Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7148
Browse
8 results
Search Results
Now showing 1 - 8 of 8
Article Citation - WoS: 278Citation - Scopus: 295Molecular Mechanisms of Drug Resistance and Its Reversal in Cancer(Taylor and Francis Ltd., 2016) Kartal Yandım, Melis; Adan Gökbulut, Aysun; Baran, YusufChemotherapy is the main strategy for the treatment of cancer. However, the main problem limiting the success of chemotherapy is the development of multidrug resistance. The resistance can be intrinsic or acquired. The resistance phenotype is associated with the tumor cells that gain a cross-resistance to a large range of drugs that are structurally and functionally different. Multidrug resistance arises via many unrelated mechanisms, such as overexpression of energy-dependent efflux proteins, decrease in uptake of the agents, increase or alteration in drug targets, modification of cell cycle checkpoints, inactivation of the agents, compartmentalization of the agents, inhibition of apoptosis and aberrant bioactive sphingolipid metabolism. Exact elucidation of resistance mechanisms and molecular and biochemical approaches to overcome multidrug resistance have been a major goal in cancer research. This review comprises the mechanisms guiding multidrug resistance in cancer chemotherapy and also touches on approaches for reversing the resistance.Article Citation - WoS: 42Citation - Scopus: 46Novel Agents Targeting Bioactive Sphingolipids for the Treatment of Cancer(Bentham Science Publishers, 2013) Adan Gökbulut, Aysun; Kartal Yandım, Melis; İskender, Güniz; Baran, YusufSphingolipids are a class of lipids that have important functions in a variety of cellular processes such as, differentiation, proliferation, senescence, apoptosis and chemotherapeutic resistance. The most widely studied bioactive shingolipids include ceramides, dihydroceramide (dhCer), ceramide-1-phosphate (C1P), glucosyl-ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P). Although the length of fatty acid chain affects the physiological role, ceramides and sphingosine are known to induce apoptosis whereas C1P, S1P and GluCer induce proliferation of cells, which causes the development of chemoresistance. Previous studies have implicated the significance of bioactive shingolipids in oncogenesis, cancer progression and drug- and radiation-resistance. Therefore, targeting the elements of sphingolipid metabolism appears important for the development of novel therapeutics or to increase the effectiveness of the current treatment strategies. Some approaches involve the development of synthetic ceramide analogs, small molecule inhibitors of enzymes such as sphingosine kinase, acid ceramidase or ceramide synthase that catalyze ceramide catabolism or its conversion to various molecular species and S1P receptor antagonists. These approaches mainly aim to up-regulate the levels of apoptotic shingolipids while the proliferative ones are down-regulated, or to directly deliver cytotoxic sphingolipids like short-chain ceramide analogs to tumor cells. It is suggested that a combination therapy with conventional cytotoxic approaches while preventing the conversion of ceramide to S1P and consequently increasing the ceramide levels would be more beneficial. This review compiles the current knowledge about sphingolipids, and mainly focuses on novel agents modulating sphingolipid pathways that represent recent therapeutic strategies for the treatment of cancer. © 2013 Bentham Science Publishers.Article Citation - WoS: 16Citation - Scopus: 18Roles of Ceramide Synthase and Ceramide Clearence Genes in Nilotinib-Induced Cell Death in Chronic Myeloidleukemia Cells(Informa Healthcare, 2011) Camgöz, Aylin; Gençer, Emel Başak; Ural, Ali Uğur; Avcu, Ferit; Baran, YusufIn this study, we aimed to increase the sensitivity of human K562 and Meg-01 chronic myeloid leukemia (CML) cells to nilotinib by targeting bioactive sphingolipids, in addition to investigating the roles of ceramide metabolizing genes in nilotinib induced apoptosis. Cytotoxic effects of nilotinib, C8:ceramide, glucosyle ceramide synthase (GCS) and sphingosine kinase-1 (SK-1) inhibitors were determined by XTT cell proliferation assay and synergism between the agents was determined by isobologram analysis. Also, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) results demonstrated that expression levels of longevity assurance (LASS) genes in response to nilotinib were correlated with sensitivity to nilotinib. For the first time, The