GCRIS

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Determination of Therapeutic Potential of Apigenin on Acute Lymphoblastic Leukemia Cells
(Izmir Institute of Technology, 2019) Uzuner, Erez; Baran, Yusuf
Acute lymphoblastic leukemia (ALL) is a hematological disorder initiating from blood-forming cells of bone marrow. ALL is characterized by the Philadelphia chromosome (Ph) arisen from a translocation between chromosome 9 and 22. This chromosome encodes BCR-ABL oncogene that is a driver regulator. BCR-ABL based studies improved tyrosine kinase inhibitors (TKI) including imatinib, dasatinib, nilotinib, and ponatinib to eliminate this disease. However, the studies on Ph+ ALL patients showed that bioactive sphingolipids have crucial roles in the elimination of the positive effects of these drugs by activating the proliferation-associated pathways, inhibition of apoptosis and increasing drug resistance of the cells treated with these drugs. In this study, therapeutic potential of apigenin, which is a natural flavonoid obtained from celery, parsley and chamomile was investigated on Ph+ ALL cell line, SD-1, and non-cancerous lung cell line Beas-2B. The cytotoxic effects of apigenin on SD-1 and Beas-2B cells were determined by MTT cell proliferation assay. The cell viability analyses on SD-1 cells were conducted by Trypan blue dye exclusion assay following apigenin treatment. Cell cycle and apoptosis analyses including Annexin V/PI-dual staining and JC-1 dye-based mitochondrial membrane potential were examined by flow cytometry. Expression levels of bioactive sphingolipids were determined by RT-PCR and western blot. The cytotoxic analyses indicated that apigenin selectively inhibits the expression of SD-1 cells whereas the IC50 value of apigenin for SD-1 cells has the anti-apoptotic roles in Beas-2B cells. SD-1 cells experience cell death via apoptosis-related pathways and apigenin might arrest the cells at G2/M phases. Indeed, the changes in the expression levels of bioactive sphingolipids genes indicated their roles in apigenin-induced apoptosis in SD-1 cells. This study investigated the cytotoxic and apoptotic effects of apigenin on SD-1 cells and the roles of apigenin in bioactive sphingolipid metabolism for the first time.
Deciphering 5-Fluorouracil Mediated Molecular Mechanisms Required for Cell Death
(Izmir Institute of Technology, 2011) Can, Geylani; Baran, Yusuf
The chemotherapy agent 5-Fluorouracil (5-FU) is an antimetabolite that has been in use to treat several cancers for decades. In cells, it is converted into three distinct fluoro-based nucleotide analogues which interfere with DNA-synthesis and repair leading to impairment of the genome and, eventually apoptotic cell death. Current knowledge also state that 5-FU induced damage is signaling through a p53-dependent induction of death inducing complex (DISC) formation and further caspase-8 activation in certain cell types and members of the TNF-receptor family has been proposes to be required for the process. Here, we introduce calcium (Ca2+) as a messenger for p53 activation in the cellular response triggered by 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of cultured colon carcinoma cells stimulates entry of extracellular Ca2+ through L-type plasma membrane channels and that this event direct posttranslational phosphorylation of at least two specific p53 serine residues (ser15 and ser33) by means of Calmodulin (CaM) activity. Obstructing this pathway by the Ca2+-chelator BAPTA or by two different inhibitors of CaM efficiently blocks 5-FU-induced cell death. The fact that a widely used therapeutic drug, such as 5-FU, is signaling by these means could provide new therapeutic intervention points, or specify new combinatorial treatment regimes.
The Roles of Ceramide Metabolizing Gennes on Resveratrol Induced Apoptosis in Human Hl60 Acute Myeloid Leukemia Cells
(Izmir Institute of Technology, 2010) Çakır, Zeynep; Baran, Yusuf
Resveratrol (3,5,4' -trihydroxy-trans-stilbene) is naturally occurring phytoalexin, which presents especially in grapes. It is a potential anticancer agent which inhibits tumor initiation, promotion, and progression. Ceramides are the central compounds of sphingolipids metabolism. They are known as second messengers regulating various cellular processes including cell growth, proliferation, differentiation and apoptosis. While ceramide acts as a strong apoptotic molecule, glucosylceramide (GluCer) and sphingosine-1-phosphate (S1P) trigger cell growth and proliferation and inhibit apoptosis. Sphingosine kinase-1 (SK-1) is an enzyme catalyzing the phosphorylation of sphingosine to sphingosine-1-phosphate while glucosylceramide synthase (GCS) converts ceramide to glucosylceramide. Thus, inhibition of GCS by N-(2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl)-decanamide, hydrochloride (PDMP) or SK-1 by sphingosine kinase-1 inhibitor, or exogenous application of ceramide analog (C8:ceramide) results in increased accumulation of ceramides. The aim of the study is to examine the roles of ceramide, glucosylceramide and sphingosine-1-phosphate in resveratrol induced apoptosis in HL60 cells. In this study, it was demonstrated cytotoxic effects of resveratrol on human acute myeloid leukemia cells in addition to identify a novel mechanism of resveratrol-induced apoptosis by targeting ceramide metabolism. And also it was shown that via targeting ceramide-generating and/or ceramide-clearance genes provided ceramide generation and/or accumulation in response to resveratrol treatment. This study showed for the first time that there were significant induction of apoptosis through increasing intracellular concentrations of ceramides in resveratrol treated HL60 cell. Taking together all these results showed that ceramides may be involved in resveratrol-induced apoptosis.

Master Degree / Yüksek Lisans Tezleri

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