%0 Journal Article 
%A Porto, Vanesa
%A Buceta, David
%A Domínguez, Blanca
%A Carneiro, Carmen
%A Borrajo, Erea
%A Fraile, María
%A Davila-Ferreira, Nerea
%A Arias, Iria R.
%A Blanco, José M.
%A Blanco, María C.
%A Devida, Juan M.
%A Giovanetti, Lisandro J.
%A Requejo, Félix G.
%A Hernández Garrido, Juan Carlos
%A Calvino Gámez, José Juan
%A López Haro, Miguel
%A Barone, Giampaolo
%A James, Andrew M.
%A García-Caballero, Tomás
%A González-Castaño, Diego M.
%A Treder, Martin
%A Huber, Wolfgang
%A Vidal, Anxo
%A Murphy, Michael P.
%A López-Quintela, M. Arturo
%A Domínguez, Fernando
%T Silver Clusters of Five Atoms as Highly Selective Antitumoral Agents Through Irreversible Oxidation of Thiols
%D 2022
%@ 1616-301X
%U http://hdl.handle.net/10498/27244
%X 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 Ag-5 clusters catalyze the complete oxidation of sulfur to S+6. Ag-5 catalytic activity increases with different oxidant species in the order O-2 MUCH LESS-THAN H2O2 < OH center dot. 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, Ag-5 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 (HRAS(G12V)) or through ARID1A mutation, sensitizes cells to Ag-5 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. Ag-5 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 Ag-5 may lead to new redox-based approaches to cancer therapy.
%~ Universidad de Cádiz