Myeza, N. orcid.org/0000-0003-3671-637X, Slabber, C. orcid.org/0000-0002-6045-7382, Munro, O.Q. orcid.org/0000-0001-8979-6321 et al. (4 more authors) (2024) An 8-aminoquinoline-naphthyl copper complex causes apoptotic cell death by modulating the expression of apoptotic regulatory proteins in breast cancer cells. European Journal of Pharmacology, 978. 176764. ISSN 0014-2999
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 IC50 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors.This is an open access article under the terms of the Creative Commons Attribution License (CC-BY-NC 4.0). |
Keywords: | 8-aminoquinoline-naphthyl-copper complex; apoptosis; inhibitor of apoptosis proteins; haem oxygenase-1; breast cancer |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Physical Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 24 Jun 2024 14:47 |
Last Modified: | 22 Jul 2024 13:30 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.ejphar.2024.176764 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:213751 |