Moleküler Biyoloji ve Genetik Bölümü Koleksiyonu

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/209

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Browsing Moleküler Biyoloji ve Genetik Bölümü Koleksiyonu by Author "0000-0002-3747-8580"

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    Article
    Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells
    (De Gruyter, 2022) Adan, Aysun; Şahin, Hande Nur; 0000-0002-3747-8580; 0000-0002-2382-3160; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Adan, Aysun; Şahin, Hande Nur
    Objectives Therapeutic potential of clinically approved FLT3 inhibitor midostaurin has been neglected in wild-type FLT3 positive acute myeloid leukemia (AML). Sphingosine kinase-1 (SK-1) having anti-proliferative functions is studied in various cancers, but not in FLT3 wild-type AML. We aimed to develop new therapeutic strategies to combat FLT3 wild-type AML by combining midostaurin with SK-1 inhibitor (SKI II) in THP1 cells. Methods The anti-proliferative effects of midostaurin, SKI II and in combination on THP1 cells were determined by MTT assay. The combination indexes were calculated using calcusyn software. SK-1 expression and PARP cleavage were checked by western blot. Cell cycle distributions (PI staining) and apoptosis (annexin-V/PI dual staining) were assessed by flow cytometry for each agent alone and in combinations. Results Midostaurin decreased SK-1 protein level. Midostaurin, SKI II and certain combinations decreased cell viability in a dose dependent manner. The combined anti-leukemic effects of the aforementioned drug combination afforded additive effect. Co-administration induced both necrosis and apoptosis via phosphatidylserine externalization, PARP cleavage and cell cycle arrest at G0/G1 and S phases. Conclusions Targeting sphingosine kinase-1 together with FLT3 inhibition could be a novel mechanism to increase limited clinic response to midostaurin in wild-type FLT3 overexpressing AML after further pre-clinical studies.
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    Pleiotropic molecular effects of dietary polyphenols resveratrol and apigenin in Leukemia
    (ELSEVIER, 2018) Adan, Aysun; Oğuz, Osman; 0000-0002-3747-8580; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Adan, Aysun; Oğuz, Osman
    Resveratrol and apigenin are commonly found polyphenols in many fruits and vegetables and recognition of these dietary polyphenols for human health owing to their biological and pharmacological features including antiinflammatory and antioxidative functions has increased recently. In addition to direct antioxidative effects, they have impacts on various important signaling pathways dysregulated in cancer, genetic and epigenetic regulators, transcription factors and even on miRNAs as anticarcinogenic compounds. Numerous in vitro and in vivo studies have demonstrated their pleiotropic molecular mechanisms of action in cancer, particularly in solid tumors. However, in recent years, significant progress has been made in studying the antileukemic effects of resveratrol and apigenin at the cellular and molecular levels. Herein, we have critically discussed the main molecular targets of resveratrol and apigenin and their promising potential as chemopreventive agents as well as their limitations, with a special emphasis on leukemias.
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    Research Project
    Resveratrolün Ph+ Akut Lenfoblastik Lösemide Terapötik Potansiyeli ve Resveratrol Tarafından Tetiklenen Apoptozda Seramid Metabolizmasının Rolü
    (TUBİTAK, 2019) Adan, Aysun; Baran, Yusuf; 0000-0002-3747-8580; 0000-0001-8354-780X; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Adan, Aysun
    Proje ile resveratrolün, Ph+ ALL hücreleri üzerindeki büyümeyi inhibe edici etkisinin arkasında yatan mekanizmalar, seramid metabolizmasının hedeflenmesi ve BCR-ABL ifadesindeki değişimler ile ilişkilendirilerek araştırılmıştır. Resveratrol, SK inhibitörü (SKI II), GSS inhibitörü (PDMP), SPT inhibitörü (Miriosin, Myriocin) ve resveratrol: inhibitör kombinasyonlarının in vitro olarak Ph+ ALL SD1 ve SUP-B15 hücreleri üzerindeki büyümeyi durdurucu ve apoptotik etkileri MTT hücre çoğalması testi, Aneksin-V/PI boyaması, kaspaz3, PARP ifadelerinin ve sitokrom c salınımının belirlenmesi (western blot) ile, sitostatik etki (hücre döngüsü üzerindeki) ise akım sitometresi (PI boyaması) ile araştırılmıştır. Resveratrol ve sfingolipid metabolizması enzimlerini hedefleyen inhibitör kombinasyonlarının BCR-ABL protein ifadesi üzerine etkisi western blot ile belirlenmiştir. Ayrıca, resveratrolün SPT, SK-1/2, GSS protein ifadeleri üzerindeki etkisi western blot ile belirlenmiştir. Her iki hücre hattında resveratrol ve SKI II ve PDMP ile kombinasyonları hücre büyümesini baskılamış, apoptozu tetiklemiş ve hücre döngüsünü S fazında tutmuştur. Resveratrol:Miriosin kombinasyonu ise hücre büyümesi ve hücre döngüsü üzerinde hücreye özgü etkiler gösterirken apoptozu her iki hücrede tetiklemiştir. Her iki hücre tipinde resveratol ve kombinasyonları sitokrom-c salınımını, kaspaz-3 kesimini ve PARP kesimini genel olarak arttırmakla beraber hücreye özgü değişimler de saptanmıştır. Resveratrol her iki hücrede SK-1/SK2 ve GSS ifadesini azaltırken SPT ifadesini arttırmıştır. Resveratrol, SKI II ve PDMP BCR-ABL ifadesini azaltırken Miriosin arttırmıştır. Resveratrol: SKI II ve PDMP kombinasyonları BCR-ABL üzerinde artışlara neden olurken Miriosin ile kombinasyon BCR-ABL ifadesini azaltmıştır. Sonuç olarak, resveratrol seramid metabolizmasını ve BCR-ABL ifadesini düzenleyerek Ph+ ALL üzerinde hücre büyümesini baskılamış ve apoptozu tetiklemiştir.
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    Article
    Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches
    (Dove Medical Press Ltd, 2022) Tecik, Melisa; Adan, Aysun; 0000-0002-3747-8580; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Adan, Aysun
    FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients. The presence of FLT3-ITD (internal tandem duplication, 20–25%) mutation and, to a lesser extent, FLT3-TKD (tyrosine kinase domain, 5– 10%) mutation is associated with poorer diagnosis and therapy response since the leukemic cells become hyperproliferative and resistant to apoptosis after continuous activation of FLT3 signaling. Targeting FLT3 has been the focus of many pre-clinical and clinical studies. Hence, many small-molecule FLT3 inhibitors (FLT3is) have been developed, some of which are approved such as midostaurin and gilteritinib to be used in different clinical settings, either in combination with chemotherapy or alone. However, many questions regarding the best treatment strategy remain to be answered. On the other hand, various FLT3-dependent and-independent resistance mechanisms could be evolved during FLT3i therapy which limit their clinical impact. Therefore, identifying molecular mechanisms of resistance and developing novel strategies to overcome this obstacle is a current interest in the field. In this review, recent studies of approved FLT3i and knowledge about major resistance mechanisms of clinically approved FLT3i’s will be discussed together with novel treatment approaches such as designing novel FLT3i and dual FLT3i and combination strategies including approved FLT3i plus small-molecule agents targeting altered molecules in the resistant cells to abrogate resistance. Moreover, how to choose an appropriate FLT3i for the patients will be summarized based on what is currently known from available clinical data. In addition, strategies beyond FLT3i’s including immunotherapeutics, small-molecule FLT3 degraders, and flavonoids will be summarized to highlight potential alternatives in FLT3-mutated AML therapy.