Silver Clusters of Five Atoms as Highly Selective Antitumoral Agents Through Irreversible Oxidation of Thiols

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 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 ≪ H 2 O 2 < 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, 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.