Yazar "Mutlu, Zeynep" seçeneğine göre listele

Listeleniyor 1 - 3 / 3
  • Küçük Resim
    Öğe
    Comparative expression analysis of dasatinib and ponatinib-regulated lncRNAs in chronic myeloid leukemia and their network analysis
    (Humana Press Inc, 2022) Kayabaşı, Çağla; Caner, Ayşe; Yılmaz Susluer, Sunde; Balcı Okcanoglu, Tuğce; Özmen Yelken, Besra; Aşık, Aycan; Mutlu, Zeynep
    LncRNAs are associated with malignancies with their tumor suppressor/oncogenic properties. Although many studies are conducted related to the mechanism of action for dasatinib and ponatinib in chronic myeloid leukemia (CML), their comparative effects on lncRNA expressions are largely unknown. Hence, we aimed to define the lncRNAs involved in the treatment of CML with dasatinib and ponatinib. We measured the cytotoxicities of dasatinib/ponatinib with CCK-8 assay and identified differentially expressed lncRNAs (DEL) by qRT-PCR. We determined the principal functions of DELs by Ingenuity Pathway Analysis (IPA) and performed gene ontology (GO) analysis for apoptosis and anti-proliferation-related lncRNAs. Apoptotic and anti-proliferative activities of dasatinib/ponatinib were confirmed by flow-cytometry. In K562 cells, dasatinib/ponatinib re-regulated lncRNAs which were dysregulated in leukemia. DELs after treatment (forty with dasatinib, thirty-seven with ponatinib) were related to increased cell death; decreased cell viability, proliferation, tumor growth, invasion, migration. Dasatinib-mediated network was related to cancer, hematological disease while ponatinib-mediated network was associated with cancer, cell death/survival, cell-to-cell signaling/interaction. Both treatments predicted activation of IFN gamma, IL1 beta, TNF as upstream regulators, specially this effect was higher in dasatinib. Comparison analysis showed that ponatinib was predicted more effective in cell death of tumor cell line than dasatinib. We confirmed that ponatinib was more potent than dasatinib to induce apoptosis and inhibit proliferation of CML cells, in consensus with IPA and GO analysis results. LncRNAs are specifically involved in anti-leukemic activities of dasatinib and ponatinib. Our findings will contribute to understanding signalization occurring in CML cells after standard treatments.
  • Küçük Resim Yok
    Öğe
    Origanum Sipyleum Methanol Extract in Combination with Ponatinib Shows Synergistic anti-Leukemic Activities on Chronic Myeloid Leukemia Cells
    (Routledge Journals, Taylor & Francis Ltd, 2022) Kayabasi, Cagla; Yilmaz Susluer, Sunde; Balci Okcanoglu, Tugce; Ozmen Yelken, Besra; Mutlu, Zeynep; Goker Bagca, Bakiye; Caliskan Kurt, Cansu
    Origanum sipyleum is used in folk medicine due to its anti-inflammatory, antimicrobial, and antioxidant properties. Ponatinib, an effective tyrosine kinase inhibitor in the treatment of chronic myeloid leukemia (CML), has severe side effects. Thus, we aimed to determine a novel herbal combination therapy that might not only increase the anti-leukemic efficacy but also reduce the dose of ponatinib in targeting CML cells. Origanum sipyleum was extracted with methanol (OSM), and secondary metabolites were determined by phytochemical screening tests. The cytotoxic effects of OSM on K562 cells were measured by WST-1 assay. Median-effect equation was used to analyze the combination of ponatinib and OSM (p-OSM). Apoptosis, proliferation, and cell-cycle were investigated by flow-cytometry. Cell-cycle-related gene expressions were evaluated by qRT-PCR. OSM that contains terpenoids, flavonoids, tannins, and anthracenes exhibited cytotoxic effects on K562 cells. The median-effect of p-OSM was found as synergistic; OSM reduced the ponatinib dose similar to 5-fold. p-OSM elevated the apoptotic and anti-proliferative activity of ponatinib. Consistently, p-OSM blocked cell-cycle progression in G(0)/G(1), S phases accompanied by regulations in TGFB2, ATR, PP2A, p18, CCND1, CCND2, and CCNA1 expressions. OSM enhanced the anti-leukemic activity of ponatinib synergistically via inducing apoptosis, suppressing proliferation, and cell-cycle. As a result, OSM might offer a potential strategy for treating patients with CML.
