Exploring the cytotoxicity, uptake, cellular response, and proteomics of mono- and dinuclear DNA light-switch complexes.

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2018
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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.
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jarman2018exploring Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Jarman, Paul James;Noakes, Felicity;Fairbanks, Simon;Smitten, Kirsty;Griffiths, Isabel;Saeed, Hiwa;Thomas, Jim Antony;Smythe, Carl G W;
Journal Journal of the American Chemical Society
Year 2018
DOI
10.1021/jacs.8b09999
URL
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