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. image