Phd Degree / Doktora

Permanent URI for this collectionhttps://hdl.handle.net/11147/2869

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2015 - 20193

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Author: search.filters.author.Baran, YusufCOAR Access Rights: search.filters.coarAccessRights.open access

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Now showing 1 - 3 of 3
  • Doctoral Thesis
    Sensitization of Philadelphia Positive Acute Lymphoblastic Leukemia Cells Resistant To Imatinib by Targeting Sphingolipid Metabolism
    (Izmir Institute of Technology, 2019) Kiraz, Yağmur; Baran, Yusuf
    Philadelphia positive acute lymphoblastic leukemia (Ph+ALL) is a common subtype of ALL and characterized by having BCR/ABL translocation. Tyrosine kinase inhibitors (TKI) such as imatinib are used for the treatment in Ph+ALL, however, 60-75% of the patients can develop resistance against the TKIs. Bioactive sphingolipids are a group of lipids that play roles in various cellular mechanisms. Previous studies showed that sphingolipids and genes in the pathway were involved in response to TKI treatment in Ph+ALL. Here, we investigated the roles of SPL on the growth inhibitory effects of imatinib and exploit sphingolipid metabolism by majorly inhibiting glucosylceramide synthase (GCS) to accumulate ceramide or sphingosine to further sensitize cells to imatinib and/or overcome resistance to imatinib in Ph+ALL. Firstly, we detected that, sphingosine kinase-1 (SK-1) a well-studied SPL enzyme inhibition did not contribute to cytotoxic effects of imatinib in SD-1 Ph+ALL cells. Moreover, we determined that imatinib is inducing de novo synthesis pathway of SPL and increasing the levels of ceramide, sphingosine, hexosylceramides and sphingomyelin in SD-1 cells. Interestingly, newly generated imatinib-resistant cell line SD-1R was detected to have an aberration in this pathway resulting in development of resistance. Combination treatment with eliglustat (GCS inhibitor) resulted in a significant increase in ceramide and sphingosine levels and reflected on cell growth and sensitized cells to imatinib. Taken together, it was shown for the first time in the literature that the cytotoxic effects of imatinib was due to induction of de novo synthesis pathway of sphingolipids and inhibition of GCS together with imatinib has synergistic cytotoxic effects on imatinib resistant Ph+ALL cells. As a conclusion, increasing the intracellular levels of ceramide (and/or sphingosine) can be a novel approach to sensitize drug resistant Ph+ALL cells.
  • Doctoral Thesis
    Expression Levels of Bioactive Sphingolipid Genes in Newly Diagnosed and Drug-Resistant Chronic Myeloid Leukemia Patients and Their Impact on the Clinical Progress
    (Izmir Institute of Technology, 2015) Kartal Yandım, Melis; Baran, Yusuf
    Bioactive sphingolipids are a family of lipids including ceramide, glucosylceramide (GC), sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) that have important functions in cellular processes including proliferation, metastasis, invasion, inflammatory response and apoptosis. Many sphingolipidregulated functions are directly related to cancer initiation, progression, and response or resistance to anti-cancer treatments. Ceramide, the central molecule of the sphingolipid metabolism, functions as a tumor-suppressor inhibiting cell division, and inducing cell differentiation, senescence and apoptosis. De novo synthesis of ceramides is regulated by ceramide synthase gene family (CERS1-6). Although ceramide is known to be a pro-apoptotic molecule, GC and S1P which are converted from ceramides by glucosylceramide synthase (GCS) and sphingosine kinase-1 (SK-1), respectively, are anti-apoptotic. Chronic myeloid leukemia is a hematological disorder arisen from the reciprocal translocation between BCR gene on chromosome 22, and ABL gene on chromosome 9, t(9;22)(q34;q11), resulting in the formation of Philadelphia (Ph) chromosome. Ph chromosome encodes BCR/ABL fusion protein having constitutively active tyrosine kinase activity. In this study, we examined the expression levels of CERS1-6, GCS, SK1, and BCR/ABL genes of 66 patients that are newly diagnosed, tyrosine kinase inhibitor (TKI)-resistant, or -sensitive. Q-PCR results showed that there were higher expression levels of apoptotic CERS1-6 in the patients TKI-treated and have shown minimum hematological response than that of the patients newly diagnosed and TKI-resistant. However, expression levels of antiapoptotic GCS and SK-1 genes were significantly higher in TKI-resistant and blastic phase patients than that of the other patients. Additionally, BCR/ABL expression levels were higher in newly diagnosed and TKIresistant patients.
  • Doctoral Thesis
    Therapeutic Potentials of Fisetin, Hesperetin and Vitexin on Chronic Myeloid Leukemia and Acute Myeloid Leukemia Cells
    (Izmir Institute of Technology, 2015) Adan Gökbulut, Aysun; Baran, Yusuf
    Fisetin, hesperetin and vitexin are plant-derived flavonoids. This thesis study aims to investigate therapeutic potentials of them on human HL60 APL and K562 CML cells since there are no studies on these cells. The effects of these compounds on APL and CML cells have been considered in terms of cytotoxicity, apoptosis and cell cycle progression. In this study, genome-wide microarray analysis has been also performed for APL and CML cells to identify the genes and networks that are responsible for fisetin and hesperetin-induced effects. In summary, we intented to explain the molecular mechanisms and global gene expression patterns related with the effects of these flavonoids on both APL and CML for the first time. There were decreases in the viability/proliferation of K562 and HL60 cells treated with fisetin, hesperetin and vitexin. Fisetin was the most effective flavonoid for the induction of apoptosis in both cells. Fisetin, hesperetin and vitexin have been found to affect cell cycle progression at different phases of the cell cycle in both CML and AML cells, thus having cytostatic effects. In conclusion, the results of this study indicated that especially fisetin and hesperetin may have therapeutic potential in APL and CML cells due to induction of apoptosis, inhibition of cell proliferation and cell cyle arrest. Moreover, the genetic networks derived from this study illuminate some of the biological pathways affected by fisetin and hesperetin treatment while providing a proof of principle for identifying candidate genes that might be targeted for CML and APL therapy.