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: 4Citation - Scopus: 4Differential in Vitro Anti-Leukemic Activity of Resveratrol Combined With Serine Palmitoyltransferase Inhibitor Myriocin in FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication (FLT3-LTD) Carrying AML Cells(Springer, 2022-02-14) Ersoz, Nur Sebnem; Adan, AysunTreatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) AML is restricted due to toxicity, drug resistance and relapse eventhough targeted therapies are clinically available. Resveratrol with its multi-targeted nature is a promising chemopreventive remaining limitedly studied in FLT3-ITD AML regarding to ceramide metabolism. Here, its cytotoxic, cytostatic and apoptotic effects are investigated in combination with serine palmitoyltransferase (SPT), the first enzyme of de novo pathway of ceramide production, inhibitor myriocin on MOLM-13 and MV4-11 cells. We assessed dose-dependent cell viability, flow cytometric cell death and cell cycle profiles of resveratrol in combination with myriocin by MTT assay, annexin-V/PI staining and PI staining respectively. Resveratrol's dose-dependent effect on SPT protein expression was also checked by western blot. Resveratrol decreased cell viability in a dose- dependent manner whereas myriocin did not affect cell proliferation effectively in both cell lines after 48h treatments. Although resveratrol induced both apoptosis and a significant S phase arrest in MV4-11 cells, it triggered apoptosis and non-significant S phase accumulation in MOLM-13 cells. Co-administrations reduced cell viability. Increased cytotoxic effect of co-treatments was further proved mechanistically through induction of apoptosis via phosphatidylserine relocalization. The cell cycle alteration in co-treatment was significant with an S phase arrest in MV4-11 cells, however, it was not effective on cell cycle progression of MOLM-13 cells. Resveratrol also increased SPT expression. Overall, modulation of SPT together with resveratrol might be the possible explanation for resveratrol's action. It could be an integrative medicine for FLT3-ITD AML after investigating its detailed mechanism of action in relation to de novo pathway of ceramide production.