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Öğe Anticancer potential of albumin bound wnt/beta-catenin pathway inhibitor niclosamide in breast cancer cells(WILEY, 2021) Arı, Ferda; Erkısa Genel, Merve; Pekel, Gonca; Ertürk, Elif; Büyükköroğlu, Gülay; Ulukaya, EnginAlbumin-based nanoparticle transport systems (nab-technology) are a new strategy in cancer treatment and we aimed to increase the effectiveness of Niclosamide using this technology. Niclosamide was bound with bovine serum albumin (BSA) by desolvation to yield nanoparticle albumin-bound Niclosamide (nab-Niclo). Nab-Niclo anticancer activity was assessed by proliferation, apoptosis and DNA damage analyses on breast cancer cells. The results implied that nab-Niclo was a more potent agent in the inhibition of cell viability than free Niclosamide and albumin. Flow cytometry analysis show that nab-Niclo triggered apoptosis by caspase and mitochondriadependent pathways in cells and nab-Niclo enhances apoptosis by induce DNA damage in cells. Overall results of this study showed that the nanoparticle form of Niclosamide is effective for breast cancer treatment, presenting a new treatment strategy that can be safe and effective for breast cancer patients.Öğe Combination of histone deacetylase inhibitor with Cu(II) 5,5- diethylbarbiturate complex induces apoptosis in breast cancer stem cells: a promising novel approach(2021) Erkısa Genel, Merve; Aztopal, Nazlıhan; Ertürk, Elif; Ulukaya, Engin; Yılmaz, Veysel Turan; Ari, FerdaBackground: Cancer stem cells (CSC) are subpopulation within the tumor that acts a part 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 combination of a histone deacetylases inhibitor, valproic acid (VPA), and Cu(II) complex [Cu(barb-?N)(barb-?2N,O)(phen-?N,N')]·H2O] on cytotoxicity/apoptosis in a stem-cell enriched population (MCF-7s) obtained from parental breast cancer cell line (MCF-7). Methods: 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-dependently. Treatment with combination of 2.5 mM VPA and 3.12 ?M Cu(II) complex induces oxidative stress in a time-dependent manner, as well as apoptosis that is 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 that further analysis is required.Öğe Investigation of the efficacy of paclitaxel on some miRNAs profiles in breast cancer stem cells(TUBITAK SCIENTIFIC & TECHNICAL RESEARCH COUNCIL TURKEY, 2021) Ertürk, Elif; Arı, Ferda; Akgün, Oguzhan; Ulukaya, Engin; Küçükali, Cem İsmail; Zeybek, ÜmitUnderstanding 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.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.