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Examination of Therapeutic Potential of Luteolin on Acute Lymphoblastic Leukemia Cells and Changes in Macromolecules
(01. Izmir Institute of Technology, 2023) Çetinkaya, Melisa; Baran, Yusuf
Acute lymphoblastic leukemia (ALL) is a genetic disease that arises from the various recurrent genetic alterations blocking the differentiation of the precursor B-and T-cells, resulting in the aberrant proliferation and survival of immature lymphoblasts within the peripheral blood and bone marrow. T-ALL is an aggressive type of ALL, and the current treatment strategies, including the high-intensity combination chemotherapy, result in different side effects which are difficult to accept or ultimately lead to the death of patients as substantial toxicity of those chemotherapeutics is known to healthy cells alongside with the cancer cells. Therefore, there is a need to identify nontoxic, costeffective, potent, and readily available treatment options for T-ALL patients. One alternative option is the flavonoids in cancer therapeutics, which are secondary metabolites of plants mainly responsible for plants' colors and flower aromas. Luteolin is an extensively researched member of the flavonoids with anticancer properties shown in various cancer types, except for the T-ALL. This study demonstrated Luteolin's time- and dose-dependent antiproliferative, cytostatic, and apoptotic effects on T-ALL cells for the first time in the literature. Also, the macromolecular changes caused in response to Luteolin treatment in T-ALL cells were examined for the first time. As a consequence, it was found that Luteolin had antiproliferative, apoptotic, and cytostatic effects on T-ALL cells, suggesting its therapeutic potential and was demonstrated to cause an increase in the lipid-to-protein ratio and the hydrocarbon chain length of the lipid acyl chains in a dose-dependent manner on T-ALL cells.
Determination of Therapeutic Potential of Luteolin for Acute Lymphoblastic Leukemia Cells
(Izmir Institute of Technology, 2019) Gürler, Sevim Beyza; Baran, Yusuf
Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by increased level of immature lymphoblasts in bone marrow and peripheral blood. The developments of lymphoblasts are genetically/epigenetically inhibited. One of the most common genetic abnormalities in ALL is BCR/ABL translocation which regulates the several pathways related to proliferation, anti-apoptotic and drug resistance through its aberrant tyrosine kinase activity. Although the current treatment strategies include targeting BCR/ABL via tyrosine kinase inhibitors; complete remission, overall survival and mortality of Ph+ ALL patients are still worse as compared to Ph- ALL patients. Therefore, new strategies combined with current treatments are needed for Ph+ ALL patients who are qualified as high risk group of ALL. Different studies showed thatluteolin has anti-cancer and anti-tumor effects on wide range cancer types including breast, colon, lung cancer except ALL in both in vitro and in vivo. In this study, the dose and time dependent cytotoxic, apoptotic and cytostatic effects of luteolin on Philadelphia chromosome +ALL cells were determined for the first time. Besides, the effect of luteolin on cell growth and proliferation of two different healthy cell lines was shown. Moreover, the effect of luteolin on bioactive sphingolipids genes which regulate the several pathways including cell proliferation, apoptosis, drug resistance and senescence in cell was determined in Ph positive ALL cells for the first time. As a consequence, luteolin has cytotoxic, apoptotic and cytostatic effects on Ph positive ALL cells and bioactive sphingolipids genes are regulated in this therapeutic potential by luteolin.
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.

Master Degree / Yüksek Lisans Tezleri

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