Osteosarcoma Stem Cell Potent Gallium(III)‐Polypyridyl Complexes Bearing Diflunisal

We report the anti‐osteosarcoma stem cell (OSC) properties of a series of gallium(III)‐polypyridyl complexes (5‐7) containing diflunisal, a non‐steroidal anti‐inflammatory drug. The most effective complex within the series, 6 (containing 3,4,7,8‐tetramethyl‐1,10‐phenanthroline), displayed similar potency towards bulk osteosarcoma cells and OSCs, in the nanomolar range. Remarkably, 6 exhibited significantly higher monolayer and sarcosphere OSC potency (up to three orders of magnitude) than clinically approved drugs used in frontline (cisplatin and doxorubicin) and secondary (etoposide, ifosfamide, and carboplatin) osteosarcoma treatments. Mechanistic studies show that 6 downregulates cyclooxygenase‐2 (COX‐2) and kills osteosarcoma cells in a COX‐2 dependent manner. Furthermore, 6 induces genomic DNA damage and caspase‐dependent apoptosis. To the best of our knowledge, 6 is the first metal complex to kill osteosarcoma cells by simultaneously inhibiting COX‐2 and damaging nuclear DNA. Breaking ‘hard‐to‐kill’ bone cancer cells with gallium: Osteosarcoma stem cells (OSCs) are linked to the poor prognosis of metastasised osteosarcoma. Here a gallium(III)‐polypyridyl complex is reported, containing the non‐steroidal anti‐inflammatory drug, diflunisal, capable of killing OSCs more effectively than frontline and secondary anti‐osteosarcoma drugs. The complex evokes cell death by inhibiting cyclooxygenase‐2 and damaging nuclear DNA.