results of this study showed for the first time that nilotinib induces apoptosis through upregulating ceramide synthase genes and downregulating SK-1 in CML cells in addition to inhibition of BCR/ABL. On the other hand, manipulating bioactive sphingolipids toward generation/accumulation of ceramides increased the apoptotic effects of nilotinib in CML cells.Article Citation - WoS: 5Citation - Scopus: 7The Roles of Antiapoptotic Sphingosine Kinase-1 and Glucosylceramide Genes in Drug Induced Cell Death of Mcf-7 Breast Cancer Cells(Zerbinis Medical Publications, 2011) Güçlüler, Gözde; Pişkin, Özden; Baran, YusufPurpose: Sphingolipids are important signaling molecules mediating cell survival, proliferation, cell cycle regulation and apoptosis. Ceramide is the most vital sphingolipid which induces growth arrest, senescence, and apoptosis. In this study, we aimed to determine the roles of sphingosine kinase- 1 (SK-1) and glucosylceramide synthase (GCS) genes in paclitaxel, doxorubicin, tamoxifen, cyclophosphamide and docetaxel induced apoptosis in human MCF-7 breast cancer cells. Methods: IC50 values (drug concentration inhibiting cell growth by 50%) of the anticancer agents were calculated using XTT cell proliferation assay. Changes in mitochondrial membrane potential (MMP) were determined using JC-1 assay kit. Changes in the mRNA levels of SK-1 and GCS genes were measured by using RT-PCR technique. Results: The results demonstrated significant decrease in cellular proliferation and increase in loss of MMP in a dose-dependent manner. Paclitaxel, doxorubicin, tamoxifen, cyclophosphamide and docetaxel application downregulated SK-1 expression while paclitaxel, tamoxifen, cyclophosphamide and docetaxel but not doxorubicin downregulated GCS comparing to untreated control cells. Conclusion: These results show for the first time that these agents induce apoptosis in MCF-7 cells by downregulating the antiapoptotic SK-1 and GCS genes that may result in accumulation of apoptotic ceramides. © 2011 Zerbinis Medical Publications.Article Citation - WoS: 37Citation - Scopus: 40A Novel Mechanism of Dasatinib-Induced Apoptosis in Chronic Myeloid Leukemia; Ceramide Synthase and Ceramide Clearance Genes(Springer Verlag, 2011) Gencer, Emel Başak; Ural, Ali Uğur; Avcu, Ferit; Baran, YusufSphingolipids are bioeffector molecules that control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramides, the central molecule of sphingolipid metabolism, are inducer of apoptosis and inhibitors of proliferation. Sphingosine-1- phosphate (S1P) and glucosyleceramide, converted from ceramides by sphingosine kinase-1 (SK-1) and glucosyleceramide synthase (GCS) enzymes, respectively, inhibit apoptosis and develop resistance to chemotherapeutic drugs. In this study, we examined the therapeutic potentials of bioactive sphingolipids in chronic myeloid leukemia (CML) alone and in combination with dasatinib in addition to investigate the roles of ceramide-metabolizing genes in dasatinib-induced apoptosis. Cytotoxic effects of dasatinib, C8:ceramide, PDMP, and SK-1 inhibitor were determined by XTT cell proliferation assay. Changes in caspase-3 enzyme activity and mitochondrial membrane potential (MMP) were measured using caspase-3 colorimetric assay and JC-1 MMP detection kit. Expression levels of ceramide-metabolizing genes were examined by qRT-PCR. Application of ceramide analogs and inhibitors of ceramide clearance genes decreased cell proliferation and induced apoptosis. Targeting bioactive sphingolipids towards generation/accumulation of ceramides increased apoptotic effects of dasatinib, synergistically. It was shown for the first time that dasatinib induces apoptosis through downregulating expression levels of antiapoptotic SK-1 but not GCS, and upregulating expression levels of ceramide synthase (CerS) genes, especially CerS1, in K562 cells. On the other hand, dasatinib downregulates expression levels of both GCS and SK-1 and upregulate apoptotic CerS2, -5 and -6 genes in Meg-01 cells. Increasing endogenous ceramide levels and decreasing prosurvival lipids, S1P, and GC, can open the way of more effective treatment of CML.Article Citation - WoS: 8Citation - Scopus: 10Bioactive Sphingolipids in Docetaxel-Induced Apoptosis in Human Prostate Cancer Cells(Elsevier Ltd., 2012) Başsoy, Esen Yonca; Baran, YusufIn this study, we examined the possible roles of ceramide/sphingosine-1-phosphate and ceramide/glucosyleceramide signaling in docetaxel-induced apoptosis by examining expression levels of