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

Date
2020-09
Advisor
Karakayalı, Özlen Konu
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Bilkent University
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English
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Thesis
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Abstract

Breast 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.

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Breast cancer, Hepatocellular carcinoma, Indole-benzimidazoles, Phenothiazines, Sorafenib synergism, Drug repurposing, Preclinical drug discovery, In vitro / in vivo toxicity profiling, Behavioral assays, Acetylcholinesterase, Comparative transcriptomics
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Published Version (Please cite this version)