Person: ARI, FERDA
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ARI
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Publication Epigenetic modulators combination with chemotherapy in breast cancer cells(Wiley, 2021-02-20) Arı, Ferda; Napieralski, Rudolf; Akgün, Oğuzhan; Magdolen, Viktor; Ulukaya, Engin; ARI, FERDA; Akgün, Oğuzhan; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü; 0000-0002-6729-7908; 0000-0002-8410-1786; A-5608-2019; AAG-7012-2021Despite the concerning adverse effects on tumour development, epigenetic drugs are very promising in cancer treatment. The aim of this study was to compare the differential effects of standard chemotherapy regimens (FEC: 5-fluorouracil plus epirubicine plus cyclophosphamide) in combination with epigenetic modulators (decitabine, valproic acid): (a) on gene methylation levels of selected tumour biomarkers (LINE-1, uPA, PAI-1, DAPK); (b) their expression status (uPA and PAI-1); (c) differentiation status (5meC and H3K27me3). Furthermore, cell survival as well as changes concerning the invasion capacity were monitored in cell culture models of breast cancer (MCF-7, MDA-MB-231). A significant overall decrease of cell survival was observed in the FEC-containing combination therapies for both cell lines. Methylation results showed a general tendency towards increased demethylation of the uPA and PAI-1 gene promoters for the MCF-7 cells, as well as the proapoptotic DAPK gene in the treatment regimens for both cell lines. The uPA and PAI-1 antigen levels were mainly increased in the supernatant of FEC-only treated MDA-MB-231 cells. DAC-only treatment induced an increase of secreted uPA protein in MCF-7 cell culture, while most of the VPA-containing regimens also induced uPA and PAI-1 expression in MCF-7 cell fractions. Epigenetically active substances can also induce a re-differentiation in tumour cells, as shown by 5meC, H3K27me3 applying ICC.Significance of the study Epigenetic modulators especially in the highly undifferentiated and highly malignant MDA-MB-231 tumour cells significantly reduced tumour malignancy thus; further clinical studies applying specific combination therapies with epigenetic modulators may be warranted.Publication Soloxolone methyl, as a 18βH-glycyrrhetinic acid derivate, may result in endoplasmic reticulum stress to induce apoptosis in breast cancer cells(Elsevier, 2021-01-15) Alper, Pınar; Salomatina, Oksana, V; Salakhutdinov, Nariman F.; Ulukaya, Engin; Arı, Ferda; Alper, Pınar; ARI, FERDA; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü; 0000-0001-9631-3551; 0000-0002-6729-7908; DUL-1586-2022; AAG-7012-2021Being one of the leading causes of cancer death among women, various chemotherapeutic agents isolated from natural compounds are used in breast cancer treatment and consequently studies to develop new drugs still continue. There are several studies on 18 beta H-glycyrrhetinic acid, a secondary metabolite which is found in Glycyrrhiza glabra (liquorice roots), as a potential anticancer agent. In this study, the cytotoxic and apoptotic effects of Soloxolone methyl compound, a semisynthetic derivative of 18 beta H-glycyrrhetinic acid were investigated on breast cancer cells (MCF-7, MDA-MBA-231). Soloxolone methyl is found to be cytotoxic on both MCF-7 and MDA-MBA-231 breast cancer cells by inducing apoptosis. Especially in MDA-MB-231 cells apoptosis is detected to be triggered by ER stress. The antigrowth effects of Soloxolone methyl were determined using MTT and ATP assays. To identify the mode of cell death (apoptosis/necrosis), fluorescent staining (Hoechst 33342 and Propidium iodide) and caspase-cleaved cytokeratin 18 (M30-antigen) analyses were used. In addition, apoptosis was investigated on gene and protein levels by PCR and Western Blotting. Soloxolone methyl decreased cell viability on cells in a dose and time-dependent manner and induced apoptosis markers. An increase on apoptotic proteins related to endoplasmic reticulum stress (IRE1-alpha, Bip, CHOP) was also determined in MDA-MB-231 cells. Moreover, an increase of apoptotic gene expressions was determined in both cells treated with Soloxolone methyl. Advance analyses should be performed to elucidate the potential of Soloxolone methyl as an anticancer agent in breast cancer treatment.Publication