  • Küçük Resim
    Öğe
    Ponatinib miRNA ifadelerini düzenleyerek meme kanseri hücrelerini hedefler
    (2021) Süslüer, Sunde; Gündüz, Cumhur; Kurt, Cansu Çalışkan; Avcı, Çığır Biray; Yelken, Besra Özmen; Kayabaşı, Çağla; Mutlu, Zeynep
    Meme kanseri kadınlarda en yaygın gözlenen kanser türüdür. Mevcut tedavilerin düşük seçicilik ya da zamanla oluşan ilaç direnci gibi eksiklerini giderebilecek yeni stratejilerin belirlenmesine ihtiyaç vardır. Çalışmamızda, çoklu hedefli bir tirozin kinaz inhibitörü olan ponati- nibin meme kanseri hücreleri üzerindeki anti-kanser etkisini değerlendirmeyi ve ponatinib yanıtında yer alan miRNA'ların biyoinformatik yaklaşım ile sinyal yolaklarındaki potansiyel işlevini tanımlamayı hedefledik. Bu amaçla, MCF-7 hücrelerinde ponatinibin sitotoksik etkileri xCELLigence ile gerçek-zamanlı olarak belirlendi. Ponatinib uygulaması sonrasında apoptoz, proliferasyon hızı, hücre döngüsündeki deği- şimler akım sitometriyle, miRNA'ların ifadelerindeki düzenlenmeler qRT-PCR ile değerlendirildi. İfadelerinde anlamlı değişim belirlenen miRNA’ların ilişkili olduğu olası mRNA’lar ve sinyal yolakları KEGG yolak analizi ile tanımlandı. Ponatinibin MCF-7 hücreleri üzerinde sitotoksik etkiye sahip olduğu (IC50: 4,59 ?M) belirlendi. Ponatinib uygulaması ile MCF-7 hücrelerinde anlamlı olarak apoptozun indüklen- diği, proliferasyonun baskılandığı ve hücre döngüsünün G0 /G1, S evrelerinde durakladığı belirlendi. Ayrıca, let-7a-5p, miR-29a-3p, miR-7-5p, miR-125b-5p, miR-212-3p ifadelerinde artış (p<0,05), miR-210-3p, miR-19b-3p, miR-140-5p, miR-181b-5p, miR-155-5p, miR-223-3p, miR-141-3p, miR-21-5p ifadelerinde azalma olduğu (p<0,05), miR-19a-3p ifadesinin ise tamamen baskılandığı belirlendi. Biyoinformatik analizler ile, ifadesi değişen miRNA’ların kanserde proteoglikanlar, Hippo, p53, TGF-beta, kanser-ilişkili, PI3K-Akt, prolaktin, hücre dön- güsü, östrojen, mTOR sinyal yolakları ile ilişkili olduğu ortaya koyuldu. Ponatinib uygulaması meme kanseri hücrelerinde apoptozu indükle- yerek, proliferasyonu baskılayarak ve hücre döngüsünü durdurarak güçlü anti-kanser aktivite sergilemiştir. Ponatinibin belirlenen anti-kanser etkilerinde miRNA’ların rolleri olabileceği gösterilmiştir. Olası miRNA-mRNA etkileşimleri ile meme kanserindeki hedef sinyal yolakları- nın tanımlanması ışığında, ponatinibin tek başına veya diğer tedavilerle kombinasyon halinde meme kanseri tedavisi için potansiyel bir strateji olabileceği görüşündeyiz.