3 was detected with ELISA assay. Cell death mode was performed by Hoechst dye 33342 and propidium iodide-based flouresent stainings (for pyknosis and membrane integrity), by M30 and M65 ELISA assays (for apoptosis and primary or secondary necrosis) as well as cyto-fluorimetric analysis (caspase 3/7 activity and annexin-V-FITC staining for early and late stage apoptosis). VPA exhibited anti-growth effect against both MCF-7 and MCF-7s cells in a dose (0.6-20 mM) and time (24, 48, 72 h) dependent manner. As expected, MCF-7s cells were found more resistant to VPA than MCF-7 cells. It was observed that VPA prevented mammosphere formation at relatively lower doses (2.5 and 5 mM) while the acetylation of histon H3 was increased. At the same doses, VPA increased the M30 levels, annexin-V-FITC positivity and caspase 3/7 activation, implying the induction of apoptosis. The secondary necrosis (late stage of apoptosis) was also evidenced by nuclear pyknosis with propidium iodide staining positivity. Taken together, inhibition of HDACs is cytotoxic to BCSCs by apoptosis. Our results suggested that targeting the epigenetic regulation of histones may be a novel approach and hold significant promise for successful treatment of breast cancer.Öğe A promising natural product, pristimerin, results in cytotoxicity against breast cancer stem cells in vitro and xenografts in vivo through apoptosis and an incomplete autopaghy in breast cancer(Academic Press Ltd- Elsevier Science Ltd, 2018) Cevatemre, Buse; Erkısa Genel, Merve; Aztopal, Nazlıhan; Karakaş Zeybek, Didem; Alper, Pınar; Tsimplouli, Chrisiida; Sereti, Evangelia; Dimas, Konstantinos; Armutak, Elif I. İkitimur; Gürevin, Ebru Gürel; Üvez, Ayça; Mori, Mattia; Berardozzi, Simone; Ingallina, Cinzia; D'Acquarica, Ilaria; Botta, Bruno; Özpolat, Bülent; Ulukaya, EnginSeveral natural products have been suggested as effective agents for the treatment of cancer. Given the important role of CSCs (Cancer Stem Cells) in cancer, which is a trendy hypothesis, it is worth investigating the effects of pristimerin on CSCs as well as on the other malignant cells (MCF-7 and MDA-MB-231) of breast cancer. The anti-growth activity of pristimerin against MCF-7 and MCF-7s (cancer stem cell enriched population) cells was investigated by real time viability monitorization (xCELLigence System (R)) and ATP assay, respectively. Mode of cell death was evaluated using electron and fluorescence microscopies, western blotting (autophagy, apoptosis and ER-stress related markers) and flow cytometry (annexin-V staining, caspase 3/7 activity, BCL-2 and PI3K expressions). Pristimerin showed an anti-growth effect on cancer cells and cancer stem cells with IC50 values ranging at 0.38-1.75 mu M. It inhibited sphere formation at relatively lower doses (<1.56 mu M). Apoptosis was induced in MCF-7 and MCF-7s cells. In addition, extensive cytoplasmic vacuolation was observed, implying an incompleted autophagy as evidenced by the increase of autophagy-related proteins (p62 and LC3-II) with an unfolded protein response (UPR). Pristimerin inhibited the growth of MCF-7 and MDA-MB-231-originated xenografts in NOD.CB17-Prkdc(scid)/J mice. In mice, apoptosis was further confirmed by cleavage of PARP, activation of caspase 3 and/or 7 and TUNEL staining. Taken together, pristimerin shows cytotoxic activity on breast cancer both in vitro and in vivo. It seems to represent a robust promising agent for the treatment of breast cancer. Pristimerin's itself or synthetic novel derivatives should be taken into consideration for novel potent anticancer agent(s). (C) 2017 Elsevier Ltd. All rights reserved.