Palladium (II) complex enhances ROS-dependent apoptotic effects via autophagy inhibition and disruption of multiple signaling pathways in colorectal cancer cells(Bentham Science Publ Ltd, 2021-01-01) Aydınlık, Şeyma; Erkısa, Merve; Arı, Ferda; Çelikler, Serap; Ulukaya, Engin; Aydınlık, Şeyma; ARI, FERDA; ÇELİKLER KASIMOĞULLARI, SERAP; 0000-0001-5238-2432; 0000-0002-6729-7908; 0000-0002-4177-3478; ABI-2909-2020; AAG-7012-2021; JCD-5015-2023Background: Inhibition of autophagy is reported to be a therapeutically effective strategy in overcoming 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 48h and cell viability was measured by SRB assay. Cell death mode was examined with M30 and M65 ELISA assays, using annexin V/propidium iodide. Autophagy was determined by Acridine Orange (AO) staining. Furthermore, the expressions of various autophagy and apoptosis-related proteins were evaluated with Western blotting. Luminex assay and the level of Reactive Oxygen Species (ROS) were examined.Results: Cell viability was found to decrease in a dose-dependent manner and CQ enhanced cytotoxic effect in Pd(II) and 5-FU treated cells in colorectal cancer cells. Our data showed that inhibition of autophagic flux significantly increased intrinsic apoptosis through the activation of ROS. We showed that combinatorial treatment with CQ induced apoptosis via the caspase-dependent mitochondrial pathway. Luminex analysis revealed that the combination resulted in a down-regulation of NF-?B/AKT/CREB signaling pathways in both cell lines, however, decreased Erk1/2 protein expression was only observed after treatment with CQ combination in HCT-15 cells.Conclusion: We suggest that the inhibition of autophagy along with Pd(II) and 5-FU treatment has a synergistic effect on KRAS-mutant colorectal cancer cells. Autophagy inhibition by CQ promotes apoptosis via blockade of the NF-?B/AKT/CREB and activation of ROS.Publication Investigation of the efficacy of paclitaxel on some miRNAs profiles in breast cancer stem cells(Tübitak Bilimsel ve Teknolojik Araştırma Kurumu, 2021-01-01) Ertürk, Elif; Arı, Ferda; Akgün, Oguzhan; Ulukaya, Engin; Küçükali, Cem İsmail; Zeybek, Ümit; ERTÜRK, ELİF; ARI, FERDA; Akgün, Oguzhan; 0000-0002-6729-7908; 0000-0002-8410-1786; 0000-0003-4875-5472; 0000-0001-9851-8577; A-5608-2019; K-5792-2018; JQI-3400-2023Understanding of the functions of microRNAs in breast cancer and breast cancer stem cells have been a hope for the development of new molecular targeted therapies. Here, it is aimed to investigate the differences in the expression levels of let-7a, miR-10b, miR-21, miR-125b, miR-145, miR-155, miR-200c, miR-221, miR-222 and miR-335, which associated with gene and proteins in MCF-7 (parental) and MCF-7s (Mammosphere/stem cell-enriched population/CD44+/CD24-cells) cells treated with paclitaxel. MCF7-s were obtained from parental MCF-7 cells. Cytotoxic activity of paclitaxel was determined by ATP assay. Total RNA isolation and cDNA conversion were performed from the samples. Changes in expression levels of miRNAs were examined by RT-qPCR. Identified target genes and proteins of miRNAs were analyzed with RT-qPCR and western blot analysis, respectively. miR-125b was significantly expressed (2.0946-fold; p = 0.021) in MCF-7s cells compared to control after treatment with paclitaxel. Downregulation of SMO, STAT3, NANOG, OCT4, SOX2, ERBB2 and ERBB3 and upregulation of TP53 genes were significant after 48 h treatment in MCF-7s cells. Protein expressions of SOX2, OCT4, SMAD4, SOX2 and OCT4 also decreased. Paclitaxel induces miR-125b expression in MCF-7s cells. Upregulation of miR-125b may be used as a biomarker for the prediction of response to paclitaxel treatment in breast cancer.Publication Combination of histone deacetylase inhibitor with cu(ii) 5,5-diethylbarbiturate complex induces apoptosis in breast cancer stem cells: A promising novel approach(Bentham Science, 2021-01-01) Erkisa, Merve; Aztopal, Nazlihan; Erturk, Elif; Ulukaya, Engin; Yilmaz, Veysel T.; Ari, Ferda; Erkisa, Merve; Aztopal, Nazlihan; YILMAZ, VEYSEL TURAN; Ari, Ferda; ARI, FERDA; ertürk; Bursa Uludağ Üniversitesi/Fen Edebiyat Fakültesi.; 0000-0002-3127-742X; 0000-0003-3118-8061; 0000-0002-2849-3332; 0000-0002-6729-7908; JQI-3400-2023; AAM-1001-2020; L-7238-2018; AAG-7012-2021; L-6687-2018Background: