Browsing by Author "ADAN, Aysun"

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    Article
    Cytotoxic Effects of Resveratrol and Its Combinations with Ceramide Metabolism Inhibitors on FLT3 Positive Acute Myeloid Leukemia
    (DergiPark, 2020) ERSÖZ, Nur Şebnem; ADAN, Aysun; https://orcid.org/0000-0002-3747-8580; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; ADAN, Aysun
    Sphingolipids determine the cell fate by regulating cell proliferation and growth. Ceramide, growth inhibitory lipid, might be produced through de novo pathway or salvage pathway, which is converted to proliferation inducers sphingosine-1-phosphate (S1P) and glucosyl ceramide (GC) by sphingosine kinase (SK) and glucosyl ceramide synthase (GCS), respectively. It is aimed to investigate therapeutic potential of resveratrol on FLT3 overexpressing acute myeloid leukemia (AML) cells by pharmacological targeting of ceramide metabolism. The cytotoxic effects of resveratrol, SK inhibitor (SKI II), GCS inhibitor (PDMP) and the combinations of resveratrol with SK-1 inhibitor and GCS inhibitor on THP-1 and OCI-AML3 FLT3 overexpressing AML cells were investigated by MTT cell viability assay in a time- and concentration-dependent manner. Apoptotic effect of resveratrol was analyzed by annexin V/PI double staining using flow cytometry. Resveratrol decreased cell viability and induced apoptosis in both cell lines (p<0.05 considered significant). There were synergistic cytotoxic effects of resveratrol with co-administration of SK-1 inhibitor and GCS inhibitor at 48 h (p<0.05 considered significant). This preliminary data showed for the first time that resveratrol might inhibit the viability of FLT3 overexpressing AML cells through targeting ceramide metabolism and inducing apoptosis, which needs to be further clarified mechanistically.
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    Article
    Glucosylceramide Synthase Is a Novel Biomarker of Midostaurin-Induced Cytotoxicity in Non-Mutant FLT3 Positive Acute Myeloid Leukemia Cells
    (2021) ŞAHİN Hande Nur; ADAN Aysun; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; ŞAHİN, Hande Nur; ADAN, Aysun
    Objective: 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 inhibi- tion 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 popula- tion 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.