Scopus İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/395
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Article Functional Combination of Resveratrol and Midostaurin Induces Cytotoxicity to Overcome Acquired Midostaurin Resistance in FLT3-ITD Expressing Acute Myeloid Leukemia Cells(Springer, 2025-08-20) Tecik, Melisa; Adan, AysunThe most important challenge in treating FLT3-ITD AML is the development of resistance to FLT3 inhibitors, such as midostaurin, via both FLT3-dependent and FLT3-independent mechanisms. The study explored the potential cytotoxic effects of combining resveratrol and midostaurin on the sensitization of midostaurin-resistant cells. MTT assay revealed resveratrol's chemo-sensitizing influence on midostaurin-resistant cells, and combination indexes (CI) were calculated using Chou-Talalay's method. Apoptosis induction and cell cycle progression was analyzed by flow cytometry. The apoptotic molecular markers caspase 3, PARP, Bcl-2, and Bax were analyzed using a western blot. Sphingosine kinase-1 (SK-1) expression, total and phosphorylated FLT3, and STAT5A levels were measured using western blotting. Resveratrol enhanced the cytotoxic effects of midostaurin additively in resistant MV4-11MR and MOLM-13MR cells. It effectively reversed midostaurin resistance by inhibiting the activating phosphorylation of FLT3, STAT5A, and modulating the expression of SK-1 while concurrently increasing the levels of cleaved caspase-3 and PARP without noticeable alterations in Bax/Bcl-2 ratios except MV4-11MR cells. Additionally, there was an arrest at the S or G0/G1 phase of the cell cycle, depending on the resistant cells, compared to midostaurin alone, but not to the control group. In conclusion, the FLT3/STAT5A axis and SK-1 might play an important role in the reversal of midostaurin resistance by resveratrol. Therefore, the concurrent administration of resveratrol plus midostaurin could potentially serve as a therapeutic approach to address midostaurin resistance and enhance the overall therapy efficacy for FLT3-ITD AML patients after being validated with future in vivo and ex vivo studies.Article Citation - WoS: 8Citation - Scopus: 9Emerging DNA Methylome Targets in FLT3-ITD Acute Myeloid Leukemia: Combination Therapy With Clinically Approved FLT3 Inhibitors(Springer, 2024-05-02) Tecik, Melisa; Adan, AysunThe internal tandem duplication (ITD) mutation of the FMS-like receptor tyrosine kinase 3 (FLT3-ITD) is the most common mutation observed in approximately 30% of acute myeloid leukemia (AML) patients. It represents poor prognosis due to continuous activation of downstream growth-promoting signaling pathways such as STAT5 and PI3K/AKT. Hence, FLT3 is considered an attractive druggable target; selective small FLT3 inhibitors (FLT3Is), such as midostaurin and quizartinib, have been clinically approved. However, patients possess generally poor remission rates and acquired resistance when FLT3I used alone. Various factors in patients could cause these adverse effects including altered epigenetic regulation, causing mainly abnormal gene expression patterns. Epigenetic modifications are required for hematopoietic stem cell (HSC) self-renewal and differentiation; however, critical driver mutations have been identified in genes controlling DNA methylation (such as DNMT3A, TET2, IDH1/2). These regulators cause leukemia pathogenesis and affect disease diagnosis and prognosis when they co-occur with FLT3-ITD mutation. Therefore, understanding the role of different epigenetic alterations in FLT3-ITD AML pathogenesis and how they modulate FLT3I's activity is important to rationalize combinational treatment approaches including FLT3Is and modulators of methylation regulators or pathways. Data from ongoing pre-clinical and clinical studies will further precisely define the potential use of epigenetic therapy together with FLT3Is especially after characterized patients' mutational status in terms of FLT3 and DNA methlome regulators.