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Exploring the Cytotoxicity, Uptake, Cellular Response, and Proteomics of Mono- and Dinuclear DNA Light-Switch Complexes

Author:
Jarman, Paul J., Noakes, Felicity, Fairbanks, Simon, Smitten, Kirsty, Griffiths, Isabel K., Saeed, Hiwa K., Thomas, Jim A., Smythe, Carl
Source:
Journal of the American Chemical Society 2018 v.141 no.7 pp. 2925-2937
ISSN:
1520-5126
Subject:
DNA, DNA replication, antineoplastic activity, apoptosis, cytotoxicity, death, drug resistance, drug therapy, genome, ligands, membrane potential, microscopy, mitochondrial membrane, neoplasm cells, neoplasms, oxidative stress, platinum, protein synthesis, proteomics
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 a modified intercalating ligand, [Ru(phen)₂(taptp)]²⁺ [taptp = 4,5,9,18-tetraazaphenanthreno[9,10-b] triphenylene], and two structurally related dinuclear, tpphz-bridged, heterometallic complexes, RuRe and RuPt. All three of these structural changes result in a switch from intercalation to groove-binding DNA interaction and concomitant reduction in cytotoxic potency, but no significant change in relative cytotoxicity toward platinum-resistant A2780CIS cancer cells, indicating that the 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 of the cells 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 multiple targeting modalities and induction of a non-apoptotic death mechanism makes these complexes highly promising chemotherapeutic cytotoxicity leads.
Agid:
6312913