In vitro antiproliferative effects and underlying mechanismds of bismuth dithiocarbamate derivatives against breast cancer cell line

Drastic increment of cancer incidence in recent years has driven metal complexes including bismuth complexes as a promising approach in anticancer drug development due to its well-known low toxicity, environmental friendliness and medical therapeutic benefits The complexes with R= (CH2CH2OH)(iPr), E...

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Main Author:	Chan, Pit Foong
Format:	Thesis
Language:	English
Published:	2019
Subjects:	Breast Neoplasms Bismuth
Online Access:	http://psasir.upm.edu.my/id/eprint/97788/1/FPSK%28p%29%202021%205%20IR.pdf
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spelling	my-upm-ir.977882022-07-04T02:55:17Z In vitro antiproliferative effects and underlying mechanismds of bismuth dithiocarbamate derivatives against breast cancer cell line 2019-07 Chan, Pit Foong Drastic increment of cancer incidence in recent years has driven metal complexes including bismuth complexes as a promising approach in anticancer drug development due to its well-known low toxicity, environmental friendliness and medical therapeutic benefits The complexes with R= (CH2CH2OH)(iPr), Et2, (CH2)4 and (CH2CH2OH)(CH3) in bismuth-dithiocarbamate, Bi[S2CN-R]3 labelled as C3, C4, C5 and C9, have been studied, respectively. This study aimed at determining the antiproliferative effect of the bismuth complexes and their underlying mechanism(s) in breast cancer cell (MCF-7) through various in vitro assays. The antiproliferative effect of the bismuth complexes was studied using Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Apoptotic cell death activities of C3, C4, C5 and C9 were performed via DNA fragmentation, acridine orange/propidium iodide (AO/PI), Annexin V and caspase activity assays. Whilst, this study further employed Human Cancer Drug Targets RT² Profiler PCR array to study the expression of 84 actively sought targets for anticancer therapeutics and drug development to delineate the underlying mechanism(s). Results showed all tested compounds (C3, C4, C5 and C9) exhibited antiproliferative effects against MCF-7 cell line with IC50 of 10.33 ± 0.06 μM, 1.26 ± 0.02 μM, 1.07 ± 0.01 μM and 25.37 ± 0.12 μM, respectively. The morphology of apoptosis including formation of DNA fragments, phosphatidylserine translocation, chromatin condensation, and membrane blebbing was shown. The compounds were found to variably increase reactive oxygen species (ROS) generation thus increased mitochondrial membrane potential (MMP). Consequently, this led to the release of cytochrome c from mitochondria, demonstrated by the data obtained by flow cytometric analysis. All four tested compounds were revealed to induce both intrinsic and extrinsic apoptotic pathways, conferred by the data obtained from Human Cancer Drug Targets RT² Profiler PCR array, along with caspases activities assay. The compounds were also reported to significantly reduce several key gene expressions such as AKT1, BIRC5, CDK1 and NFκB1. The NF-κB signalling pathway was inhibited with the activation of Lys48-linked polyubiquitination thus led to NF-κB degradation. Conclusively, this study evidenced the anticancer property of C3, C4, C5 and C9 against breast cancer by initiating intrinsic and extrinsic apoptosis pathway and lays the foundation in the development of new bismuth based chemotherapeutic drugs. Breast Neoplasms Bismuth 2019-07 Thesis http://psasir.upm.edu.my/id/eprint/97788/ http://psasir.upm.edu.my/id/eprint/97788/1/FPSK%28p%29%202021%205%20IR.pdf text en public doctoral Universiti Putra Malaysia Breast Neoplasms Bismuth Abdul Hamid @ Abdul Razak, Roslida
institution	Universiti Putra Malaysia
collection	PSAS Institutional Repository
language	English
advisor	Abdul Hamid @ Abdul Razak, Roslida
topic	Breast Neoplasms Bismuth
spellingShingle	Breast Neoplasms Bismuth Chan, Pit Foong In vitro antiproliferative effects and underlying mechanismds of bismuth dithiocarbamate derivatives against breast cancer cell line
description	Drastic increment of cancer incidence in recent years has driven metal complexes including bismuth complexes as a promising approach in anticancer drug development due to its well-known low toxicity, environmental friendliness and medical therapeutic benefits The complexes with R= (CH2CH2OH)(iPr), Et2, (CH2)4 and (CH2CH2OH)(CH3) in bismuth-dithiocarbamate, Bi[S2CN-R]3 labelled as C3, C4, C5 and C9, have been studied, respectively. This study aimed at determining the antiproliferative effect of the bismuth complexes and their underlying mechanism(s) in breast cancer cell (MCF-7) through various in vitro assays. The antiproliferative effect of the bismuth complexes was studied using Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Apoptotic cell death activities of C3, C4, C5 and C9 were performed via DNA fragmentation, acridine orange/propidium iodide (AO/PI), Annexin V and caspase activity assays. Whilst, this study further employed Human Cancer Drug Targets RT² Profiler PCR array to study the expression of 84 actively sought targets for anticancer therapeutics and drug development to delineate the underlying mechanism(s). Results showed all tested compounds (C3, C4, C5 and C9) exhibited antiproliferative effects against MCF-7 cell line with IC50 of 10.33 ± 0.06 μM, 1.26 ± 0.02 μM, 1.07 ± 0.01 μM and 25.37 ± 0.12 μM, respectively. The morphology of apoptosis including formation of DNA fragments, phosphatidylserine translocation, chromatin condensation, and membrane blebbing was shown. The compounds were found to variably increase reactive oxygen species (ROS) generation thus increased mitochondrial membrane potential (MMP). Consequently, this led to the release of cytochrome c from mitochondria, demonstrated by the data obtained by flow cytometric analysis. All four tested compounds were revealed to induce both intrinsic and extrinsic apoptotic pathways, conferred by the data obtained from Human Cancer Drug Targets RT² Profiler PCR array, along with caspases activities assay. The compounds were also reported to significantly reduce several key gene expressions such as AKT1, BIRC5, CDK1 and NFκB1. The NF-κB signalling pathway was inhibited with the activation of Lys48-linked polyubiquitination thus led to NF-κB degradation. Conclusively, this study evidenced the anticancer property of C3, C4, C5 and C9 against breast cancer by initiating intrinsic and extrinsic apoptosis pathway and lays the foundation in the development of new bismuth based chemotherapeutic drugs.
format	Thesis
qualification_level	Doctorate
author	Chan, Pit Foong
author_facet	Chan, Pit Foong
author_sort	Chan, Pit Foong
title	In vitro antiproliferative effects and underlying mechanismds of bismuth dithiocarbamate derivatives against breast cancer cell line
title_short	In vitro antiproliferative effects and underlying mechanismds of bismuth dithiocarbamate derivatives against breast cancer cell line
title_full	In vitro antiproliferative effects and underlying mechanismds of bismuth dithiocarbamate derivatives against breast cancer cell line
title_fullStr	In vitro antiproliferative effects and underlying mechanismds of bismuth dithiocarbamate derivatives against breast cancer cell line
title_full_unstemmed	In vitro antiproliferative effects and underlying mechanismds of bismuth dithiocarbamate derivatives against breast cancer cell line
title_sort	in vitro antiproliferative effects and underlying mechanismds of bismuth dithiocarbamate derivatives against breast cancer cell line
granting_institution	Universiti Putra Malaysia
publishDate	2019
url	http://psasir.upm.edu.my/id/eprint/97788/1/FPSK%28p%29%202021%205%20IR.pdf
_version_	1747813806219722752

In vitro antiproliferative effects and underlying mechanismds of bismuth dithiocarbamate derivatives against breast cancer cell line

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