Scopus İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/395
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Article Citation - WoS: 43Citation - Scopus: 49The Pleiotropic Effects of Fisetin and Hesperetin on Human Acute Promyelocytic Leukemia Cells Are Mediated Through Apoptosis, Cell Cycle Arrest, and Alterations in Signaling Networks(Sage Publications Ltd, 2015-06-17) Adan, Aysun; Baran, YusufFisetin and hesperetin, flavonoids from various plants, have several pharmaceutical activities including antioxidative, anti-inflammatory, and anticancer effects. However, studies elucidating the role and the mechanism(s) of action of fisetin and hesperetin in acute promyelocytic leukemia are absent. In this study, we investigated the mechanism of the antiproliferative and apoptotic actions exerted by fisetin and hesperetin on human HL60 acute promyelocytic leukemia cells. The viability of HL60 cells was evaluated using the MTT assay, apoptosis by annexin V/propidium iodide (PI) staining and cell cycle distribution using flow cytometry, and changes in caspase-3 enzyme activity and mitochondrial transmembrane potential. Moreover, we performed whole-genome microarray gene expression analysis to reveal genes affected by fisetin and hesperetin that can be important for developing of future targeted therapy. Based on data obtained from microarray analysis, we also described biological networks modulated after fisetin and hesperetin treatment by KEGG and IPA analysis. Fisetin and hesperetin treatment showed a concentration- and time-dependent inhibition of proliferation and induced G2/M arrest for both agents and G0/G1 arrest for hesperetin at only the highest concentrations. There was a disruption of mitochondrial membrane potential together with increased caspase-3 activity. Furthermore, fisetin- and hesperetin-triggered apoptosis was confirmed by annexin V/PI analysis. The microarray gene profiling analysis revealed some important biological pathways including mitogen-activated protein kinases (MAPK) and inhibitor of DNA binding (ID) signaling pathways altered by fisetin and hesperetin treatment as well as gave a list of genes modulated a parts per thousand yen2-fold involved in cell proliferation, cell division, and apoptosis. Altogether, data suggested that fisetin and hesperetin have anticancer properties and deserve further investigation.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 - WoS: 653Citation - Scopus: 739Flow Cytometry: Basic Principles and Applications(Taylor & Francis Ltd, 2016-01-14) Adan, Aysun; Alizada, Gunel; Kiraz, Yagmur; Baran, Yusuf; Nalbant, AytenFlow cytometry is a sophisticated instrument measuring multiple physical characteristics of a single cell such as size and granularity simultaneously as the cell flows in suspension through a measuring device. Its working depends on the light scattering features of the cells under investigation, which may be derived from dyes or monoclonal antibodies targeting either extracellular molecules located on the surface or intracellular molecules inside the cell. This approach makes flow cytometry a powerful tool for detailed analysis of complex populations in a short period of time. This review covers the general principles and selected applications of flow cytometry such as immunophenotyping of peripheral blood cells, analysis of apoptosis and detection of cytokines. Additionally, this report provides a basic understanding of flow cytometry technology essential for all users as well as the methods used to analyze and interpret the data. Moreover, recent progresses in flow cytometry have been discussed in order to give an opinion about the future importance of this technology.Article Citation - WoS: 40Citation - Scopus: 49Fisetin and Hesperetin Induced Apoptosis and Cell Cycle Arrest in Chronic Myeloid Leukemia Cells Accompanied by Modulation of Cellular Signaling(Sage Publications Ltd, 2015-09-25) Adan, Aysun; Baran, YusufFisetin and hesperetin, naturally occurring flavonoids, have been reported as novel antioxidants with chemopreventive/chemotherapeutic potential against various types of cancer. However, their mechanism of action in CML is still unknown. This particular study aims to evaluate the therapeutic potentials of fisetin and hesperetin and their effects on cell proliferation, apoptosis, and cell cycle progression in human K562 CML cells. The results indicated that fisetin and hesperetin inhibited cell proliferation and triggered programmed cell death in these cells. The latter was confirmed by mitochondrial membrane depolarization and an increase in caspase-3 activation. In addition to that, we have detected S and G2/Mcell cycle arrests and G0/G1 arrest upon fisetin and hesperetin treatment, respectively. To identify the altered genes and genetic networks in response to fisetin and hesperetin, whole-genome microarray analysis was performed. The microarray gene profiling analysis revealed some important signaling pathways including JAK/STAT pathway, KIT receptor signaling, and growth hormone receptor signaling that were altered upon fisetin and hesperetin treatment. Moreover, microarray data suggested potential candidate genes for targeted CML therapy. Fisetin and hesperetin significantly modulated the expression of genes involved in cell proliferation and division, apoptosis, cell cycle regulation, and other significant cellular processes such as replication, transcription, and translation. In conclusion, our results suggest that fisetin and hesperetin as potential natural agents for CML therapy.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.Article Citation - Scopus: 3Combined Effect of Midostaurin and Sphingosine Kinase-1 İnhibitor on FMS-Like Tyrosine Kinase 3 (FLT3) Wild Type Acute Myeloid Leukemia Cells(De Gruyter Open Ltd, 2022) Şahin, Hande Nur; Adan, AysunObjectives: 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. © 2022 Elsevier B.V., All rights reserved.