Identification of preclinical implications for novel indole-benzimidazoles and phenothiazines using in vitro cancer cell line and in vivo zebrafish models

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buir.advisorKarakayalı, Özlen Konu
dc.contributor.authorYaman, Murat
dc.date.accessioned2020-10-13T05:55:57Z
dc.date.available2020-10-13T05:55:57Z
dc.date.copyright2020-09
dc.date.issued2020-09
dc.date.submitted2020-09-29
dc.departmentGraduate Program in Neuroscienceen_US
dc.descriptionCataloged from PDF version of article.en_US
dc.descriptionThesis (Ph.D.): Bilkent University, Department of Neuroscience, İhsan Doğramacı Bilkent University, 2020.en_US
dc.descriptionIncludes bibliographical references (leaves 108-139).en_US
dc.description.abstractBreast cancer (BC) and hepatocellular carcinoma (HCC) are two major health problems with significant mortality rates. Although drug therapies are available, therapeutic success remains limited. Because of low bioavailability, high toxicity and recurring drug resistance, novel therapeutic options are essential. In the present thesis, a multitude of in vitro, in silico and in vivo approaches were executed to test anti-cancer effects and preclinical potentials of novel indole-benzimidazoles and phenothiazines in BC and HCC, respectively. In the first component of the thesis, I evaluated BC cell line toxicity and estrogen receptor (ER) relationship of novel indole-benzimidazole derivatives using in vitro cancer lines, in vivo zebrafish embryos/larvae, and in silico comparative transcriptomics analyses. In the second part, antipsychotic compounds phenothiazines (PTZ) were repurposed for HCC therapy. Therefore, generic PTZ derivatives alone or in combination with sorafenib (SFB) were tested using in vitro cancer lines followed by zebrafish developmental assays and embryonic stage xenografts. In addition, RNAseq analyses were performed on trifluoperazine (TFP), SFB, and TFP+SFB combination treated Hep3B cells to understand synergistic/antagonistic effects of the drugs at gene expression level. Lastly, anti-HCC potential of novel PTZ derivatives were explored by in vitro and in vivo screenings. Moreover, effects of the novel and generic derivatives on neural pathways were evaluated by cholinesterase assays and motor response measurements. The findings of the dissertation present potential leads for conducting further preclinical studies tailored towards novel BC and HCC therapies.en_US
dc.description.degreePh.D.en_US
dc.description.statementofresponsibilityby Murat Yamanen_US
dc.embargo.release2021-03-29
dc.format.extentxvi, 174 leaves + 20 leaves : illustrations, charts, tables ; 30 cm.en_US
dc.identifier.itemidB160504
dc.identifier.urihttp://hdl.handle.net/11693/54208
dc.language.isoEnglishen_US
dc.publisherBilkent Universityen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectBreast canceren_US
dc.subjectHepatocellular carcinomaen_US
dc.subjectIndole-benzimidazolesen_US
dc.subjectPhenothiazinesen_US
dc.subjectSorafenib synergismen_US
dc.subjectDrug repurposingen_US
dc.subjectPreclinical drug discoveryen_US
dc.subjectIn vitro / in vivo toxicity profilingen_US
dc.subjectBehavioral assaysen_US
dc.subjectAcetylcholinesteraseen_US
dc.subjectComparative transcriptomicsen_US
dc.titleIdentification of preclinical implications for novel indole-benzimidazoles and phenothiazines using in vitro cancer cell line and in vivo zebrafish modelsen_US
dc.title.alternativeIn vitro kanser hücre hatları ve in vivo zebrabalığı modelleri kullanılarak yeni indol-benzimidazoller ve fenotiyazinler için preklinik etkilerin tanımlanmasıen_US
dc.typeThesisen_US
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