Induction of Redox-Mediated Cell Death in ER-Positive and ER-Negative Breast Cancer Cells by a Copper(II)-Phenolate Complex: An In Vitro and In Silico Study

Vaiyapuri Subbarayan Periasamy; Anvarbatcha Riyasdeen; Venugopal Rajendiran; Mallayan Palaniandavar; Hanumanthappa Krishnamurthy; Ali Abdullah Alshatwi; Mohammad Abdulkader Akbarsha

doi:10.3390/molecules25194504

Induction of Redox-Mediated Cell Death in ER-Positive and ER-Negative Breast Cancer Cells by a Copper(II)-Phenolate Complex: An In Vitro and In Silico Study

Molecules. 2020 Oct 1;25(19):4504. doi: 10.3390/molecules25194504.

Authors

Vaiyapuri Subbarayan Periasamy^{1

2}, Anvarbatcha Riyasdeen¹, Venugopal Rajendiran³, Mallayan Palaniandavar⁴, Hanumanthappa Krishnamurthy⁵, Ali Abdullah Alshatwi², Mohammad Abdulkader Akbarsha^{6

7}

Affiliations

¹ Department of Animal Science, Bharathidasan University, Tiruchirappalli 620024, India.
² Department of Food and Nutrition, College of Food and Agricultural Sciences, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia.
³ Department of Chemistry, School of Basic and Applied Sciences, Central University of Tamil Nadu, Thiruvarur 610005, India.
⁴ Department of Chemistry, Bharathidasan University, Tiruchirappalli 620024, India.
⁵ National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore 560065, India.
⁶ Mahatma Gandhi-Doerenkamp Center (MGDC) for Alternatives to Use of Animals in Life Science Education, Bharathidasan University, Tiruchirappalli 620024, India.
⁷ Research Co-ordinator, National College (Autonomous), Tiruchirappalli 620001, India.

Abstract

This research was aimed at finding the cytotoxic potential of the mixed ligand copper(II) complex [Cu(tdp)(phen)](ClO₄)-where H(tdp) is the tetradentate ligand 2-[(2-(2-hydroxyethylamino)-ethylimino)methyl]phenol, and phen is 1,10-phenanthroline-to two genotypically different breast cancer cells, MCF-7 (p53⁺ and ER⁺) and MDA-MB-231 (p53^- and ER^-). The complex has been already shown to be cytotoxic to ME180 cervical carcinoma cells. The special focus in this study was the induction of cell death by apoptosis and necrosis, and its link with ROS. The treatment brought about nuclear fragmentation, phosphatidylserine externalization, disruption of mitochondrial trans-membrane potential, DNA damage, cell cycle arrest at sub-G1 phase, and increase of ROS generation, followed by apoptotic death of cells during early hours and a late onset of necrosis in the cells surviving the apoptosis. The efficacy of the complex against genotypically different breast cancer cells is attributed to a strong association through p53-mitochondrial redox-cell cycle junction. The ADMET properties and docking of the complex at the active site of Top1 are desirable attributes of a lead molecule for development into a therapeutic. Thus, it is shown that the copper(II)-phenolate complex[Cu(tdp)(phen)]⁺ offers potential to be developed into a therapeutic for breast cancers in general and ER-negative ones in particular.

Keywords: ROS; anticancer agents; apoptosis; breast cancer; cell cycle arrest; copper(II)-phenolate complex; necrosis.

MeSH terms

Breast Neoplasms / pathology*
Cell Cycle / drug effects
Cell Death / drug effects
Cell Line, Tumor
Comet Assay
Computer Simulation*
Copper / pharmacology*
DNA Breaks, Double-Stranded / drug effects
DNA Damage
DNA, Neoplasm / metabolism
Female
Fluorescence
Humans
Hydroxybenzoates / pharmacology*
Membrane Potential, Mitochondrial / drug effects
Molecular Docking Simulation
Oxidation-Reduction
Reactive Oxygen Species / metabolism
Receptors, Estrogen / metabolism*
Staining and Labeling

Substances

DNA, Neoplasm
Hydroxybenzoates
Reactive Oxygen Species
Receptors, Estrogen
Copper
phenolic acid