Osteosarcoma Stem Cell Potent Gallium(III)-Polypyridyl Complexes Bearing Diflunisal.
Zhiyin XiaoGinevra PasseriJoshua Northcote-SmithKuldip SinghKogularamanan SuntharalingamPublished in: Chemistry (Weinheim an der Bergstrasse, Germany) (2021)
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.
Keyphrases
- induced apoptosis
- cell cycle arrest
- stem cells
- dna damage
- endoplasmic reticulum stress
- cell death
- oxidative stress
- anti inflammatory
- signaling pathway
- pi k akt
- healthcare
- randomized controlled trial
- emergency department
- squamous cell carcinoma
- nitric oxide
- drug delivery
- mesenchymal stem cells
- drug induced
- rectal cancer
- copy number
- electronic health record
- genome wide
- nitric oxide synthase