Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
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Review Citation - WoS: 9Citation - Scopus: 7Micrornas and Long Non-Coding Rnas as Novel Targets in Anti-Cancer Drug Development(Bentham Science Publishers, 2023) Çetinkaya, Melisa; Baran, YusufNon-coding RNAs comprise the majority of RNAs that have been transcribed from the human genome, and these non-coding RNAs have essential regulatory roles in the cellular processes. They have been discovered to influence the expression of the genes, including tumor-suppressive and oncogenes, that establish the non-coding RNAs as novel targets for anti-cancer drug development. Among non-coding RNAs, microRNAs have been extensively studied in terms of cancer biology, and some microRNA-based therapeutics have been reached in clinical studies. Even though most of the research regarding targeting non-coding RNAs for anti-cancer drug development focused on microRNAs, long non-coding RNAs have also started to gain importance as potential therapeutic targets for cancer therapy. In this chapter, the strategies and importance of targeting microRNAs and long non-coding RNAs will be described, along with the clinical studies that involve microRNA-based cancer therapeutics and preclinical studies that involve long non-coding RNA-based therapeutics. Finally, the delivery strategies that have great importance in the effective delivery of the non-coding RNA-based cancer therapeutics, hence the therapy's effectiveness, will be described.Conference Object Peptıde Targeted Core Cross-lınked Mıcelles For Dox Delıvery To Her2 Expressıng Cancer Cells(Mary Ann Liebert, 2022) Bayram, Nazende Nur; Ulu, Gizem Tuğçe; Gürdap, Seda; İşoğlu, İsmail Alper; Baran, Yusuf; Dinçer İşoğlu, SevilIn this study, we prepared a novel targeted and extra stable micellar nanocarrier that can facilitate intracellular drug release. First, ((N-3-sulfopropyl-N, N-dimethylammonium)ethyl methacrylate was synthesized by RAFT polymerization, and it was followed by copolymerization of macroCTA with AEM in the presence of an aciddegradable cross-linker. Then, a peptide estimated by phage display for HER-2 recognition was incorporated into these core cross-linked micelles with carbodiimide reaction.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: 13Citation - Scopus: 13Her2-Targeted, Degradable Core Cross-Linked Micelles for Specific and Dual Ph-Sensitive Dox Release(John Wiley and Sons Inc., 2021) Bayram, Nazende Nur; Ulu, Gizem Tuğçe; Topuzoğulları, Murat; Baran, Yusuf; Dinçer İşoğlu, SevilHere, a targeted, dual-pH responsive, and stable micelle nanocarrier is designed, which specifically selects an HER2 receptor on breast cancer cells. Intracellularly degradable and stabilized micelles are prepared by core cross-linking via reversible addition-fragmentation chain-transfer (RAFT) polymerization with an acid-sensitive cross-linker followed by the conjugation of maleimide-doxorubicin to the pyridyl disulfide-modified micelles. Multifunctional nanocarriers are obtained by coupling HER2-specific peptide. Formation of micelles, addition of peptide and doxorubicin (DOX) are confirmed structurally by spectroscopical techniques. Size and morphological characterization are performed by Zetasizer and transmission electron microscope (TEM). For the physicochemical verification of the synergistic acid-triggered degradation induced by acetal and hydrazone bond degradation, Infrared spectroscopy and particle size measurements are used. Drug release studies show that DOX release is accelerated at acidic pH. DOX-conjugated HER2-specific peptide-carrying nanocarriers significantly enhance cytotoxicity toward SKBR-3 cells. More importantly, no selectivity toward MCF-10A cells is observed compared to HER2(+) SKBR-3 cells. Formulations cause apoptosis depending on Bax and Caspase-3 and cell cycle arrest in G2 phase. This study shows a novel system for HER2-targeted therapy of breast cancer with a multifunctional nanocarrier, which has higher stability, dual pH-sensitivity, selectivity, and it can be an efficient way of targeted anticancer drug delivery.Article Citation - WoS: 426Citation - Scopus: 470Cell Proliferation and Cytotoxicity Assays(Bentham Science Publishers, 2016) Adan, Aysun; Kiraz, Yağmur; Baran, YusufCell viability is defined as the number of healthy cells in a sample and proliferation of cells is a vital indicator for understanding the mechanisms in action of certain genes, proteins and pathways involved cell survival or death after exposing to toxic agents. Generally, methods used to determine viability are also common for the detection of cell proliferation. Cell cytotoxicity and proliferation assays are generally used for drug screening to detect whether the test molecules have effects on cell proliferation or display direct cytotoxic effects. Regardless of the type of cell-based assay being used, it is important to know how many viable cells are remaining at the end of the experiment. There are a variety of assay methods based on various cell functions such as enzyme activity, cell membrane permeability, cell