Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Article Citation - WoS: 16Cumulative Clinical Experience From a Decade of Use: Imatinib as First-Line Treatment of Chronic Myeloid Leukemia(Dove Medical Press Ltd., 2012) Baran, Yusuf; Saydam, GürayChronic myeloid leukemia (CML) is a malignant disease that originates in the bone marrow and is designated by the presence of the Philadelphia (Ph+) chromosome, a translocation between chromosomes 9 and 22. Targeted therapy against CML commenced with the development of small-molecule tyrosine kinase inhibitors (TKIs) exerting their effect against the oncogenic breakpoint cluster region (BCR)-ABL fusion protein. Imatinib emerged as the first successful example of a TKI used for the treatment of chronic-phase CML patients and resulted in significant improvements in response rate and overall survival compared with previous treatments. However, a significant portion of patients failed to respond to the therapy and developed resistance against imatinib. Second-generation TKIs nilotinib and dasatinib were to have higher efficiency in clinical trials in imatinib- resistant or intolerant CML patients com pared with imatinib. Identification of novel strategies such as dose escalation, drug combination therapy, and use of novel BCR-ABL inhibitors may eventually overcome resistance against BCR-ABL TKIs. This article reviews the history of CML, including the treatment strategies used prediscovery of TKIs and the preclinical and clinical data obtained after the use of imatinib, and the second-generation TKIs developed for the treatment of CML.Article Citation - WoS: 15Citation - Scopus: 13Environmentally Responsive Dual-Targeting Nanoparticles: Improving Drug Accumulation in Cancer Cells as a Way of Preventing Anticancer Drug Efflux(John Wiley and Sons Inc., 2018) Dağlıoğlu, CenkDrug targeting and stimuli-responsive drug release are 2 active areas of cancer research and hold tremendous potential in the management of cancer drug resistance. In this study, I addressed this issue and focused on the synthesis and characterization of pH-responsive Fe3O4@SiO2(FITC)-BTN/folic acid/DOX multifunctional nanoparticles aiming to increase drug accumulation in malignancies with both dual active targeting and endosomal drug release properties. Dye-doped silica magnetic-fluorescent composite was constructed by a simple coprecipitation of Fe+2/Fe+3 salts followed by sol-gel formation and dual-targeting function was obtained by conjugating folate and biotin moieties on the silica surface of nanoparticles via an esterification reaction. Doxorubicin was then successfully attached on the amine-functionalized nanoparticles using a pH-sensitive Schiff-base formation. The physicochemical characterization of the structure was performed by dynamic light scattering, zeta potential measurement, X-ray diffraction, Fourier transform infrared spectroscopy, electron microscopy techniques, and an in vitro pH-dependent release study. Cellular uptake and cytotoxicity experiments demonstrated an enhanced intracellular delivery and reduction of cancer cell viability in the cervical carcinoma HeLa cell line. Furthermore, proapoptotic studies showed that the nanoparticles increased the apoptotic rates within the same cancer cells. The preliminary cell tests confirm the potential of these multifunctional nanoparticles against the development of drug resistance in cancer cells.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: 49Citation - Scopus: 50Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation(Springer Verlag, 2011) Baran, Yusuf; Bielawski, Jacek; Gündüz, Ufuk; Öğretmen, BesimPurpose: 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.