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dc.contributor.advisorÇetin-Atalay, Rengül
dc.contributor.authorGüven, Ebru Bilget
dc.date.accessioned2016-01-08T18:24:58Z
dc.date.available2016-01-08T18:24:58Z
dc.date.issued2012
dc.identifier.urihttp://hdl.handle.net/11693/15812
dc.descriptionAnkara : The Department of Molecular Biology and Genetics and Graduate School of Engineering and Science of Bilkent University, 2012.en_US
dc.descriptionThesis (Ph. D.) -- Bilkent University, 2012.en_US
dc.descriptionIncludes bibliographical refences.en_US
dc.description.abstractHepatocellular carcinoma (HCC) as a, heterogeneous, multi-step, slowprogressing disease, has very limited treatment options due to its chemoresistant nature and late diagnosis. According to World Health Organization (WHO) reports HCC is a major public health problem. Each year, 748,000 new cases appear and 696,000 people lose their lives, all due to liver cancer alone. Sorafenib, the multi-tyrosine kinase inhibitor, is still the only (Food and Drug Administration) FDA-approved drug available for treatment. Therefore, there is an urgent need for novel, target-specific drugs based on the underlying molecular mechanisms of liver carcinogenesis. In this Ph.D. dissertation, synthetic purine, purine nucleoside analogs, aminotriazole and thiadiazine derivatives were evaluated for their cytotoxic activities and mechanisms of action against liver cancer. These novel molecules were selected because of their potential kinase inhibitory activity. Protein kinases, involved in signaling pathways, are the main enzymes of target-specific drug discovery; therefore, discovery of novel, putative protein kinase inhibitors as drug candidates can be promising for the treatment of primary liver cancer. Initially, sulforhodamine B (SRB) assay was used to screen the novel smallmolecules for their cytotoxic activities against breast, colon and liver cancer cell lines. Active molecules, then, were further exploited on a panel of HCC cell lines. The differential IC50 (half-maximal inhibitory concentration) values obtained, might indicate that these small-molecules interfere with cell signaling; since, these cell lines have individual characteristics of cell signaling activities. Further investigations are envisaged for the identification of the molecular mechanisms that these putative kinase inhibitors are involved in. Among the 228 newly synthesized putative kinase inhibitors, 3 smallmolecules were identified as promising anti-cancer agents against liver cancer with druggable cytotoxic activities and remarkable kinase inhibition potentials. The purine analogue, AUM32, and the purine nucleoside analogue, AUM42, were revealed as pro-senescence therapeutic agents in liver cancer. Both drug candidates were shown to initiate senescence-induced cell death and the underlying mechanism was confirmed for AUM42 as the induction of p15(INK4b) and the correlated decrease in Rb phosphorylation. Synthetic 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivative, ClAT-TM, is the other effective small-molecule with kinase inhibition potential. Upon ClATTM treatment, liver cancer cells experience a growth inhibition accompanying with dramatic morphological changes. Rounded, swollen and eventually detached cells were shown to be arrested in the G2/M stage of the cell cycle and eventually undergo apoptosis. Moreover, ROS (reactive oxygen species) accumulation and the activation of JNK signaling pathway were found as associated with the mechanism of action ClAT-TM cytotoxicity.en_US
dc.description.statementofresponsibilityGüven, Ebru Bilgeten_US
dc.format.extentxxiv, 204 leaves, illustrations, graphsen_US
dc.language.isoEnglishen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject.lccWI735 .G88 2012en_US
dc.subject.lcshCarcinoma, Hepatocellular.en_US
dc.subject.lcshCancer--Genetic aspects.en_US
dc.subject.lcshDNA-Protein interaction.en_US
dc.subject.lcshProtein interaction.en_US
dc.subject.lcshCancer cells.en_US
dc.subject.lcshLiver cancer.en_US
dc.titleIdentification of putative protein kinase inhibitors acting on liver cancer cellsen_US
dc.typeThesisen_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.publisherBilkent Universityen_US
dc.description.degreePh.D.en_US


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