adherence, ATP production, co-enzyme production, and nucleotide uptake activity. These methods could be basically classified into different categories: (I) dye exclusion methods such as trypan blue dye exclusion assay, (II) methods based on metabolic activity, (III) ATP assay, (IV) sulforhodamine B assay, (V) protease viability marker assay, (VI) clonogenic cell survival assay, (VII) DNA synthesis cell proliferation assays and (V) raman micro-spectroscopy. In order to choose the optimal viability assay, the cell type, applied culture conditions, and the specific questions being asked should be considered in detail. This particular review aims to provide an overview of common cell proliferation and cytotoxicity assays together with their own advantages and disadvantages, their methodologies, comparisons and intended purposes.Article Citation - WoS: 36Citation - Scopus: 38Effect of Molecular Architecture on Cell Interactions and Stealth Properties of Peg(American Chemical Society, 2017) Özer, İmran; Tomak, Aysel; Zareie, Hadi M.; Baran, Yusuf; Bulmuş, VolgaPEGylation, covalent attachment of PEG to therapeutic biomolecules, in which suboptimal pharmacokinetic profiles limiting their therapeutic utility are of concern, is a widely applied technology. However, this technology has been challenged by reduced bioactivity of biomolecules upon PEGylation and immunogenicity of PEG triggering immune response and abrogating clinical efficacy, which collectively necessitate development of stealth polymer alternatives. Here we demonstrate that comb-shape poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA), a stealth polymer alternative, has a more compact structure than PEG and self-organize into nanoparticles in a molecular weight dependent manner. Most notably, we show that comb-shape POEGMA promotes significantly higher cellular uptake and exhibits less steric hindrance imposed on the conjugated biomolecule than PEG. Collectively, comb-shape POEGMA offers a versatile alternative to PEG for stealth polymer-biomolecule conjugation applications.Article Citation - WoS: 62Citation - Scopus: 80Anti-Proliferative, Apoptotic and Signal Transduction Effects of Hesperidin in Non-Small Cell Lung Cancer Cells(Springer Verlag, 2015) Çinçin, Zeynep Birsu; Ünlü, Miray; Kıran, Bayram; Bireller, Elif Sinem; Baran, Yusuf; Çakmakoğlu, BediaPurpose: Hesperidin, a glycoside flavonoid, is thought to act as an anti-cancer agent, since it has been found to exhibit both pro-apoptotic and anti-proliferative effects in several cancer cell types. The mechanisms underlying hesperidin-induced growth arrest and apoptosis are, however, not well understood. Here, we aimed to investigate the anti-proliferative and apoptotic effects of hesperidin on non-small cell lung cancer (NSCLC) cells and to investigate the mechanisms involved. Methods: The anti-proliferative and apoptotic effects of hesperidin on two NSCLC-derived cell lines, A549 and NCI-H358, were determined using a WST-1 colorimetric assay, a LDH cytotoxicity assay, a Cell Death Detection assay, an AnnexinV-FITC assay, a caspase-3 assay and a JC-1 assay, respectively, all in a time- and dose-dependent manner. As a control, non-cancerous MRC-5 lung fibroblasts were included. Changes in whole genome gene expression profiles were assessed using an Illumina Human HT-12v4 beadchip microarray platform, and subsequent data analyses were performed using an Illumina Genome Studio and Ingenuity Pathway Analyser (IPA). Results: We found that after hesperidin treatment, A549 and NCI-H358 cells exhibited decreasing cell proliferation and increasing caspase-3 and other apoptosis-related activities, in conjunction with decreasing mitochondrial membrane potential activities, in a dose- and time-dependent manner. Through a GO analysis, by which changes in gene expression profiles were compared, we found that the FGF and NF-κB signal transduction pathways were most significantly affected in the hesperidin treated NCI-H358 and A549 NSCLC cells. Conclusions: Our results indicate that hesperidin elicits an in vitro growth inhibitory effect on NSCLC cells by modulating immune response-related pathways that affect apoptosis. When confirmed in vivo, hesperidin may serve as a novel anti-proliferative agent for non-small cell lung cancer.Article Citation - WoS: 6Citation - Scopus: 7Nilotinib Does Not Alter the Secretory Functions of Carotid Artery Endothelial Cells in a Prothrombotic or Antithrombotic Fashion(SAGE Publications Inc., 2015) Katgı, Abdullah; Sevindik, Ömer Gökmen; Adan Gökbulut, Aysun; Özsan, Güner Hayri; Yüksel, Faize; Solmaz, Şerife Medeni; Alacacıoğlu, İnci; Özcan, Mehmet Ali; Demirkan, Fatih; Baran, Yusuf; Pişkin, ÖzdenBackground: There have been concerns about the possible prothrombotic effects of nilotinib, especially in patients having cardiovascular risk factors. The potential mechanism behind the increased risk of thromboembolic events is still not clear. Objectives: In this study, we aimed to evaluate possible harmful effects of nilotinib on endothelial cells. To this aim, we examined proliferative capacity and secretory functions of