Anti‐Breast Cancer Stem Cell Properties of Silver(I)‐Non‐Steroidal Anti‐Inflammatory Drug Complexes

The synthesis and characterisation of a series of silver(I) complexes (1–7) containing non‐steroidal anti‐inflammatory drugs (NSAIDs) and triphenylphosphine ligands is reported. The diclofenac‐containing silver(I) complex 1 exhibits micromolar potency towards bulk breast cancer cells and breast cancer stem cells (CSCs) cultured in monolayers. Notably, the silver(I) complex 1 displays up to 9.4‐fold higher potency towards three‐dimensional mammospheres than cisplatin (a clinically used anticancer metallodrug) and salinomycin (a breast‐CSC active small molecule). Mechanistic studies show that the silver(I) complex 1 readily interacts with thiol‐containing biomolecules in solution and elevates intracellular reactive oxygen species levels in breast CSCs. Interestingly the silver(I) complex 1 does not perturb cyclooxygenase‐2 (COX‐2) expression in breast CSCs and its cytotoxicity is unaffected in the presence of prostaglandin E2, implicative of a COX‐2 independent mechanism of action.