Porto González, VanesaBuceta Fernández, DavidDomínguez Loidi, BlancaCarneiro Freire, María del CarmenBorrajo Alonso, EreaFraile Piñeiro, MaríaDavila Ferreira, NereaRodríguez Arias, IriaBlanco Trillo, José ManuelBlanco Varela, María del CarmenDevida, Juan MarceloGiovanetti, Lisandro JoséRequejo, Félix GregorioHernández Garrido, Juan CarlosCalvino Gámez, José JuanLópez Haro, MiguelBarone, GiampaoloJames, Andrew M.García-Caballero Parada, TomásGonzález Castaño, Diego MiguelTreder, MartinHuber, WolfgangVidal Figueroa, AnxoMichael, P. MurphyLópez Quintela, Manuel ArturoDomínguez Puente, Fernando Ignacio2022-09-192022-09-192022Porto, V., Buceta, D., Domínguez, B., Carneiro, C., Borrajo, E., Fraile, M., . . . Domínguez, F. (2022). Silver clusters of five atoms as highly selective antitumoral agents through irreversible oxidation of thiols. Advanced Functional Materials, 32(29), 2113028-n/a1616-301Xhttp://hdl.handle.net/10347/29229Low 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 therapyeng© 2022 The Authors. Advanced Functional Materials published by Wiley-VCH GmbH This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly citedAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Cancer therapyCatalysisLow atomicity clustersSilver clustersSulfur oxidationjournal article10.1002/adfm.2021130281616-3028open access