Browsing by Author "Gunduz, Ufuk"

Now showing 1 - 7 of 7

Citation Count: 19
Apoptotic Effects of Resveratrol, a Grape Polyphenol, on Imatinib-Sensitive and Resistant K562 Chronic Myeloid Leukemia Cells
(int inst Anticancer Research, 2012) Can, Geylani; Cakir, Zeynep; Kartal, Melts; Gunduz, Ufuk; Baran, Yusuf; Baran, Yusuf
Aim: To examine the antiproliferative and apoptotic effects of resveratrol on imatinib-sensitive and imatinib-resistant K562 chronic myeloid leukemia cells. Materials and Methods: Antiproliferative effects of resveratrol were determined by the 3-Bis[2-methoxy-4-nitro-5-sulphophenyl]-2H-tetrazolium-5-carboxanilide inner salt (XTT) cell proliferation assay. Apoptotic effects of resveratrol on sensitive K562 and resistant K562/IMA-3 cells were determined through changes in caspase-3 activity, loss of mitochondrial membrane potential (MMP), and apoptosis by annexin V-(FITC). Results: The concentrations of resveratrol that inhibited cell growth by 50% (IC50) were calculated as 85 and 122 mu M for K562 and K562/IMA-3 cells, respectively. There were 1.91-, 7.42- and 14.73-fold increases in loss of MMP in K562 cells treated with 10, 50, and 100 mu M resveratrol, respectively. The same concentrations of resveratrol resulted in 2.21-, 3.30- and 7.65-fold increases in loss of MMP in K562/IMA3 cells. Caspase-3 activity increased 1.04-, 2.77- and 4.8-fold in K562 and 1.02-, 1.41- and 3.46-fold in K562/IMA3 cells in response to the same concentrations of resveratrol, respectively. Apoptosis was induced in 58.7%- and 43.3% of K562 and K562/IMA-3 cells, respectively, in response to 100 mu M resveratrol. Conclusion: Taken together these results may suggest potential use of resveratrol in CML, as well as in patients with primary and/or acquired resistance to imatinib.
Citation Count: 6
Effect of cobalt-60 (γ radiation) on multidrug-resistant multiple myeloma cell lines
(Portland Press Ltd, 2011) Mutlu, Pelin; Baran, Yusuf; Ural, A. Ugur; Avcu, Ferit; Dirican, Bahar; Beyzadeoglu, Murat; Gunduz, Ufuk; Baran, Yusuf
Emergence of resistance to chemotherapy and radiotherapy is a major obstacle for the successful treatment of MM (multiple myeloma). Prednisone, vincristine and melphalan are commonly used chemotherapeutic agents for the treatment of MM. In the current study, we examined the presence of possible cross-resistance between these drugs and gamma (gamma) radiation. Prednisone, vincristine and melphalan resistant RPMI-8226 and U-266 MM cells were generated by stepwise increasing concentrations of the drugs. The sensitive and resistant cells were exposed to 200- and 800 cGy gamma radiation, and proliferation was examined by XTT {2,3-bis(2-methoxy-4-nitro-5-sulfopheny1)-5-Rphenylamino)carbonyl]-2H-tetrazolium hydroxide) assay. The results showed that Prednisone- and melphalan-resistant RPMI-8226 cells were also cross-resistant to 200 and 800 cGy gamma radiation application, while vincristine-resistant cells did not show resistance. On the other hand, Prednisone-, vincristine- and melphalan-resistant U-266 cells showed cross-resistance to 200- and 800 cGy gamma radiation application. These results demonstrated that MM cells resistant to anticancer agents respond to radiation in different levels. These findings may be important in the clinical applications of radiation therapy in the treatment of vincristine resistant MM.
Citation Count: 38
Mechanisms of cellular resistance to imatinib in human chronic myeloid leukemia cells
(Taylor & Francis Ltd, 2007) Baran, Yusuf; Ural, Ali Ugur; Gunduz, Ufuk; Baran, Yusuf
A 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.
Citation Count: 25
Multidrug Resistance Mediated by MRP1 Gene Overexpression in Breast Cancer Patients
(Taylor & Francis inc, 2009) Abaan, Ogan Demir; Mutlu, Pelin Kaya; Baran, Yusuf; Atalay, Can; Gunduz, Ufuk; Baran, Yusuf
Multidrug 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.
Citation Count: 7
Nilotinib significantly induces apoptosis in imatinib resistant K562 cells with wild-type BCR-ABL, as effectively as in parental sensitive counterparts
(Taylor & Francis Ltd, 2010) Ekiz, Huseyin Atakan; Can, Geylani; Gunduz, Ufuk; Baran, Yusuf; Baran, Yusuf
Chronic 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.
Citation Count: 46
Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation
(Springer, 2011) Baran, Yusuf; Bielawski, Jacek; Gunduz, Ufuk; Ogretmen, Besim; Baran, Yusuf
Purpose Drug resistance presents a major obstacle for the treatment of some patients with chronic myeloid leukemia (CML). Pro-apoptotic ceramide mediates imatinib-induced apoptosis, and metabolism of ceramide by glucosylceramide synthase (GCS) activity, converting ceramide to glucosyl ceramide, might contribute to imatinib resistance. In this study, we investigated the role of ceramide metabolism by GCS in the regulation of imatinib-induced apoptosis in drug-sensitive and drug-resistant K562 and K562/IMA-0.2 and K562/IMA-1 human CML cells, which exhibit about 2.3- and 19-fold imatinib resistance, respectively. Methods Cytotoxic effects of PDMP and imatinib were determined by XTT cell proliferation assay. Expression levels of GCS were determined by RT-PCR and western blot. Intracellular ceramide levels were determined by LC-MS. Cell viability analyses was conducted by Trypan blue dye exclusion assay. Cell cycle and apoptosis analyses were examined by flow cytometry. Results We first showed that mRNA and protein levels of GCS are increased in drug-resistant K562/IMA as compared to sensitive K562 cells. Next, forced expression of GCS in sensitive K562 cells conferred resistance to imatinib-induced apoptosis. In reciprocal experiments, targeting GCS using its known inhibitor, PDMP, enhanced ceramide accumulation and increased cell death in response to imatinib in K562/IMA cells. Conclusion Our data suggest the involvement of GCS in resistance to imatinib-induced apoptosis, and that targeting GCS by PDMP increased imatinib-induced cell death in drug-sensitive and drug-resistant K562 cells via enhancing ceramide accumulation.
Citation Count: 12
An update on molecular biology and drug resistance mechanisms of multiple myeloma
(Elsevier Science inc, 2015) Mutlu, Pelin; Kiraz, Yagmur; Gunduz, Ufuk; Baran, Yusuf; Baran, Yusuf
Multiple myeloma (MM), a neoplasm of plasma cells, is the second most common hematological malignancy. Incidance rates increase after age 40. MM is most commonly seen in men and African-American population. There are several factors to this, such as obesity, environmental factors, family history, genetic factors and monoclonal gammopathies of undetermined significance (MGUS) that have been implicated as potentially etiologic. Development of MM involves a series of complex molecular events, including chromosomal abnormalities, oncogene activation and growth factor dysregulation. Chemotherapy is the most commonly used treatment strategy in MM. However, MM is a difficult disease to treat because of its marked resistance to chemotherapy. MM has been shown to be commonly multidrug resistance (MDR)-negative at diagnosis and associated with a high incidence of MDR expression at relapse. This review deals with the molecular aspects of MM, drug resistance mechanisms during treatment and also possible new applications for overcoming drug resistance. (C) 2015 Elsevier Ireland Ltd. All rights reserved.