Öğe Synthesis, structures and anticancer potentials of platinum(II) saccharinate complexes of tertiary phosphines with phenyl and cyclohexyl groups targeting mitochondria and DNA(Elsevier France-Editions Scientifiques Medicales Elsevier, 2018) Yılmaz, Veysel T.; İçsel, Ceyda; Turgut, Ömer R.; Aygün, Muhittin; Erkısa Genel, Merve; Türkdemir, Mehmet H.; Ulukaya, EnginA series of new Pt(II) saccharinate complexes containing PR3 ligands (PPh3, PPh2Cy, PPhCy2 and PCy3) with progressive phenyl (Ph) replacement by cyclohexyl (Cy) were synthesized and structurally characterized by lR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes was tested against human breast (MCF-7), lung (A549), colon (HCT116), and prostate (DU145) cancer cell lines as well as against normal bronchial epithelial (BEAS-2B) cells. Trans-configured complexes 1, 3 and 5 emerged as potential anticancer drug candidates. The mechanism of action of the potent complexes was then investigated in detail. The three complexes interacted with DNA by groove binding and with HSA via hydrophobic IIA subdomain. Furthermore, the complexes cleaved plasmid DNA efficiently. Cellular uptake studies in MCF-7 cells showed that the biologically active complexes were mainly localized in cytoplasm. The cytotoxic activity was a function of the lipophilicity and cellular accumulation of the complexes. As determined by M30, Annexin V and Caspase 3/7 activity assays, the complexes induced apoptosis in MCF-7 and HCT116 cells. Mechanistic studies showed that the potent complexes cause excessive generation of reactive oxygen species (ROS) and display a dual action, concurrently targeting both mitochondria and genomic DNA. (C) 2018 Elsevier Masson SAS. All rights reserved.Öğe Structural studies and cytotoxic activity of a new dinuclear coordination compound of palladium(II)-2,2:6,2-terpyridine with rigid dianionic 1,2,4-triazole-3-sulfonate linker(Wiley, 2018) Büyükekşi, Sebile Işık; Erkısa Genel, Merve; Şengül, Abdurrahman; Ulukaya, Engin; Oral, Arzu YılmaztepeA new dinuclear coordination compound of palladium(II), [Pd-2(terpy)(2)(-tas-N-1,N-4)]SO(4)11H(2)O (1), was synthesized by tethering a doubly deprotonated 1,2,4-triazole-3-sulfonate (tas) linker generated in situ via oxidation of 1,2,4-triazole-3-thione (tat) under the synthetic conditions. X-ray diffraction analysis reveals that tat molecules adopt the thione form in the solid state, and are combined in infinite chains by symmetrically related classical intermolecular hydrogen bonds N1H1S1, N3H3N2 to give rise to R-2(2)(7) pattern in one-dimensional chains along the b-axis propagating along the a-axis. Further short contacts through lone pairs of N2S1 on the rings between the adjacent chains along the a-axis lead to a two-dimensional network structure. Compound 1 was characterized using infrared, H-1 NMR and UV-visible spectroscopies, electrospray ionization mass spectrometry and X-ray crystallography. The crystal structure determination of 1 reveals that the Pd(II) ions are coordinated with four nitrogen atoms: three from terpy and one from tas acting as an end-to-end (-1,4) bridging ligand. The Pd(II) ions in 1 adopt a distorted square planar geometry. The anti-growth effect of 1 was tested on colorectal cancer (HCT-15), non-small-cell lung cancer (A549), prostate cancer (PC-3) and cervical cancer (HeLa) cell lines using sulforhodamine B viability assay. The cytotoxic effect was further confirmed using adenosine triphosphate viability assay. Compound 1 shows a promising cytotoxic activity in the diverse cancer cell models in vitro (p <0.0001).