Use of Cobalt(III) and Copper(II) Complexes With Thiosemicarbazone Ligands and Berberine Chloride as Anti-Cancer Agents Against Triple Negative Breast Cancer

Author

Duaa Rashad Alajroush, Old Dominion UniversityFollow

Date of Award

Summer 2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry & Biochemistry

Program/Concentration

Chemistry

Committee Director

Alvin A. Holder

Committee Member

Stephen J. Beebe

Committee Member

James W. Lee

Committee Member

Steven M. Pascal

Abstract

It is a worrying fact that chemotherapeutic options for treating triple negative breast cancer are limited in nature, including the use of inorganic pharmaceuticals such as cisplatin and its analogues. It has been reported that cisplatin has undesirable side effects when used as a chemotherapeutic drug. As such, there is a need to use non-platinum-containing complexes as chemotherapeutic agents. Based on that issue, it has been reported by our research group and others that cobalt- and copper-containing complexes have shown great potential in anti-cancer properties when compared to cisplatin. In this research project, the cytotoxic effects of the following complexes: [Co(phen)2(MeATSC)](NO₃)₃•1.5H₂O•C₂H₅OH 1 (where phen = 1,10-phenanthroline and MeATSC = 9-anthraldehyde-N(4)-methylthiosemicarbazone) and [Cu(acetylethTSC)Cl]Cl•0.25C₂H₅OH 2 (where acetylethTSC = (E)-N-ethyl-2-[1-(thiazol-2- yl)ethylidene]hydrazinecarbothioamide) were carried out on cancer MDA-MB-231 VIM RFP and non-cancer MCF-10A cell lines by using the CCK-8 viability assay.

Moreover, the cell death mechanisms induced after treatment with the complexes were investigated in cancer cells. From the data acquired via in vitro studies, the IC₅₀ values of complex 1 were 17.59 and 61.26 μM in cancer and non-cancer cells, respectively. The IC₅₀ values of complex 2 were 5.63 and 12.19 μM for cancer and non-cancer cells, respectively. Complex 1 induced cancer cell death via activation of oxidative stress which activated apoptosis and pyroptosis; while complex 2 induced cell cycle arrest in the S phase and DNA cleavage.

Furthermore, the copper(II) complex [Cu(chromoneTSC)Cl_2]•5H₂O•0.0625C₂H₅OH 3 (where chromneTSC = (E)-N-Ethyl-2-((4-oxo-4H-chromen-3-yl)methylene)- hydrazinecarbothioamide) was synthesized and characterized; then used to carry out in vitro studies in combination with berberine chloride (BBC). The combination treatment significantly inhibited the proliferation of breast cancer cells in a dose- and time-dependent manner with a lower cytotoxic effect on non-cancer cells. The co-treatment group significantly increased the number of cells in G2 phase, indicating the growth arrest of cancer cells. Moreover, the combination group showed induction of both intrinsic and extrinsic apoptotic pathways. The results also showed induction of necroptosis via the activation of RIPK3-MLKL pathway.

Rights

In Copyright.

URI: http://rightsstatements.org/vocab/InC/1.0/ This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).

DOI

10.25777/gknk-9k91

ISBN

9798384454267

Recommended Citation

Alajroush, Duaa R.. "Use of Cobalt(III) and Copper(II) Complexes With Thiosemicarbazone Ligands and Berberine Chloride as Anti-Cancer Agents Against Triple Negative Breast Cancer" (2024). Doctor of Philosophy (PhD), Dissertation, Chemistry & Biochemistry, Old Dominion University, DOI: 10.25777/gknk-9k91
https://digitalcommons.odu.edu/chemistry_etds/224