Lyon, R.F., Southam, H.M., Trevitt, C.R. et al. (4 more authors) (2022) CORM-3 induces DNA damage through Ru(II) binding to DNA. Biochemical Journal, 479 (13). pp. 1429-1439. ISSN 0264-6021
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | cancer; cisplatin; CORM; DNA damage; NMR; ruthenium |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) |
Funding Information: | Funder Grant number WELLCOME TRUST (THE) 103844/Z/14/Z BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/P007066/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 03 Nov 2022 11:35 |
Last Modified: | 03 Nov 2022 11:35 |
Status: | Published |
Publisher: | Portland Press Ltd. |
Refereed: | Yes |
Identification Number: | 10.1042/bcj20220254 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:192930 |