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: 7Citation - Scopus: 9Genomewide Elucidation of Drug Resistance Mechanisms for Systemically Used Antifungal Drugs Amphotericin B, Caspofungin, and Voriconazole in the Budding Yeast(American Society for Microbiology, 2019) Balkan, Çiğdem; Ercan, İlkcan; Işık, Esin; Akdeniz, Esra Şahin; Balcıoğlu, Orhan; Kodedova, Marie; Koç, AhmetThere are only a few antifungal drugs used systemically in treatment, and invasive fungal infections that are resistant to these drugs are an emerging problem in health care. In this study, we performed a high-copy-number genomic DNA (gDNA) library screening to find and characterize genes that reduce susceptibility to amphotericin B, caspofungin, and voriconazole in Saccharomyces cerevisiae. We identified the PDR16 and PMP3 genes for amphotericin B, the RMD9 and SWH1 genes for caspofungin, and the MRS3 and TRI1 genes for voriconazole. The deletion mutants for PDR16 and PMP3 were drug susceptible, but the other mutants had no apparent susceptibility. Quantitative-PCR analyses suggested that the corresponding drugs upregulated expression of the PDR16, PMP3, SWH1, and MRS3 genes. To further characterize these genes, we also profiled the global expression patterns of the cells after treatment with the antifungals and determined the genes and paths that were up-or downregulated. We also cloned Candida albicans homologs of the PDR16, PMP3, MRS3, and TRI1 genes and expressed them in S. cerevisiae. Heterologous expression of Candida homologs also provided reduced drug susceptibility to the budding yeast cells. Our analyses suggest the involvement of new genes in antifungal drug resistance.Article Citation - WoS: 104Citation - Scopus: 123The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance(MDPI, 2019) Rudzinska, Magdalena; Parodi, Alessandro; Soond, Surinder M.; Vinarov, Andrey Z.; Korolev, Dmitry O.; Morozov, Andrey O.; Zamyatnin, Andrey A., Jr.; Dağlıoğlu, Cenk; Tutar, YusufCysteine cathepsins are lysosomal enzymes belonging to the papain family. Their expression is misregulated in a wide variety of tumors, and ample data prove their involvement in cancer progression, angiogenesis, metastasis, and in the occurrence of drug resistance. However, while their overexpression is usually associated with highly aggressive tumor phenotypes, their mechanistic role in cancer progression is still to be determined to develop new therapeutic strategies. In this review, we highlight the literature related to the role of the cysteine cathepsins in cancer biology, with particular emphasis on their input into tumor biology.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: 8Citation - Scopus: 8Multidrug Resistance in Chronic Myeloid Leukemia(TÜBİTAK, 2014) Ünlü, Miray; Kiraz, Yağmur; Kacı, Fatma Necmiye; Özcan, Mehmet Ali; Baran, YusufChronic myeloid leukemia (CML) is characterized by the accumulation of Philadelphia chromosome-positive (Ph+) myeloid cells. Ph+ cells occur via a reciprocal translocation between the long arms of chromosomes 9 and 22 resulting in constitutively active Bcr-abl fusion protein. Tyrosine kinase inhibitors (TKIs) are used against the kinase activity of Bcr-abl fusion protein for the effective treatment of CML. However, the development of drug resistance, directed by different genetic mechanisms, is the major problem of clinical applications of TKIs. These mechanisms include mutations in the TKI binding site of Bcr-abl, overexpression of Bcr-abl, overexpression of ATP binding cassette transporters, aberrant ceramide metabolism, inhibition of apoptosis, and changes in expression levels of microRNAs. Recently, many studies have focused on understanding the molecular mechanisms of drug resistance in cancer while targeting therapies providing reversal of resistance. Cancer stem cells also have roles in tumor initiation, maintenance, progression, metastasis, and drug resistance. Uncovering the mechanisms of drug resistance can provide more efficient treatment of cancer since these findings may provide novel targets for a complete cure. In this review, we discuss recent findings on the mechanisms of multidrug resistance and its reversal in CML. © TÜBİTAK.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: 46Citation - Scopus: 53Therapeutic Potential of Targeting Ceramide/Glucosylceramide Pathway in Cancer(Springer Verlag, 2013) Kartal Yandım, Melis; Apohan, Elif; Baran, YusufSphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDP-glucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance. © 2012 Springer-Verlag Berlin Heidelberg.Article Citation - WoS: 7Citation - Scopus: 8Mir-17 in Imatinib Resistance and Response To Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Cells(Zerbinis Medical Publications, 2013) Fıratlıgil, Burcu; Biray Avcı, Çığır; Baran, YusufIn this study we examined the expression levels of miR-17 which possesses oncogenic activities through downregulation of CDKN1A, p21 and E2F1 tumor suppressor genes, in imatinib sensitive and resistant chronic myeloid leukemia (CML) cells. On the other hand, we also determined the expression levels of miR-17 in response to tyrosine kinase inhibitors imatinib, nilotinib and dasatinib used for the treatment of CML. Methods: The expression profiles of miR-17 were analysed by Stem-Loop reverse transcription (RT) polymerase chain reaction (PCR). Results: The results revealed significant increase in the expression levels of miR-17 in imatinib sensitive and resistant cells compared to peripheral blood mononuclear cells (PBMCs). On the other hand, significant decrease was observed in miR-17 levels in response to imatinib, nilotinib and dasatinib. Conclusion: These results may imply that miR-17 can be used for diagnosis and treatment of CML.Article Citation - WoS: 108Citation - Scopus: 119Sphingosine Kinase-1 and Sphingosine 1-Phosphate Receptor 2 Mediate Bcr-Abl1 Stability and Drug Resistance by Modulation of Protein Phosphatase 2a(American Society of Hematology, 2011) Salas, Arelis; Ponnusamy, Suriyan; Senkal, Can E.; Meyers-Needham, Marisa; Selvam, Shanmugam Panneer; Saddoughi, Sahar A.; Apohan, Elif; Sentelle, R. David; Smith, Charles; Gault, Christopher R.; Obeid, Lina M.; El-Shewy, Hesham M.; Oaks, Joshua; Santhanam, Ramasamy; Marcucci, Guido; Baran, Yusuf; Mahajan, Sandeep; Fernandes, Daniel; Stuart, Robert; Perrotti, Danilo; Öğretmen, BesimThe mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinib-resistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1-/- MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib- or nilotinib-induced growth inhibition in primary CD34+ mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, expressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1-derived mouse allografts. Since SK-1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type- or mutant-Bcr-Abl1 thereby overcoming drug resistance. © 2011 by The American Society of Hematology.Article Citation - WoS: 7Citation - Scopus: 9Effect of Cobalt-60 (? Radiation) on Multidrug-Resistant Multiple Myeloma Cell Lines(Portland Press, 2011) Mutlu, Pelin; Baran, Yusuf; Ural, Ali Ugur; Avcu, Ferit; Dirican, Bahar; Beyzadeoglu, Murat; Gündüz, UfukEmergence 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 (γ) 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 c radiation, and proliferation was examined by XTT {2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-t etrazolium hydroxide} assay. The results showed that Prednisone- and melphalan-resistant RPMI-8226 cells were also cross-resistant to 200 and 800 cGy γ 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 c 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. © The Author(s) Journal compilation