期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 27, 期 55, 页码 13846-13854出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202102207
关键词
antitumour agents; COX-2 inhibition; DNA damage; gallium; osteosarcoma stem cells
资金
- EPSRC New Investigator Award [EP/S005544/1]
- National Natural Science Foundation of China [21807047]
- EPSRC [EP/S005544/1] Funding Source: UKRI
In this study, a series of gallium-polypyridyl complexes were found to possess anti-osteosarcoma stem cell properties, with complex 6 showing high potency by simultaneously inhibiting COX-2 and damaging nuclear DNA to kill osteosarcoma cells effectively.
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.
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