the glucosyleceramide synthase and sphingosine kinase-1 and ceramide synthase gene family. As confirmed by isobologram analysis, docetaxel in combination with agents that increase intracellular ceramide levels increased the cytotoxic and apoptotic effects of docetaxel synergistically. More importantly, RT-PCR results revealed that expression levels of glucosyleceramide synthase and sphingosine kinase-1 were downregulated and ceramide synthase genes were upregulated in response to docetaxel. This study identifies mechanisms underlying the involvement of ceramide metabolizing genes in docetaxel-induced apoptosis in prostate cancer cells. © 2012 Elsevier Masson SAS.Article Citation - WoS: 42Citation - Scopus: 48The Roles of Bioactive Sphingolipids in Resveratrol-Induced Apoptosis in Hl60 Acute Myeloid Leukemia Cells(Springer Verlag, 2011) Çakır, Zeynep; Saydam, Güray; Şahin, Fahri; Baran, YusufPurpose Acute promyelocytic leukemia results from a translocation between 15 and 17 chromosomes that produce PML/RARa fusion protein. PML/RARa inhibits differentiation of myeloid precursor cells at stem cell level. Resveratrol is a phytoalexin that exerts cytotoxic effects on cancer cells. Ceramides have crucial roles in cell growth, proliferation, differentiation, drug resistance, and apoptosis. In this study, we examined the possible cytotoxic effects of resveratrol on acute myeloid leukemia cells and determined the roles of ceramide-metabolizing genes in resveratrol-induced apoptosis, in addition to investigating the possibility of increasing the sensitivity of HL60 cells to resveratrol by manipulating sphingolipids. Methods Cytotoxic effects of resveratrol, C8:ceramide, PDMP, and SK-1 inhibitor were determined by XTT cell proliferation assay. Changes in caspase-3 enzyme activity and mitochondrial membrane potential (MMP) were measured using caspase-3 colorimetric assay and JC-1 MMP detection kit. Expression levels of ceramide-metabolizing genes were examined by RT-PCR. Results The results revealed that manipulations of ceramide metabolism toward generation or accumulation of apoptotic ceramides increased apoptotic effects of resveratrol in HL60 cells, synergistically. More importantly, gene expression analyses revealed that resveratrol-induced apoptosis via increasing expression levels of ceramide generating genes and decreasing expression levels of antiapoptotic sphingosine kinase-1 and glucosylceramide synthase genes. Conclusion These results showed for the first time that increasing intracellular levels of ceramides by biochemical approaches has also increased sensitivity of HL60 cells to resveratrol. We also showed that resveratrol induces apoptosis through manipulating ceramide-metabolizing genes that resulted in the accumulation of ceramides in HL60 cells.Article Citation - WoS: 32Citation - Scopus: 34Therapeutic Applications of Bioactive Sphingolipids in Hematological Malignancies(John Wiley and Sons Inc., 2010) Ekiz, Hüseyin Atakan; Baran, YusufSphingolipids are sphingosine-based lipid molecules that have important functions in cellular signal transduction and in a variety of cellular processes including proliferation, differentiation, programmed cell death (apoptosis) and responses to stressful conditions. Ceramides, dihydroceramide, sphingosine and sphingosine-1-phosphate are examples of those bioactive sphingolipids. They have a major impact on determination of the cell fate by contributing to the cell survival or cell death through apoptosis. Despite the number of carbon atoms in the fatty acid chain changes the physiological role; ceramides generally exert suppressive roles on the cell proliferation. There have been several enzymes identified in this pathway that are responsible for the conversion of ceramide into other sphingolipid derivatives. Those derivatives also have differential roles on those cellular processes. Sphingosine-1-phosphate is an example of such sphingolipid derivatives which has antiapoptotic effects. As they have significant impacts particularly on the cell death and survival, bioactive sphingolipids have a great potential to be targets in cancer therapy. Increasing number of studies indicates that sphingolipid derivatives are important in the progression of hematological malignancies, and they are also involved in the resistance to current chemotherapeutic options. This review compiles the current knowledge in this area for enlightening the therapeutic potentials of bioactive sphingolipids in various leukemias. © 2010 UICC.