Öğe Pd(II) and Pt(II) saccharinate complexes of bis(diphenylphosphino) propane/butane: synthesis, structure, antiproliferative activity and mechanism of action(Elsevier France-Editions Scientifiques Medicales Elsevier, 2018) Yılmaz, Veysel T.; İçsel, Ceyda; Aygün, Muhittin; Erkısa Genel, Merve; Ulukaya, Engin[M(sac)(2)(dppp)] (1 and 2), [M(dppp)(2)](sac)(2) (3 and 4) and [M(sac)(2)(dppb)] (5 and 6) complexes, where M = Pd-II (1, 3 and 5) and Pt-II (2, 4 and 6), sac = saccharinate, dppp = 1,3-bis(diphenylphosphino)propane and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes against human lung (A549), breast (MCF-7), prostate (DU145) and colon (HCT116) cancer cell lines showed that the cationic complexes of dppp (3 and 4) and neutral Pt complex of dppb (6) were the most active agents of series. 3 and 4 exhibited antiproliferative activity, while 6 was highly cytotoxic compared to cisplatin. These complexes were therefore subjected to further investigations to ascertain the possible role of lipophilicity, cellular uptake and DNA/EISA binding in their biological activity. Flow cytometry analysis revealed that complex 6 induced apoptotic cell death in A549 and HCT116 cells and caused the cell cycle arrest at the S phase and overproduction of reactive oxygen species (ROS), giving rise to mitochondria) depolarization and DNA damage. (C) 2018 Elsevier Masson SAS. All rights reserved.Öğe Usnea filipendula induces apoptosis in human colon cancer cell lines(Wolters Kluwer Medknow Publications, 2018) Disoma, C.; Erkısa Genel, Merve; Oran, S.; Alioğlu, I.; Ulukaya, Engin; Arı, F.Lichens are complex organisms living in a symbiotic relationship with fungi and algae have recently received special interest in cancer research. The cytotoxic activities of Usnea filipendula Stirt. lichen extract was investigated on colon cancer cell lines, HCT-15 and HT-29. Sulphorhodamine B and ATP cell viability tests were used to monitor cytotoxic activity. The mode of cell death (apoptosis/necrosis) was determined using caspase-cleaved cytokeratin 18 (M30), caspase-3/7 activity and fluorescence staining techniques that included, Annexin-V, Hoechst 33342 and propidium iodide. Usnea filipendula showed dose and time-dependent antiproliferative effect in HCT-15 and HT-29 cells. The IC50 values in HCT-15 and HT-29 cells were 17.92 and 41.87 mu g/ml, respectively. The extract induced apoptosis in both cell lines especially in HCT-15 cells in which caspase-3/7 activity was increased. Usnea filipendula was cytotoxic to colon cancer HCT-15 and HT-29 cell lines by inducing early or late apoptosis as evidenced by translocation of phosphatidylserine, pyknotic nuclei and nuclear condensation. Further studies would help to understand the full potential of Usnea filipendula as a novel anticancer therapy.Öğe Development of near-infrared region luminescent N-acetyl-L-cysteine-coated Ag2S quantum dots with differential therapeutic effect(Future Medicine Ltd, 2019) Buz, Pelin Turhan; Duman, Fatma Demir; Erkısa Genel, Merve; Demirci, Gözde; Arı, Ferda; Ulukaya, Engin; Acar, Havva YağcıAim: N-acetyl-L-cysteine (NAC) is a free radical scavenger. We developed NAC-coated Ag2S (NAC-Ag2S) quantum dot (QD) as an optical imaging and therapeutic agent. Materials & methods: QDs were synthesized in water. Their optical imaging potential and toxicity were studied in vitro. Results: NAC-Ag2S QDs have strong emission, that is tunable between 748 and 840 nm, and are stable in biologically relevant media. QDs showed significant differences both in cell internalization and toxicity in vitro. QDs were quite toxic to breast and cervical cancer cells but not to lung derived cells despite the higher uptake. NAC-Ag2S reduces reactive oxygen species (ROS) but causes cell death via DNA damage and apoptosis. Conclusion: NAC-Ag2S QDs are stable and strong signal-generating theranostic agents offering selective therapeutic effects.