University of Sheffield | February 2019 | New compound could help treat ovarian cancer
Two departments at the University of Sheffield have collaborated to explore new drug types that could work against types of treatment resistant cancers.
Researchers from the Department of Chemistry and the Department of Biomedical Science have screened new compounds made in the lab against a “panel” of cancers that were sensitive and resistant to standard cancer therapy.
The study’s lead author Professor Jim Thomas, of the Department of Chemistry, said: “Many cancer cells – about 20 per cent – become resistant to common treatments by learning to ignore the internal signals that tell them to undergo programed cell death, known as apoptosis.
“We have identified a compound that kills cancer cells that avoids the need for apoptosis, and so the usual resistance mechanism doesn’t work against our compound.
“The compound is as potent as common current chemotherapeutics, but crucially retains its potency against treatment-resistant cancers. By looking at the cellular response from the cancers we found the new drug lead works by two different mechanisms simultaneously, making it much more difficult for cancers to develop resistance toward them during treatment.
“We think this compound could be particularly effective against ovarian cancer.” (Source: University of Sheffield)
Read the news release in full from University of Sheffield
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.
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