Identification of preclinical implications for novel indole-benzimidazoles and phenothiazines using in vitro cancer cell line and in vivo zebrafish models
Author(s)
Advisor
Karakayalı, Özlen KonuDate
2020-09Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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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.
Keywords
Breast cancerHepatocellular carcinoma
Indole-benzimidazoles
Phenothiazines
Sorafenib synergism
Drug repurposing
Preclinical drug discovery
In vitro / in vivo toxicity profiling
Behavioral assays
Acetylcholinesterase
Comparative transcriptomics