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Published on: January 31, 2018
Exploring the Cytotoxicity, Uptake, Cellular Response, and Proteomics of Mono- and Dinuclear DNA Light-Switch
Paul J Jarman1, Felicity Noakes1,2, Simon Fairbanks2
1Department of Biomedical Science , University of Sheffield , Sheffield S10 2TN , U.K.
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.
Insights
New metal complexes show promise as platinum-resistant cancer treatments. These compounds induce rapid cell death via oncosis, not apoptosis, offering a novel therapeutic strategy against drug-resistant tumors.
Area of Science:
- Coordination Chemistry
- Chemical Biology
- Cancer Research
Background:
- Drug resistance to platinum-based chemotherapy is a major clinical challenge, often linked to apoptosis evasion.
- Metal complexes offer alternative anticancer strategies, particularly those interacting with DNA.
- Understanding mechanisms of cell death induced by novel agents is crucial for therapeutic development.
Purpose of the Study:
- To compare the DNA binding modes and cytotoxic effects of novel ruthenium complexes with varying structures.
- To investigate the cell death mechanisms induced by these complexes, especially in platinum-resistant cancer cells.
- To explore the potential of these complexes as leads for new chemotherapeutics.
Main Methods:
- Synthesis and characterization of mononuclear and dinuclear ruthenium complexes.
- Assessment of DNA interaction modes (intercalation vs. groove binding) and cytotoxicity.
- Live-cell microscopy utilizing a light-switch effect to monitor cell death timing.
- Quantitative proteomic analysis to identify cellular pathways affected by the complexes.
Main Results:
- Structural modifications shifted DNA binding from intercalation to groove binding, reducing potency but not overcoming platinum resistance.
- All complexes induced rapid cell death via oncosis, bypassing typical apoptotic pathways.
- Proteomic analysis revealed cellular responses related to oxidative stress and DNA repair.
Conclusions:
- The DNA binding mode is not the primary factor in platinum resistance for these complexes.
- Induction of oncosis represents a novel non-apoptotic cell death mechanism for cancer therapy.
- These ruthenium complexes are promising leads for developing novel chemotherapeutics against resistant cancers.
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