Öğe Effective and new potent drug combination: histone deacetylase and Wnt/beta-catenin pathway inhibitors in lung carcinoma cells(Wiley, 2019) Akgün, Oğuzhan; Erkısa Genel, Merve; Arı, FerdaLung cancer is the most commonly diagnosed cancer worldwide with a high mortality rate. In this study, the therapeutic effect of combination valproic acid and niclosamide was investigated on human lung cancer cell line. The effects of the compounds alone and combination therapy on cell viability were determined by sulforhodamine B and adenosine 5 '-triphosphate viability assays. Flow cytometry was used to determine the cell death mechanism and DNA damage levels responsible for the cytotoxic effects of combination therapy. The presence of apoptosis in cells was supported by fluorescence microscopy and also by using inhibitors of the apoptotic signaling pathway. The increase in cellular reactive oxygen species (ROS) level in combination therapy was determined by H2DCFDA staining. The effect of N-acetyl-l-cysteine combination on ROS increase was investigated on cell viability. In addition, the expression levels of the proteins associated with epigenetic regulation and cell death were analyzed by Western blotting and gene expression levels were determined using real-time quantitative polymerase chain reaction.It was observed that the combination therapy showed a cytotoxic effect on the A549 lung cancer cells compared to the individual use of the inhibitors. The absence of this effect on normal lung cells revealed the presence of a selective toxic effect. When the mechanism of cytotoxicity is examined, it has been observed that combination therapy initiates the activation of tumor necrosis receptors and causes apoptosis by activated caspase. It was also observed that this extrinsic apoptotic pathway was activated on the mitochondrial pathway. In addition, ER stress and mitochondrial membrane potential loss associated with increased ROS levels induce cell death. When the data in this study were evaluated, combination therapy caused a dramatic decrease in cell viability by inducing the extrinsic apoptotic pathway in lung cancer cell line. Therefore, it was concluded that it can be used as an effective and new treatment option for lung cancer.Öğe Synthesis, characterization, anticancer and antioxidant activity of new nickel(II) and copper(II) flavonoid complexes(Elsevier, 2019) Alper, Pınar; Erkısa Genel, Merve; Gençkal, Hasene Mutlu; Şahin, Saliha; Ulukaya, Engin; Arı, FerdaFlavonoids are natural products which are known to have biological activity for human health. In this study, new mixed ligand complexes of Ni(II) and Cu(II) were synthesized by using flavonoid (quercetin or naringenin) and heterocyclic imine (2,2':6',2 ''-terpyridine or 2,2'-bipyiridine) ligands. The new complexes are [Ni(narH-1)(terpy)Cl]center dot 4H(2)O (1, nar = naringenin, terpy = 2,2':6',2 ''-terpyridine), [Cu(narH-1)(terpy)Cl]center dot H2O (2), and [Cu(queH-1)(bpy)(O3N)]center dot 1.5H(2)O (3, que = quercetin, bpy = 2,2'-bipyiridine). The structural features of the synthesized mixed ligand complexes were investigated using elemental analysis, thermogravimetric analysis, Fourier transform infrared spectroscopy, magnetic susceptibility and molar conductivity measurements. The resulting data demonstrated an octahedral geometry for Complex 1 and Complex 2 and square pyramidal geometry for Complex 3. Antioxidant capacity and total phenolic content of Complexes 1-3 were measured by the Folin-Ciocalteu and ABTS methods. Anti- proliferative effect of complexes were tested by SRB and ATP assays on MCF-7 (breast cancer), A549 (nonsmall cell lung cancer), PC-3 (prostate cancer) and HeLa (human cervical cancer) cell lines. Apoptosis was identified using by the fluorescence imaging, caspase cleaved cytokeratin-18 and flow cytometry analysis. Complex 2 and 3 had high total phenolic content and antioxidant activity. Complex 2 was found to show selective cytotoxicity through the induction of apoptosis on MCF-7 cells with having a very low IC50 value (<0.8 mu M; the half maximum inhibitory concentration) while its ligands showed much higher cytotoxicity (IC50 > 50 mu M). In conclusion, Complex 2 is a highly promising and novel compound for breast cancer and warrants further animal experiments. (C) 2019 Elsevier B.V. All rights reserved.