Cancer Stem Cells (CSCs) are a subpopulation within the tumor that play a role in the initiation, progression, recurrence, resistance to drugs and metastasis of cancer. It is well known that epigenetic changes lead to tumor formation in cancer stem cells and show drug resistance. Epigenetic modulators and /or their combination with different agents have been used in cancer therapy.Objective: In our study, we scope out the effects of a combination of a histone deacetylases inhibitor, Valproic Acid (VPA), and Cu(II) complex [Cu(barb-kappa N)( barb-kappa 2N,O)(phen-kappa N,N')]center dot H2O] on cytotoxicity/apoptosis in a stem-cell enriched population (MCF-7s) obtained from parental breast cancer cell line (MCF-7).Methods: The viability of the cells was measured by the ATP assay. Apoptosis was elucidated via the assessment of caspase-cleaved cytokeratin 18 (M30 ELISA) and a group of flow cytometry analysis (caspase 3/7 activity, phosphatidylserine translocation by annexin V-FITC assay, DNA damage and oxidative stress) and 2',7'-dichlorofluorescein diacetate staining.Results: The VPA combined with Cu(II) complex showed anti-proliferative activity on MCF-7s cells in a dose-and time-dependent manner. Treatment with a combination of 2.5 mM VPA and 3.12 mu M Cu(II) complex induced oxidative stress in a time-dependent manner, as well as apoptosis evidenced by the increase in caspase 3/7 activity, positive annexin-V-FITC, and increase in M30 levels.Conclusion: The results suggest that the combination therapy induces apoptosis following increased oxidative stress, thereby making it a possible promising therapeutic strategy for which further analysis is required.Publication Toxicity assessment of hypericum olympicum subsp. olympicum l. on human lymphocytes and breast cancer cell lines(Univ South Bohemia, 2020-01-01) Balıkçı, Necmiye; Sarımahmut, Mehmet; Arı, Ferda; Aztopal, Nazlıhan; Özel, Mustafa Zafer; Ulukaya, Engin; Çelikler, Serap; Balıkçı, Necmiye; SARIMAHMUT, MEHMET; ARI, FERDA; Aztopal, Nazlıhan; Ulukaya, Engin; ÇELİKLER KASIMOĞULLARI, SERAP; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü; 0000-0003-2647-5875; 0000-0002-6729-7908; 0000-0003-3118-8061; 0000-0003-4875-5472; 0000-0002-4177-3478; JCN-7113-2023; AAG-7012-2021; AAV-4886-2020; K-5792-2018; L-6687-2018; JCD-5015-2023; ENX-2092-2022There is a limited number of studies about the constituents of Hypericum olympicum subsp. olympicum and its genotoxic and cytotoxic potency. We examined the possible antigenotoxic/genotoxic properties of methanolic extract of H. olympicum subsp. olympicum (HOE) on human lymphocytes by employing sister chromatid exchange, micronucleus and comet assay and analyzed its chemical composition by GCxGC-TOF/MS. The anti-growth activity against MCF-7 and MDA-MB-231 cell lines was assessed by using the ATP viability assay. Cell death mode was investigated with fluorescence staining and ELISA assays. The major components of the flower and trunk were determined as eicosane, heptacosane, 2-propen-1-ol, hexahydrofarnesyl acetone and alpha-muurolene. HOE caused significant DNA damage at selected doses (250-750 mu g/ml) while chromosomal damage was observed at higher concentrations (500 and 750 mu g/ml). HOE demonstrated anti-growth activity in a dose-dependent manner between 3.13-100 mu g/ml. Pyknotic nuclei were observed at 100 mu g/ml concentration of HOE in both cell lines. In conclusion, HOE demonstrated cytotoxic effects in a cell type-dependent manner, however its genotoxic effects were observed at relatively higher doses.Publication Palladium (II)-based novel approach to kill cancer stem cells of breast cancer(Oxford Univ Press, 2015-12-01) Ulukaya, Engin; Aydınlık, Seyma; Erkısa, Merve; Arı, Ferda; Yılmaz, Veysel Turan; Ulukaya, Engin; Aydınlık, Seyma; Erkısa, Merve; ARI, FERDA; YILMAZ, VEYSEL TURAN; Uludağ Üniversitesi/Tıp Fakültesi; Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Kimya Bölümü; 0000-0003-4875-5472; 0000-0002-3127-742X; 0000-0002-6729-7908; 0000-0002-2849-3332; AAG-7012-2021; L-7238-2018; AAM-1001-2020; K-5792-2018; CEV-4436-2022Publication New copper(ii) complexes containing tryptophan based schiff bases as promising antiproliferative agents on breast cancer cells(Elsevier, 