Browsing by Subject "Glioblastoma"

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Open Access
Drug repurposing and investigation of novel combinations for glioblastoma therapeutics using in vitro and zebrafish in vivo models
(2024-01) Tok, Güneş
Glioblastoma is the most common and aggressive brain cancer type with the survival rate less than 2 years after diagnosis. Yet, potent drug treatments used in patients are limited and the field is in need of development of new potential drugs. In this study, repurposing of approved drugs alone or in combination and novel drugs are investigated in terms of inhibition of cell viability, glial fluorescent signals and their effects on behavior in zebrafish larval models. The main aim of this study was to test whether phenothiazines, trifluoperazine and a novel molecule 10, could be repurposed for glioblastoma treatment with lower dosages and more potency when combined with Sorafenib, an approved drug, in glioblastoma cell lines and zebrafish larvae. Those drug combinations were not found as toxic in the dosages studied while acted on glia cells in zebrafish transgenic larval models. Last but not least, behavior and stress response of the wild type and heterozygous mutant ache larvae in comparison with homozygous siblings were tested upon drug administration to assess genotype by drug interactions. Combination treatments exhibited higher efficacies suggesting phenothiazines with sorafenib could have potential in glioblastoma treatment. Genotype specific effects of individual and combination treatments on larval light-dark behavior, stress response and recovery exhibited potential for passage of blood brain barrier by the tested drugs. The established protocols for genotype and drug interactions could be applied to other kinases in combination with phenothiazines.
Open Access
Farnesylthiosalicylic acid-loaded lipid–polyethylene glycol–polymer hybrid nanoparticles for treatment of glioblastoma
(Blackwell Publishing Ltd, 2017) Kaffashi, A.; Lüle, S.; Pehlivan, S. B.; Sarısözen, C.; Vural, İ.; Koşucu, H.; Demir, T.; Buğdaycı, K. E.; Söylemezoğlu, F.; Oğuz, K. K.; Mut, M.
Objectives: We aimed to develop lipid–polyethylene glycol (PEG)–polymer hybrid nanoparticles, which have high affinity to tumour tissue with active ingredient, a new generation antineoplastic drug, farnesylthiosalicylic acid (FTA) for treatment of glioblastoma. Method: Farnesylthiosalicylic acid-loaded poly(lactic-co-glycolic acid)-1,2 distearoyl-glycerol-3-phospho-ethanolamine-N [methoxy (PEG)-2000] ammonium salt (PLGA-DSPE-PEG) with or without 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) hybrid nanoparticles has been prepared and evaluated for in-vitro characterization. Cytotoxicity of FTA-loaded nanoparticles along with its efficacy on rat glioma-2 (RG2) cells was also evaluated both in vitro (in comparison with non-malignant cell line, L929) and in vivo. Key findings: Scanning electron microscopy studies showed that all formulations prepared had smooth surface and spherical in shape. FTA and FTA-loaded nanoparticles have cytotoxic activity against RG2 glioma cell lines in cell culture studies, which further increases with addition of DOTAP. Magnetic resonance imaging and histopathologic evaluation on RG2 tumour cells in rat glioma model (49 female Wistar rats, 250–300 g) comparing intravenous and intratumoral injections of the drug have been performed and FTA-loaded nanoparticles reduced tumour size significantly in in-vivo studies, with higher efficiency of intratumoral administration than intravenous route. Conclusion: Farnesylthiosalicylic acid-loaded PLGA-DSPE-PEG-DOTAP hybrid nanoparticles are proven to be effective against glioblastoma in both in-vitro and in-vivo experiments. © 2017 Royal Pharmaceutical Society
Open Access
Herpes simplex virus 1 amplicon vector-mediated siRNA targeting epidermal growth factor receptor inhibits growth of human glioma cells in vivo
(2005) Saydam O.; Glauser, D.L.; Heid I.; Turkeri G.; Hilbe, M.; Jacobs, A.H.; Ackermann, M.; Fraefel, C.
In primary glioblastomas and other tumor types, the epidermal growth factor receptor (EGFR) is frequently observed with alterations, such as amplification, structural rearrangements, or overexpression of the gene, suggesting an important role in glial tumorigenesis and progression. In this study, we investigated whether posttranscriptional gene silencing by vector-mediated RNAi to inhibit EGFR expression can reduce the growth of cultured human gli36 glioma cells. To "knock down" EGFR expression, we have created HSV-1-based amplicons that contain the RNA polymerase III-dependent H1 promoter to express double-stranded hairpin RNA directed against EGFR at two different locations (pHSVsiEGFR I and pHSVsiEGFR II). We demonstrate that both pHSVsiEGFR I and pHSVsiEGFR II mediated knock-down of transiently transfected full-length EGFR or endogenous EGFR in a dose-dependent manner. The knock-down of EGFR resulted in the growth inhibition of human glioblastoma (gli36-luc) cells both in culture and in athymic mice in vivo. Cell cycle analysis and annexin V staining revealed that siRNA-mediated suppression of EGFR induced apoptosis. Overall HSV-1 amplicons can mediate efficient and specific posttranscriptional gene silencing. Copyright © The American Society of Gene Therapy.
