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

Anticancer Agents Med Chem. 2022;22(6):1159-1170. doi: 10.2174/1871520621666210726132543.

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; apoptosis; autophagy; cell cycle arrest; copper complex; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Autophagy
  • Breast Neoplasms* / drug therapy
  • Caspase 3
  • Caspase 9
  • Cell Line, Tumor
  • Cell Proliferation
  • Copper* / pharmacology
  • Female
  • Humans
  • Hydroxychloroquine
  • MCF-7 Cells
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein

Substances

  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • Hydroxychloroquine
  • Copper
  • Caspase 3
  • Caspase 9