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Osteosarcoma Stem Cell Potent Gallium(III)‐Polypyridyl Complexes Bearing Diflunisal
Author(s) -
Xiao Zhiyin,
Passeri Ginevra,
NorthcoteSmith Joshua,
Singh Kuldip,
Suntharalingam Kogularamanan
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202102207
Subject(s) - osteosarcoma , carboplatin , cisplatin , chemistry , cancer research , doxorubicin , potency , apoptosis , stem cell , etoposide , pharmacology , in vitro , biochemistry , medicine , chemotherapy , microbiology and biotechnology , biology
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.