Scopus İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/395
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Article Citation - WoS: 18Citation - Scopus: 20Resveratrol Triggers Anti-Proliferative and Apoptotic Effects in FLT3-LTD Acute Myeloid Leukemia Cells via Inhibiting Ceramide Catabolism Enzymes(Humana Press inc, 2022-01-20) Ersoz, Nur Sebnem; Adan, AysunResveratrol possesses well-defined anti-carcinogenic activities. However, how resveratrol exerts its anti-leukemic actions by modulating anti-apoptotic ceramide catabolism enzymes, mainly sphingosine kinase (SK-1) and glucosylceramide synthase (GCS), in FLT3-ITD AML remains unclear. Resveratrol, SKI II (SK inhibitor) and PDMP (GCS inhibitor) were evaluated alone or in combinations for their effect on cell proliferation (MTT assay), apoptosis (annexin V-FITC/PI staining by flow cytometry) and cell cycle progression (PI staining by flow cytometry) in MOLM-13 and MV4-11 cells. The combination indexes (CIs) were calculated based on cell proliferation data using CompuSyn software. Caspase-3 and PARP activation, changes in SK-1 and GCS levels by resveratrol alone or PARP cleavage in co-treatments were determined by western blot. Resveratrol and inhibitors alone inhibited cell proliferation in a dose- and time-dependent manner. Resveratrol downregulated SK-1 and GCS expression in both cell lines. It induced apoptosis by phosphatidylserine (PS) exposure together with caspase-3 and PARP cleavage and arrested the cell cycle slightly at the S phase. Co-administrations intensified resveratrol's effect by inhibiting cell proliferation synergistically (A CI of < 1) or additively (A CI 1.0-1.1) and inducing apoptosis via PS relocalization and PARP cleavage. Resveratrol plus SKI II did not affect cell cycle progression significantly, however, resveratrol plus PDMP blocked cycle progression at G0/G1 and S phases for MOLM-13 cells and MV4-11 cells, respectively. Overall, resveratrol may inhibit FLT3-ITD AML cell proliferation by inhibiting ceramide catabolism and be evaluated as a chemopreventive after detailed analysis of the crosstalk between resveratrol and ceramide catabolism pathway.Article Citation - Scopus: 1Glucosylceramide Synthase is a Novel Biomarker of Midostaurin-Induced Cytotoxicity in Non-Mutant FLT3 Positive Acute Myeloid Leukemia Cells(Istanbul University Press, 2021-12-03) Şahin, Hande Nur; Adan, AysunObjective: Glucosylceramide (GC) synthesized by glucosylce-ramide synthase (GCS) favors cell survival and proliferation in many cancers. However, it’s role in Fms-like tyrosine kinase 3 (FLT3) non-mutant Acute Myeloid Leukemia (AML) pathogenesis is not clarified. Midostaurin, a multi-kinase inhibitor, clinically benefits FLT3-mutated AML, however, its clinical efficacy is under-estimat-ed in FLT3 non-mutant AML. This study aimed to investigate the efficacy of combination of midostaurin with GCS inhibitor in FLT3 AML cell carrying wild-type FLT3 and the underlying molecular mechanisms. Material and Method: Cytotoxic and cytostatic effects of mido-staurin, PDMP (GCS inhibitor) alone and in combination on THP1 cells were determined by MTT assay and flow cytometric propidi-um iodide (PI) staining, respectively. Calcusyn software was used to calculate combination indexes (CIs). GCS expression was checked by western blot. Results: Midostaurin downregulated GCS. Simultaneous inhibition of FLT3 and GCS resulted in suppression of cell proliferation as compared to untreated control. Combinations showed synergistic cytotoxic effects (CI<1). Co-treatments increased cell cycle population at G2/M phase. Conclusion: Inhibition of GCS enhances the efficacy of midostau-rin in FLT3 non-mutant AML, which could be a novel therapeutic approach to increase midostaurin’s limited usage in the clinic after detailed mechanistic studies. © 2023 Elsevier B.V., All rights reserved.