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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Induction of Apoptosis and Autophagy by Ternary Copper Complex Towards Breast Cancer Cells

Author(s): Zheng Yang Lee, Chee Hong Leong, Krystal U. Ling Lim, Christopher Chun Sing Wong, Pornwasu Pongtheerawan, Sathiavani A. Arikrishnan, Kian Leong Tan, Jian Sheng Loh, May Lee Low, Chee Wun How, Yong Sze Ong, Yin Sim Tor and Jhi Biau Foo*

Volume 22, Issue 6, 2022

Published on: 26 July, 2021

Page: [1159 - 1170] Pages: 12

DOI: 10.2174/1871520621666210726132543

Price: $65

Abstract

Background: Copper complex has been gaining much attention in anticancer research as a targeted agent since cancer cells uptake more copper than non-cancerous cells. Our group synthesised a ternary copper complex, which is composed of 1,10-phenanthroline and tyrosine [Cu(phen)(L-tyr)Cl].3H20. These two payloads have been designed to cleave DNA and inhibit protein degradation system (proteasome) concurrently in cancer cells, making this copper complex a dual-target compound.

Objective: The current study was carried out to investigate the mode of cell death and the role of autophagy induced by [Cu(phen)(L-tyr)Cl].3H20 in MCF-7 and MDA-MB-231 breast cancer cells.

Methods: Growth inhibition of [Cu(phen)(L-tyr)Cl].3H20 towards MDA-MB-231 and human non-cancerous MCF10A breast cells was determined by MTT assay. Annexin-V-FITC/PI and cell cycle analysis were evaluated by flow cytometry. The expression of p53, Bax, caspase-9, caspase-7, caspase-3 and LC3 was determined using western blot analysis. The cells were then co-treated with hydroxychloroquine to ascertain the role of autophagy induced by [Cu(phen)(L-tyr)Cl].3H20.

Results: [Cu(phen)(L-tyr)Cl].3H20 inhibited the growth of cancer cells dose-dependently with less toxicity towards MCF10A cells. Additionally, [Cu(phen)(L-tyr)Cl].3H20 induced apoptosis and cell cycle arrest towards MCF-7 and MDA-MB-231 breast cancer cells possibly via regulation of p53, Bax, caspase-9, caspase-3 and capase-7. The expression of LC3II was upregulated in both cancer cell lines upon treatment with [Cu(phen)(L-tyr) Cl].3H20, indicating the induction of autophagy. Co-treatment with autophagy inhibitor hydroxychloroquine significantly enhanced growth inhibition of both cell lines, suggesting that autophagy induced by [Cu(phen)(L-tyr) Cl].3H20 in both breast cancer cells promoted cell survival.

Conclusion: [Cu(phen)(L-tyr)Cl].3H20 holds great potential to be developed for breast cancer treatment.

Keywords: Breast cancer, copper complex, apoptosis, cell cycle arrest, autophagy, p53.

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