Embargo
Investigation of ALCAM's role in glioblastoma senescence
(2024-06) Oğurlu, Tuba Sena
Glioblastoma (GBM) is a type of glioma that is the most common brain tumor in the Central Nervous System. Based on this classification, it is the highest-grade astrocytoma (grade IV), highly aggressive and invasive brain cancer. The primary treatment for GBM involves surgical resection to remove as much of the tumor as possible. This is typically followed by radiotherapy and concurrent temozolomide (TMZ) chemotherapy. Despite these multimodal approaches, the prognosis for GBM patients remains poor, with a median survival of approximately 12-16 months. It is already known that the high invasiveness causes the cancer to reach other tissues in the body. If the cells could migrate to other regions but couldn't proliferate, this would increase the lifespan following the diagnosis. Therefore, one of the most important reasons why these treatments are not effective is the fact that cells can escape senescence induced by TMZ. New genetic tools or targets are needed to help to keep the cells in senescence state or to induce senescence more effectively. Here, in this study, we wanted to investigate the role of Activated Cell Adhesion Molecule (ALCAM) in GBM senescence. In the literature, it has been shown that GBM patient survival decreases with the increased ALCAM level. Moreover, in patient-derived xenografts, cells with overexpressed soluble ALCAM showed more aggressiveness. On the contrary, when ALCAM was decreased in GBM cell lines, the colony formation ability increased. Therefore, the role of ALCAM in senescence and especially in GBM senescence, if there is, has remained elusive. To shed light on this unclarified relationship, we used ALCAM targeting small interfering ribonucleic acid (siRNA) and constructed plasmid overexpressing it to manipulate the ALCAM gene level in GBM cells. Expression levels of senescence markers and SA-βgal staining percentage were investigated upon these manipulations. Although significant changes were observed in senescence markers, we cannot say they were consistent or relatable. There is a need for a more comprehensive study to understand the correct relationship. Moreover, conditions like tumor microenvironment, stem cell subpopulation percentage and combinatorial effects should be considered.
Open Access
Simultaneous miRNA and mRNA transcriptome profiling of glioblastoma samples reveals a novel set of OncomiR candidates and their target genes
(Elsevier, 2018) Güllüoğlu, Ş.; Tüysüz, E. C.; Şahin, M.; Kuşkucu, A.; Yaltırık, C. K.; Türe, U.; Küçükkaraduman, Barış; Akbar, Muhammad Waqas; Güre, Ali Osmay; Bayrak, Ö. F.; Dalan, A. B.
Although glioblastomas are common, there remains a need to elucidate the underlying mechanisms behind their initiation and progression and identify molecular pathways for improving treatment. In this study, sixteen fresh-frozen glioblastoma samples and seven samples of healthy brain tissues were analyzed with miRNA and whole transcriptome microarray chips. Candidate miRNAs and mRNAs were selected to validate expression in fifty patient samples in total with the criteria of abundance, relevance and prediction scores. miRNA and target mRNA relationships were assessed by inhibiting selected miRNAs in glioblastoma cells. Functional tests have been conducted in order to see the effects of miRNAs on invasion, migration and apoptosis of GBM cells. Analyses were carried out to determine correlations between selected molecules and clinicopathological features. 1332 genes and 319 miRNAs were found to be dysregulated by the microarrays. The results were combined and analyzed with Transcriptome Analysis Console 3 software and the DAVID online database. Primary differential pathways included Ras, HIF-1, MAPK signaling and cell adhesion. OncomiR candidates 21-5p, 92b-3p, 182-5p and 339-5p for glioblastoma negatively correlated with notable mRNA targets both in tissues and in in vitro experiments. miR-21-5p and miR-339-5p significantly affected migration, invasion and apoptosis of GBM cells in vitro. Significant correlations with overall survival, tumor volume, recurrence and age at diagnosis were discovered. In this article we present valuable integrated microarray analysis of glioblastoma samples regarding miRNA and gene-expression levels. Notable biomarkers and miRNA-mRNA interactions have been identified, some of which correlated with clinicopathological features in our cohort.
Open Access
Zebrafish glioma xenograft models: in vıvo investıgatıon of injection methods and development of a streamlit application
(2023-10-20) Tombuloğlu, Rüya
Glioblastoma (GBM) is one of the most aggressive and lethal forms of primary brain cancer, posing significant challenges to effective treatment and patient outcomes. Despite extensive research efforts, our understanding of GBM biology and the development of novel therapeutic strategies remains limited. Zebrafish xenograft models have emerged as a promising tool in cancer research, offering unique advantages in studying GBM. This thesis explores the utility of zebrafish xenograft models in advancing our understanding of GBM. Due to their genetic and physiological similarities to humans, zebrafish provide an excellent platform for studying GBM pathogenesis, tumor progression, and drug screening. Their transparency during early development allows for real-time visualization of tumor growth, invasion, and response to treatments. Moreover, zebrafish models enable rapid and cost-effective high-throughput drug screening, accelerating the identification of potential GBM therapeutics. In this thesis, I focused on creating an application named ZenofishDb Glioma, which is a more evolved and focused version of our previous database called ZenofishDb. ZenofishDb Glioma has been created using Python Streamlit, and comprises only the glioma studies and uses Natural Language Processing (NLP) to classify better, and effectively find and summarize information about zebrafish glioma xenograft models. In addition, after searching ZenofishDb Glioma, I decided to investigate an experimental protocol for injection of glioblastoma cells in the zebrafish model to test effects of injected cell numbers. Using MGG-119-GFP cells and Casper zebrafish, I injected different numbers of cells at different locations and stages, i.e., blastula and 2 days post fertilization, and observed there were significant differences between groups at 5 dpf using multiple quantification strategies. In conclusion, ZenofishDb Glioma can help design effective xenotransplantation strategies and make comparisons to understand how different experimental parameters affect the outcome of zebrafish glioma xenograft models.