Jhetam, Z., Martins-Furness, C., Slabber, C. et al. (3 more authors) (2025) Copper complexes induce haem oxygenase-1 (HMOX1) and cause apoptotic cell death in pancreatic cancer cells. Journal of Inorganic Biochemistry, 264. 112815. ISSN 0162-0134
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic malignancy, has a dismal 5-year survival rate, making palliative chemotherapy the only treatment option. Targeted therapy has limited efficacy in PDAC, underscoring the need for novel therapeutic approaches. The inducible stress-response protein, haem oxygenase-1 (HMOX1), has been implicated in treatment failure in PDAC. Copper coordination complexes have shown promise as anticancer agents against various cancers, and are associated with apoptotic cell death. The different ligands to which copper is complexed, determine the specificity and efficacy of each complex. Three different classes of copper complexes were evaluated for anti-cancer activity against AsPC-1 and MIA PaCa-2 pancreatic cancer cell lines. A copper-phenanthroline-theophylline complex (CuPhTh2), a copper-8-aminoquinoline-naphthyl complex (Cu8AqN), and two copper-aromatic-isoindoline complexes (CuAIsI) were effective inhibitors of cell proliferation with clinically relevant IC50 values below 5 μM. The copper complexes caused reactive oxygen species (ROS) formation, promoted annexin-V binding, disrupted the mitochondrial membrane potential (MMP) and activated caspase-9 and caspase-3/7, confirming apoptotic cell death. Expression of nuclear HMOX1 was increased in both cell lines, with the CuPhTh2 complex being the most active. Inhibition of HMOX1 activity significantly decreased the IC50 values of these copper complexes suggesting that HMOX1 inhibition may alter treatment outcomes in PDAC.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
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-ND 4.0). |
Keywords: | Pancreatic cancer, Haem oxygenase-1, Copper complexes, Intrinsic apoptosis |
Dates: |
|
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: | 02 Jan 2025 14:48 |
Last Modified: | 02 Jan 2025 14:48 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.jinorgbio.2024.112815 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:221145 |