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dc.contributor.advisorYuluğ, Işık G.
dc.contributor.authorDurmaz, İrem
dc.date.accessioned2016-05-02T10:44:10Z
dc.date.available2016-05-02T10:44:10Z
dc.date.copyright2015-12
dc.date.issued2015-12
dc.date.submitted2016-01
dc.identifier.urihttp://hdl.handle.net/11693/29030
dc.descriptionCataloged from PDF version of thesis.en_US
dc.descriptionIncludes bibliographical references (leaves 103-118).en_US
dc.descriptionThesis (Ph. D.): Bilkent University, Department of Molecular Biology and Genetics, İhsan Doğramacı Bilkent University, 2015.en_US
dc.description.abstractHepatocellular carcinoma is the second deadliest and fifth most common cancer type worldwide. Due to the limited therapy options, it is crucial to develop novel targeted therapeutic agents that provide better prognosis and enhance life quality of patients. The specific aim of this thesis was to identify and characterize novel compounds with anticancer properties in liver cancer. Three groups of molecules were investigated. First group were cardiac glycosides extracted and purified from Digitalis Ferruginea. Extensive analysis Glycoside Lanatoside C revealed that these molecules induced ROS accumulation in liver cancer cells with differential downstream targets in mesenchymal-like PTENdeficient drug-resistant Mahlavu and epithelial-like PTEN-adequate drug-sensitive Huh7 liver cancer cells. Xenograft models on nude mice also confirmed the anticancer activities of Lanatoside C in vivo with decreased tumor volume and weight. The second group of compounds were novel molecules that contains triazolothiadiazine and triazolothiadiazole scaffold, derived from known NSAIDs (ibuprofen, naproxen and flurbiprofen). Results indicated that SubG1/G1 cell cycle arrest is induced in treated cells. In addition, extensive molecular analysis disclosed oxidative stress induction and COX activity inhibition leading to ASK1 activation and Akt inhibition. The levels of downstream elements GSK3β, β-catenin and CyclinD1 were also altered. Apoptosis was characterized as the cell death mechanism that is triggered by these molecules in liver cancer cells. Novel nucleobase/nucleoside analogues were the third group of molecules explored in this study. 24 of 127 investigated compounds showed significant cytotoxicity during initial screening. 6 molecules were selected for further molecular analysis upon real-time cytotoxicity assay. It was observed that the molecules induced SubG1/G1 cell cycle arrest through Src pathway inhibition. CyclinE-cdk2 complex formation was prevented then the inhibition of Rb leading to a decrease in cell growth and proliferation and induction of apoptosis in liver cancer cells. This thesis disclosed the mode of action of three groups molecules, glycosides are pure examples of drug repurposing. NSAID represent the modified small molecule compounds for novel targets and finally nucleobase analogs are novel compounds as anti metabolites.en_US
dc.description.statementofresponsibilityby İrem Durmaz.en_US
dc.format.extentxxi, 144 leaves : illustrations (some colour), charts.en_US
dc.language.isoEnglishen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectHepatocellular carcinomaen_US
dc.subjectCardiac glycosideen_US
dc.subjectNSAIDsen_US
dc.subjectApoptosisen_US
dc.subjectNucleobaseen_US
dc.subjectNucleosideen_US
dc.subjectTriazolen_US
dc.subjectThiadiazineen_US
dc.subjectDrug repurposingen_US
dc.subjectAnticanceren_US
dc.titleDiscovery of novel agents for liver cancer therapeutics and characterization of their bioactivities on cellular pathwaysen_US
dc.title.alternativeKaraciğer kanseri tedavisi için yeni maddelerin keşfedilmesi ve hücresel sinyal ağları üzerindeki biyoaktivitelerinin karakterizasyonuen_US
dc.typeThesisen_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.publisherBilkent Universityen_US
dc.description.degreeM.S.en_US
dc.identifier.itemidB152684
dc.embargo.release2018-01-07


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