Kişi: ARI, FERDA
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Yayın Sadece Metadata 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.Yayın Sadece Metadata 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.Yayın Açık Erişim Glutathione S-Transferase activity in tissues of rats exposed to fenarimol(Inst Tecnologia Parana, 2021-01-01) Özçelebi, Halime; Arı, Ferda; Dere, Egemen; Özçelebi, Halime; ARI, FERDA; DERE, EGEMEN; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü; 0000-0002-6729-7908; 0000-0002-2048-3252; 0000-0001-9572-1051; AAG-7012-2021The unconscious use of pesticides causes various adverse effects on non-target organisms, including humans. Enzymes that control metabolism become the target of the pesticide and the organs are damaged due to toxic effects. Glutathione s-transferase (GST, EC 2.5.1.18), an important enzyme of the detoxification mechanism and antioxidant defense system, can be affected by such toxic substances. Therefore, the effect of fenarimol on GST enzyme activity was investigated in our study. For this, 200 mg/kg fenarimol was administered intraperitoneally to male and female rats at different periods (2, 4, 8, 16, 32, 64 and 72 hours). After application, GST enzyme activity was analysed in the liver, kidney, brain and small intestine tissues of the rats. According to our results, activation (liver, kidney, small intestine) or inhibition (brain) of the generally GST enzyme was observed in the tissues of rats exposed to fenarimol. It is thought that the increase and/or decrease in this enzyme activity may be the cause of the toxic effect of fenarimol.Yayın Sadece Metadata 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.Yayın Açık Erişim 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.Yayın Sadece Metadata 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.