healthy human carotid artery endothelial cells (HCtAECs) in response to nilotinib. Methods: 3-(4,5-Dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation method was used to determine antiproliferative effects of nilotinib on HCtAECs. The HCtAECs were incubated with 5, 10, and 100 nmol/L doses of nilotinib for 72 hours. Then, in order to assess the endothelial function, levels of nitric oxide (NO), von Willebrand factor (vWF), tissue plasminogen activator, plasminogen activator inhibitor 1 (PAI-1), and endothelin 1 (ET-1) were evaluated using enzyme-linked immunosorbent assay from tissue culture supernatants. Results: There were slight but statistically significant decreases in cell proliferation in response to nilotinib. Nilotinib increased the secretion of t-PA, PAI-1, and vWF in a dose-dependent manner when compared with the untreated control group. The ET-1 secretion was lower in 5 nmol/L and higher in 10 and 100 nmol/L nilotinib-treated cells as compared to untreated cells. Regarding NO secretion, lower levels were observed in 5 and 10 nmol/L, and higher levels were detected in 100 nmol/L nilotinib-treated cells as compared to untreated control group cells. Conclusion: Considering the results obtained in our study, nilotinib does not affect the functions of endothelial cells either in a prothrombotic or an antithrombotic fashion, despite a dose-dependent decline in cell viability.Article Citation - WoS: 32Citation - Scopus: 39Fluorine-18 Fluorodeoxyglucose Pet-Ct for Extranodal Staging of Non-Hodgkin and Hodgkin Lymphoma(Turkish Society of Radiology, 2014) Ömür, Özgür; Baran, Yusuf; Oral, Aylin; Ceylan, YeşimPurpose We aimed to evaluate the role of fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) involving care-dose unenhanced CT to detect extranodal involvement in patients with non-Hodgkin and Hodgkin lymphoma. Materials and Methods Lymphoma patients (35 Hodgkin lymphoma, 75 non-Hodgkin lymphoma) who were referred for 18F-FDG PET-CT imaging, following a diagnostic contrast-enhanced CT (CE-CT) performed within the last month, were included in our study. A total of 129 PET-CT images, and all radiologic, clinical, and pathological records of these patients were retrospectively reviewed. Results In total, 137 hypermetabolic extranodal infiltration sites were detected by 18F-FDG PET-CT in 62 of 110 patients. There were no positive findings by CE-CT that reflected organ involvement in 40 of 137 18F-FDG-positive sites. The κ statistics revealed fair agreement between PET-CT and CE-CT for the detection of extranodal involvement (κ=0.60). The organs showing a disagreement between the two modalities were the spleen, bone marrow, bone, and thyroid and prostate glands. In all lesions that were negative at CE-CT, there was a diffuse 18F-FDG uptake pattern in the PET-CT images. The frequency of extranodal involvement was 51% and 58% in Hodgkin and non-Hodgkin lymphoma patients, respectively. There was a high positive correlation between the maximum standardized uptake values of the highest 18F-FDG-accumulating lymph nodes and extranodal sites (r=0.67) in patients with nodal and extranodal involvement. Conclusion 18F-FDG PET-CT is a more effective technique than CE-CT for the evaluation of extranodal involvement in Hodgkin and non-Hodgkin lymphoma patients. PET-CT has a significant advantage for the diagnosis of diffusely infiltrating organs without mass lesions or contrast enhancement compared to CE-CT.Article Citation - WoS: 26Citation - Scopus: 28Therapeutic Potential of Apigenin, a Plant Flavonoid, for Imatinib-Sensitive and Resistant Chronic Myeloid Leukemia Cells(Routledge, 2014) Solmaz, Soner; Adan Gökbulut, Aysun; Çinçin, Zeynep Birsu; Özdoğu, Hakan; Boğa, Can; Çakmakoğlu, Bedia; Kozanoğlu, İlknur; Baran, YusufDespite the presence of many therapeutic regimens like imatinib and other tyrosine kinase inhibitors, the development of resistance, intolerance, and side effects makes chronic myeloid leukemia (CML) therapy challenging. Thus, there is a need to discover novel drugs for CML patients. In this study, we attempted to assess apigenin, a common plant dietary flavonoid, in terms of its cytotoxic, apoptotic, and cytostatic effects on imatinib-sensitive and resistant Philadelphia-positive CML cells. We analyzed apigenin's effects on cell proliferation, apoptosis, caspase-3 activity, loss of mitochondrial membrane potential, and cell cycle progression in K562 and K562/IMA3 cells. Furthermore, we described genes and gene networks that are modulated in CML in response to apigenin. Results of our study revealed that apigenin has cytotoxic and apoptotic effects on both cell types. We also displayed that apigenin induced G2/M arrest in K562 cells while arresting K562/IMA3 cells in S phase especially at the highest apigenin concentration. The expression analysis identified a set of genes that were regulated by apigenin in K652 and K562/IMA3 cells. Association of modulated genes with biological functional groups identified several networks affected by apigenin including cell survival, proliferation, cell death, cell cycle, and cell signalling pathways.