Jarman, P., Noakes, F., Fairbanks, S. et al. (5 more authors) (2019) Exploring the cytotoxicity, uptake, cellular response, and proteomics of mono- and dinuclear DNA light-switch complexes. Journal of the American Chemical Society, 141 (7). pp. 2925-2937. ISSN 0002-7863
Abstract
Drug resistance to platinum chemotherapeutics targeting DNA often involves abrogation of apoptosis, and has emerged as a significant challenge in modern, non-targeted chemotherapy. Consequently, there is great interest in the anti-cancer properties of metal complexes - particularly those that interact with DNA - and mechanisms of consequent cell death. Herein we compare a parent cytotoxic complex [Ru(phen)2(tpphz)]2+ [phen = 1,10-phenanthroline, tpphz = tetrapyridyl [3,2-a:2',3'-c:3'',2''-h:2''',3'''-j] phenazine], with a mononuclear analogue with modified intercalating ligand, [Ru(phen)2(taptp)]2+,[taptp = 4,5,9,18-tetraazaphenanthreno[9,10-b] triphenylene], and two structurally related di-nuclear, tpphz-bridged, heterometallic complexes, RuRe and RuPt. These changes result in a switch from intercalation to groove binding DNA interaction, concomitant reduction in cytotoxic potency, but no significant change in relative cytotoxicity toward platinum-resistant A2780CIS cancer cells, indicating that DNA interaction mode is not critical for the mechanism of platinum resistance. All variants exhibited a light-switch effect, which for the first time, was exploited to investigate timing of cell death by live cell microscopy. Surprisingly, cell death occurred rapidly as a consequence of oncosis, characterized by loss of cytoplasmic volume control, absence of significant mitochondrial membrane potential loss, and lack of activation of apoptotic cell death markers. Importantly, a novel, quantitative proteomic analysis of the A2780 cell genome following exposure to either mononuclear complex reveals changes in protein expression associated with global cell responses to oxidative stress, and DNA replication/repair cellular pathways. This combination of a multiple targeting modality and induction of a non-apoptotic death mechanism makes these complexes highly promising chemotherapeutic cytotoxicity leads.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 American Chemical Society. This is an author produced version of a paper subsequently published in Journal of the American Chemical Society. Uploaded in accordance with the publisher's self-archiving policy. |
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 ENGINEERING AND PHYSICAL SCIENCE RESEARCH COUNCIL (EPSRC) UNSPECIFIED |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 14 Jan 2019 10:37 |
Last Modified: | 25 Nov 2021 10:04 |
Status: | Published |
Publisher: | American Chemical Society |
Refereed: | Yes |
Identification Number: | 10.1021/jacs.8b09999 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:140791 |