A Breast Cancer Stem Active Cobalt(III)‐Cyclam Complex Containing Flufenamic Acid with Immunogenic Potential

Abstract The cytotoxic and immunogenic‐activating properties of a cobalt(III)‐cyclam complex bearing the non‐steroidal anti‐inflammatory drug, flufenamic acid is reported within the context of anti‐cancer stem cell (CSC) drug discovery. The cobalt(III)‐cyclam complex 1 displays sub‐micromolar potency towards breast CSCs grown in monolayers, 24‐fold and 31‐fold greater than salinomycin (an established anti‐breast CSC agent) and cisplatin (an anticancer metallopharmaceutical), respectively. Strikingly, the cobalt(III)‐cyclam complex 1 is 69‐fold and 50‐fold more potent than salinomycin and cisplatin towards three‐dimensionally cultured breast CSC mammospheres. Mechanistic studies reveal that 1 induces DNA damage, inhibits cyclooxygenase‐2 expression, and prompts caspase‐dependent apoptosis. Breast CSCs treated with 1 exhibit damage‐associated molecular patterns characteristic of immunogenic cell death and are phagocytosed by macrophages. As far as we are aware, 1 is the first cobalt complex of any oxidation state or geometry to display both cytotoxic and immunogenic‐activating effects on breast CSCs.