Öğe Mixed ligand complexes of Co(II), Ni(II) and Cu(II) with quercetin and diimine ligands: synthesis, characterization, anti-cancer and anti-oxidant activity(Springer, 2020) Gençkal, Hasene; Erkısa Genel, Merve; Alper, Pınar; Şahin, Saliha; Ulukaya, Engin; Arı, FerdaIn this work, mixed ligand complexes of Co(II) Ni(II) and Cu(II) were synthesized using quercetin and diimine (1,10-phenanthroline or 2,2 '-bipyiridine) ligands. The obtained Ni(II) and Co(II) complexes are new and the Cu(II) complexes are synthesized by different method from the literature. The characterization of complexes was performed by elemental analysis, thermogravimetric analysis, ESI-MS, UV-visible and infrared spectral analyses, magnetic susceptibility and molar conductivity measurements. It was found that quercetin, diimine and metal(II) ion form 1:1:1 complexes. Resulting data supported octahedral geometry for Ni(II) and Co(II) complexes and square pyramidal geometry for Cu(II) complexes. The proposed compositions are [Co(queH-1)Cl(phen)(H2O)]center dot 2H(2)O (1, queH = quercetin, phen = 1,10-phenanthroline), [Ni(queH-1)Cl(phen)(H2O)]center dot 2H(2)O (2), [Cu(queH-1)Cl(phen)]center dot 2.5H(2)O (3) and [Cu(queH-1)Cl(bpy)]center dot 2H(2)O (4, bpy = 2,2 '-bipyiridine). Antioxidant capacity and total phenolic content of complexes measured by Folin-Ciocalteu and ABTS methods. Anti-cancer effect of these compounds were tested against different cancer cells (A549, PC-3, HeLa and MCF-7). Apoptosis identified by the fluorescence imaging, caspase cleaved cytokeratin-18 and flow cytometry analysis (annexin V, caspase 3/7, mitochondria membrane potential and oxidative stress). As a result, Cu(II) complexes are more effective than the other compounds and Complex 3 is a promising anti-cancer compound against breast cancer MCF-7 and MDA-MB-231 cells (IC50 values are 2.4 and 5.4 mu M for 48 h, respectively). Flow cytometry analysis exhibited that Complex 3 caused apoptosis in MCF-7 cells. These results support that Complex 3 has anticancer activity and can be a potential anticancer agent especially in breast cancer.Öğe Highly promising antitumor agent of a novel Platinum(II) complex bearing a tetradentate chelating ligand(Amer Chemical Soc, 2020) Yılmaz, İsmail; Akar, Remzi Okan; Erkısa Genel, Merve; Selvi, Selin; Şengül, Abdurrahman; Ulukaya, EnginA new mononuclear cationic platinum(II) coordination compound with 6,6'-bis(NH-benzimidazol-2-yl)-2,2'-bipyridine (L) ligand having N-4-tetradentate binding pocket [Pt(L)]-Cl-2.2H(2)O (Complex 1) was synthesized and characterized by FTIR(ATR), UV-vis, H-1 NMR, APCI and MALDI MS, and CHN analysis. The antigrowth effect of Complex 1 was tested in breast cancer (MDA-MB-231), lung cancer (A549), colorectal cancer (HCT-116), prostate cancer (PC-3) cell lines, and bronchial epithelial cell line (BEAS-2B) by the SRB and ATP cell viability assays. Apoptosis was detected with Annexin V, mitopotential, BCL-2 inactivation, and gamma H2AX assays by flow cytometry. Complex 1 was found to have cytotoxic activity of MDA-MB-231, A549, HCT-116, and PC-3 cancer cell lines in a dose-dependent manner for 48 h. Complex 1 has been found to cause cell death through different mechanisms depending on the type of cancer. The findings indicated that complex induced intrinsic apoptosis with the increased mitochondrial membrane depolarization level, Bcl-2 inactivation, and DNA damage in PC-3 and A549 cell lines.
