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An 8-aminoquinoline-naphthyl copper complex causes apoptotic cell death by modulating the expression of apoptotic regulatory proteins in breast cancer cells.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2024 Sep 05; Vol. 978, pp. 176764. Date of Electronic Publication: 2024 Jun 20. - Publication Year :
- 2024
-
Abstract
- Breast cancer is one of the most common cancers globally and a leading cause of cancer-related deaths among women. Despite the combination of chemotherapy with targeted therapy, including monoclonal antibodies and kinase inhibitors, drug resistance and treatment failure remain a common occurrence. Copper, complexed to various organic ligands, has gained attention as potential chemotherapeutic agents due to its perceived decreased toxicity to normal cells. The cytotoxic efficacy and the mechanism of cell death of an 8-aminoquinoline-naphthyl copper complex (Cu8AqN) in MCF-7 and MDA-MB-231 breast cancer cell lines was investigated. The complex inhibited the growth of MCF-7 and MDA-MB-231 cells with IC <subscript>50</subscript> values of 2.54 ± 0.69 μM and 3.31 ± 0.06 μM, respectively. Nuclear fragmentation, annexin V binding, and increased caspase-3/7 activity indicated apoptotic cell death. The loss of mitochondrial membrane potential, an increase in caspase-9 activity, the absence of active caspase-8 and a decrease of tumour necrosis factor receptor 1(TNFR1) expression supported activation of the intrinsic apoptotic pathway. Increased ROS formation and increased expression of haem oxygenase-1 (HMOX-1) indicated activation of cellular stress pathways. Expression of p21 protein in the nuclei was increased indicating cell cycle arrest, whilst the expression of inhibitor of apoptosis proteins (IAPs); cIAP1, XIAP and survivin were decreased, creating a pro-apoptotic environment. Phosphorylated p53 species; phospho-p53(S15), phospho-p53(S46), and phospho-p53(S392) accumulated in MCF-7 cells indicating the potential of Cu8AqN to restore p53 function in the cells. In combination, the data indicates that Cu8AqN is a useful lead molecule worthy of further exploration as a potential anti-cancer drug.<br />Competing Interests: Declaration of competing interest None.<br /> (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
MCF-7 Cells
Cell Line, Tumor
Female
Reactive Oxygen Species metabolism
Gene Expression Regulation, Neoplastic drug effects
Membrane Potential, Mitochondrial drug effects
Cell Proliferation drug effects
Naphthalenes pharmacology
Apoptosis drug effects
Breast Neoplasms pathology
Breast Neoplasms drug therapy
Breast Neoplasms metabolism
Copper pharmacology
Copper chemistry
Aminoquinolines pharmacology
Apoptosis Regulatory Proteins metabolism
Antineoplastic Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 978
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38908670
- Full Text :
- https://doi.org/10.1016/j.ejphar.2024.176764