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The Osteosarcoma Stem Cell Activity of a Gallium(III)‐Phenanthroline Complex Appended to Salicylate

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Osteosarcoma is the most commonly diagnosed primary bone cancer and has strikingly low survival rates. Here we report the anti-osteosarcoma properties of a six-coordinate gallium(III) complex with two polypridyl ligands and salicylate, a non-steroidal anti-inflammatory drug. The gallium(III) complex kills bulk osteosarcoma cells and osteosarcoma stem cells in the micromolar range by evoking apoptosis through DNA damage and cyclooxygenase-2 downregulation.


Abstract

We report the synthesis, characterisation, and anti-osteosarcoma properties of a gallium(III) complex (1) comprising of two 1,10-phenanthroline ligands and salicylate, a non-steroidal anti-inflammatory drug. The gallium(III) complex 1 displays micromolar potency towards bulk osteosarcoma cells and osteosarcoma stem cells (OSCs). Notably, the gallium(III) complex 1 exhibits significantly higher toxicity towards OSCs grown in monolayer and three-dimensional cultures than cisplatin, a frontline anti-osteosarcoma drug. Nuclei isolation and immunoblotting studies show that the gallium(III) complex 1 enters osteosarcoma cell nuclei and induces DNA damage. Flow cytometry and cytotoxicity studies (in the presence of prostaglandin E2) indicate that the gallium(III) complex 1 downregulates cyclooxygenase-2 (COX-2) expression and kills osteosarcoma cells in a COX-2-dependent manner. Further, the mode of osteosarcoma cell death evoked by the gallium(III) complex 1 is characterised as caspase-dependent apoptosis.

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