WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7150
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Article Citation - WoS: 37Mechanisms of Cellular Resistance To Imatinib in Human Chronic Myeloid Leukemia Cells(Taylor and Francis Ltd., 2007) Baran, Yusuf; Baran, Yusuf; Ural, Ali Uğur; Gündüz, Ufuk; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyA major advancement in the treatment of chronic myeloid leukemia (CML) has been the development of imatinib, which has shown striking activity in the chronic phase and the accelerated phase, but less so in the blast phase of the disease. Despite high rates of hematologic and cytogenetic responses to therapy, the emergence of resistance to imatinib has been recognized as a major problem in the treatment of patients with CML. Various cellular mechanisms may be involved in the nature of cellular resistance. Increased amount of target, alteration in structure of target proteins, decreased drug uptake and increased detoxification are well-known mechanisms of resistance. On the other hand, in some cases, even if anticancer drugs reach their sites of action, bypassing drug efflux system of the cells, some cells still may survive via the dysregulation of apoptotic signalling. In this study, mechanisms of resistance to imatinib-induced apoptosis in human Meg-01 CML cells were examined. Continuous exposure of cells to step-wise increasing concentrations of imatinib resulted in the selection of 200- and 1000 nM imatinib-resistant sub-lines referred to as Meg-01/IMA-0,2 and Meg-01/1MA-1, respectively. MTT cell proliferation, cell cycle analyses and trypan blue dye exclusion analyses showed that Meg-0l/IMA-1 cells were resistant to imatinib-induced apoptosis as compared to parental sensitive cells. There was an increased expression of BCR/ABL, Bcl-2 and an increase in mitochondrial membrane potential (MMP) detected in resistant cells comparing to parental sensitive cells. There was no mutation detected in imatinib binding site of ABL kinase region. Various diverse mechanisms have been reported for their involvement in the multidrug resistance. In this study, it has been shown that the degree of BCR/ABL expression appears to be directly proportional to the levels of imatinib resistance. In addition, there have been BCR/ABL-independent mechanisms reported for deriving resistance against imatinib. Our results revealed that besides BCR/ABL overexpression, imatinib resistance also depends on the inhibition of apoptosis as a result of up-regulation of anti-apoptotic stimuli and down-regulation of pro-apoptotic stimuli through MMP but does not depend on any mutation on imatinib binding site of ABL kinase.Article Citation - WoS: 16Citation - Scopus: 16Multidrug Resistance Mediated by Mrp1 Gene Overexpression in Breast Cancer Patients(Taylor and Francis Ltd., 2009) Abaan, Ogan Demir; Baran, Yusuf; Baran, Yusuf; Atalay, Can; Gündüz, Ufuk; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyMultidrug resistance (MDR) is a serious handicap towards the effective treatment of breast cancer patients. One of the most prevalent MDR mechanisms is through the overexpression of genes coding the proteins called Multidrug Resistance-associated Proteins (MRPs). The aim of this study was to investigate the expression of MRP1 in tumor tissues from breast cancer patients. In this study, a semi-quantitative RT-PCR approach was utilized. Our results suggest that MRP1 overexpression can mediate MDR in patients. Pre-evaluation of the level of such MDR mediators before chemotherapy can increase the efficacy of the treatment.Article Citation - WoS: 7Citation - Scopus: 7Nilotinib Significantly Induces Apoptosis in Imatinib Resistant K562 Cells With Wild-Type Bcr-Abl, as Effectively as in Parental Sensitive Counterparts(Taylor and Francis Ltd., 2010) Ekiz, Hüseyin Atakan; Can, Geylani; Baran, Yusuf; Baran, Yusuf; Ekiz, Hüseyin Atakan; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyChronic myeloid leukemia (CML) is a hematological malignancy characterized by high levels of immature white blood cells. CML is caused by the translocation between chromosomes 9 and 22 (which results in the formation of the Philadelphia chromosome) creating BCR-ABL fusion protein. Imatinib and nilotinib are chemotherapeutic drugs which specifically bind to the BCR-ABL and inhibit cancer cells. Nilotinib is more effective in this respect than imatinib. We have shown that nilotinib induces apoptosis in imatinib-resistant K562 CML cells which have the wild-type BCR-ABL fusion gene almost to the same extent as it does in the parental sensitive cells by the increase in caspase-3 enzyme activity and the decrease in mitochondrial membrane potential. This effect of nilotinib, even in low concentrations, may indicate the efficacy of the usage of nilotinib in imatinib-resistant CML with less risk of undesired cytotoxic effects in the remaining cells of the body. © 2010 W. S. Maney & Son Ltd.Article Citation - WoS: 33Citation - Scopus: 35Upregulation of Multi Drug Resistance Genes in Doxorubicin Resistant Human Acute Myelogeneous Leukemia Cells and Reversal of the Resistance(Taylor and Francis Ltd., 2007) Baran, Yusuf; Baran, Yusuf; Gür, Bala; Kaya, Pelin; Ural, Ali Uğur; Avcu, Ferit; Gündüz, Ufuk; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyThe major problem in the treatment of acute myeloid leukemia (AML) patients results from multidrug resistance to administered anticancer agents. Drug resistance proteins, MDR1 and MRP1, which work as drug efflux pumps, can mediate the multidrug resistance of human leukemia cells. In this study, the mechanisms of resistance to doxorubicin-induced cell death in human HL60 AML cells were examined. Continuous exposure of cells to step-wise increasing concentrations of doxorubicin resulted in the selection of HL60/DOX cells, which expressed about 10.7-fold resistance as compared to parental sensitive cells. The expression analyses of MRP1 and MDR1 drug efflux proteins in doxorubicin-sensitive and -resistant HL60 cells revealed that there was an upregulation of MRP1 gene in HL60/DOX cells as compared to parental sensitive cells. On the other hand, while there was no expression of MDR1 gene in parental cells, the expression of MDR1 gene was upregulated in HL60/DOX cells. HL60/DOX cells also showed cross-resistance to cytosine arabinoside (Ara-c). This resistance was reversed by a combination therapy of Ara-c and cyclosporine A. However, the expression levels of CD15 and CD16 surface markers were significantly decreased in HL60/DOX cells.