Dual-Action NSAID-Gold(I) Alkynyl Hybrids for Synergistic Anti-Inflammatory and Anticancer Therapy of Colorectal Cancer

Sáez, Javier ; Herrera-Marcos, Luis Vicente (Universidad de Zaragoza) ; Rodríguez-Yoldi, María Jesús (Universidad de Zaragoza) ; Gimeno, M. Concepción ; Cerrada, Elena (Universidad de Zaragoza)

Resumen: Colorectal cancer (CRC) remains a major global health challenge, in which chronic inflammation and redox dysregulation are key drivers of tumor progression. Here, we report a rationally designed family of NSAID-derived alkyne ligands coordinated to JohnPhos–gold(I) fragments, affording eight new alkynyl gold(I) derivatives. Complexes based on naproxen, ibuprofen, and salicylic acid derivatives display potent antiproliferative activity against Caco-2/TC7 colon cancer cells, outperforming oxaliplatin and being comparable to auranofin, while showing markedly reduced cytotoxicity in breast cancer lines and nonmalignant cells, thus indicating promising selectivity. Mechanistic studies revealed that the most active complex, [Au(L1)JP] (1), which contains a naproxen-derived alkyne, inhibits thioredoxin reductase (TrxR), triggers ROS overproduction, disrupts mitochondrial membrane potential, and induces G1-phase arrest while only marginally increasing apoptosis. This suggests the involvement of additional forms of cell death or cytostatic effects. Additionally, complex 1 selectively inhibits the enzyme cyclooxygenase-2 (COX-2) over COX-1 and reduces IL-8 expression without affecting PTGS2 transcription, highlighting a post-transcriptional anti-inflammatory action. These results support NSAID-derived alkynyl gold(I) complexes as promising multitarget agents for colorectal cancer intervention, combining disruption and COX-2 modulation.

Idioma: Inglés

DOI: 10.1021/acs.inorgchem.5c05908

Año: 2026

Publicado en: Inorganic Chemistry 65, 13 (2026), 7210-7223
ISSN: 0020-1669

Financiación: info:eu-repo/grantAgreement/ES/CIBERObn/CB06-03-1012
Financiación: info:eu-repo/grantAgreement/ES/DGA/B16-23R
Financiación: info:eu-repo/grantAgreement/ES/DGA/E07-23R
Financiación: info:eu-repo/grantAgreement/ES/MICIU AEI/PID2022-136861NB-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Química Inorgánica (Dpto. Química Inorgánica)
Área (Departamento): Área Fisiología (Dpto. Farmac.Fisiol.y Med.L.F.)
Área (Departamento): Área Farmacología (Dpto. Farmac.Fisiol.y Med.L.F.)