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. The existence of cancer stem cells (CSCs) is related to metastasis and relapse. A series of four‐coordinate silver(I) complexes containing non‐steroidal anti‐inflammatory drugs and triphenylphosphine is reported to kill breast CSCs grown in monolayers and three‐dimensional cultures within the micromolar range. The silver(I) complexes interact with thiol‐containing biomolecules and elevate intracellular reactive oxygen species levels in CSCs.