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2022-07-04Rights
(c) 2022 The Authors. This is an Open Access article distributed under the Creative Commons CC-BY license (https://creativecommons.org/licenses/by/4.0/)Peer-Reviewed
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openAccessAccepted for publication
2022-06-21
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When the 'CO-releasing molecule-3', CORM-3 (Ru(CO)3Cl(glycinate)), is dissolved in water it forms a range of ruthenium complexes. These are taken up by cells and bind to intracellular ligands, notably thiols such as cysteine and glutathione, where the Ru(II) reaches high intracellular concentrations. Here, we show that the Ru(II) ion also binds to DNA, at exposed guanosine N7 positions. It therefore has a similar cellular target to the anticancer drug cisplatin, but not identical, because Ru(II) shows no evidence of forming intramolecular crossbridges in the DNA. The reaction is slow, and with excess Ru, intermolecular DNA crossbridges are formed. The addition of CORM-3 to human colorectal cancer cells leads to strand breaks in the DNA, as assessed by the alkaline comet assay. DNA damage is inhibited by growth media containing amino acids, which bind to extracellular Ru and prevent its entry into cells. We conclude that the cytotoxicity of Ru(II) is different from that of platinum, making it a promising development target for cancer therapeutics.Version
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Lyon RF, Southam HM, Trevitt CR et al (2022) CORM-3 induces DNA damage through Ru(II) binding to DNA. Biochemical Journal. 479(13): 1429-1439.Link to Version of Record
https://doi.org/10.1042/bcj20220254Type
Articleae974a485f413a2113503eed53cd6c53
https://doi.org/10.1042/bcj20220254