Silver Clusters of Five Atoms as Highly Selective Antitumoral Agents Through Irreversible Oxidation of Thiols
Authors
Porto, V
Buceta, D
Domínguez, B
Carneiro, C
Borrajo, E
Fraile, M
Davila-Ferreira, N
Arias, IR
Blanco, JM
Blanco, MC
Devida, JM
Giovanetti, LJ
Requejo, FG
Hernández-Garrido, JC
Calvino, JJ
López-Haro, M
Barone, G
James, AM
García-Caballero, T
González-Castaño, DM
Treder, M
Huber, W
Vidal, A
Murphy, MP
Domínguez, F
Publication Date
2022Journal Title
Advanced Functional Materials
ISSN
1616-301X
Publisher
Wiley
Language
en
Type
Article
This Version
AO
VoR
Metadata
Show full item recordCitation
Porto, V., Buceta, D., Domínguez, B., Carneiro, C., Borrajo, E., Fraile, M., Davila-Ferreira, N., et al. (2022). Silver Clusters of Five Atoms as Highly Selective Antitumoral Agents Through Irreversible Oxidation of Thiols. Advanced Functional Materials https://doi.org/10.1002/adfm.202113028
Abstract
Abstract: Low atomicity clusters present properties dependent on the size, due to the quantum confinement, with well‐defined electronic structures and high stability. Here it is shown that Ag5 clusters catalyze the complete oxidation of sulfur to S+6. Ag5 catalytic activity increases with different oxidant species in the order O2 ≪ H2O2 < OH•. Selective oxidation of thiols on the cysteine residues of glutathione and thioredoxin is the primary mechanism human cells have to maintain redox homeostasis. Contingent upon oxidant concentration, Ag5 catalyzes the irreversible oxidation of glutathione and thioredoxin, triggering apoptosis. Modification of the intracellular environment to a more oxidized state to mimic conditions within cancer cells through the expression of an activated oncogene (HRASG12V) or through ARID1A mutation, sensitizes cells to Ag5 mediated apoptosis. While cancers evolve to evade treatments designed to target pathways or genetic mutations that drive them, they cannot evade a treatment that takes advantage of aberrant redox homeostasis, which is essential for tumor progression and metastasis. Ag5 has antitumor activity in mice with orthotopic lung tumors reducing primary tumor size, and the burden of affected lymphatic nodes. The findings suggest the unique intracellular redox chemistry of Ag5 may lead to new redox‐based approaches to cancer therapy.
Keywords
Research Article, Research Articles, cancer therapy, catalysis, low atomicity clusters, silver clusters, sulfur oxidation
Sponsorship
Medical Research Council (MC_U105663142)
European Commission Horizon 2020 (H2020) Research Infrastructures (RI) (823717)
Identifiers
adfm202113028
External DOI: https://doi.org/10.1002/adfm.202113028
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335098
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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