2023-12-28) Zorlu, Yunus; Arı, Ferda; ARI, FERDA; Gültekin, Büşra; Özbağcı, Duygu Inci; İNCİ ÖZBAĞCI, DUYGU; Aydın, İpek; İPEK, AYDIN; Aydın, Rahmiye; AYDIN, RAHMİYE; Bursa Uludağ Üniversitesi/Fen Edebiyat Fakültesi/Kimya Bölümü.; Bursa Uludağ Üniversitesi/Fen Edebiyat Fakültesi/Biyoloji Bölümü.; 0000-0002-0443-1129; 0000-0002-0483-9642; 0000-0003-4944-0181; 0000-0002-6729-7908; 0000-0003-2811-1872; G-2201-2019; IUO-8513-2023; AAG-7012-2021Three new copper(II) complexes, [Cu(5-ClSal-Trp)(H2O)2] (1), [Cu(5-ClSal-Trp)(phen)] & sdot;C2H5OH (2) and [Cu (3,5-ClSal-Trp)(phen)] (3) (5-ClSal-Trp: Schiff base derived from 5-chlorosalicylaldehyde and L-tryptophan, 3,5-ClSal-Trp: Schiff base derived from 3,5-dichlorosalicylaldehyde and L-tryptophan, phen: 1,10-phenanthroline), have been synthesized and characterized by electronic absorption spectroscopy, CHN analysis, FTIR, ESI-MS and XRD techniques. Interaction of the complexes 1-3 with biomolecules {calf thymus DNA (CT-DNA) and bovine serum albumin (BSA)} has been investigated by electronic absorption and fluorescence spectroscopy. The results show that the complexes 1-3 can bind to CT-DNA via a moderate intercalation mode. Moreover, the fluorescence quenching mechanism between the complexes 1-3 and BSA is a static quenching process. Radical scavenging activity studies reveal that the complexes 1-3 show a moderate activity. Antiproliferative effects of the complexes 1-3 on both breast cancer cells (MCF-7 and MDA-MB-231) and healthy breast epithelial cells (MCF-10A) were also investigated using the Sulforhodamine B (SRB) viability assay. The results demonstrated that the complexes 1-3 exhibited a more pronounced cytotoxic effect on cancer cells compared to normal breast epithelial cells. Among the complexes, the best cytotoxic activity was obtained for the complex 3 against both human breast cancer cell lines. Further analysis indicated that the complex 3 induced apoptosis, as evidenced by fluorescent staining, positive Annexin-V-FITC staining, and the involvement of caspase. Subsequent to the administration of the complex 3, an evaluation of intracellular reactive oxygen species (ROS) generation was conducted through the utilization of dihydroethidium (DHE) fluorescent staining.Publication Design, synthesis and anticancer activity of new benzofuran-chalcone hybrids and their water soluble sodium salts(Wiley-v C H Verlag Gmbh, 2023-03-06) Coskun, Demet; Coşkun, Mehmet Fatih; Çınar-Asa, Sibel; Akgün, Oğuzhan; Akgün, Halime; Arı, Ferda; ARI, FERDA; Bursa Uludağ Üniversitesi/Fen Edebiyat Fakültesi/Biyoloji Bölümü.; 0000-0002-8410-1786; 0000-0002-2048-3252; 0000-0002-6729-7908; A-5608-2019; ADX-9980-2022; AAG-7012-2021In this study, firstly, 1-(7-ethoxy-1-benzofuran-2-yl) ethanone and 1,1'-(7-ethoxy-1-benzofuran-2,4-diyl)diethanone were synthesized for the starting reagent purposes. The synthesized benzofuran-chalcone salts were soluble in water at room temperature. Structural analysis of the synthesized compounds was characterized by elemental analysis, FT-IR and NMR spectroscopy techniques. The anticancer activities of the compounds were determined by SRB viability assay in human lung cancer (A549, H1299) and breast cancer (MCF-7, MDA-MB-231) cell lines. Findings for apoptosis were determined by flow cytometry analysis and the PARP-ELISA method. The results of the in vitro SRB analysis of the compounds showed that some of the chalcone hybrids were very effective on both types of cancer in a dose and time-dependent manner. Treatment of all cancer cell types with these hybrids resulted in a significant increase in the percentage of early and mainly late apoptotic cells, demonstrating their apoptosis-inducing effects via the Caspase 3/7 Activity.Publication The mechanism for anticancer and apoptosis-inducing properties of cu(ii) complex with quercetin and 1,10-phenanthroline(Wiley-v C H Verlag Gmbh, 2022-10-13) Cevatemre, Buse; Ari, Ferda; ARI, FERDA; Done, Gülseven; Akgün, Oğuzhan; Akgün, Halime; Gençkal, Hasene Mutlu; MUTLU GENÇKAL, HASENE; Bursa Uludağ Üniversitesi/Fen Edebiyat Fakültesi/Biyoloji Bölümü.; Bursa Uludağ Üniversitesi/Fen Edebiyat Fakültesi/Kimya Bölümü.; 0000-0002-6729-7908; 0000-0002-8410-1786; 0000-0002-2048-3252; 0000-0002-0026-7755; AAG-7012-2021; A-5608-2019This 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.