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Production and Detection of Reactive Oxygen Species ROS in Cancers
Published on: November 21, 2011
In Vivo Selectivity and Localization of Reactive Oxygen Species (ROS) Induction by Osmium Anticancer Complexes That
James P C Coverdale1, Hannah E Bridgewater1, Ji-Inn Song1
1Department of Chemistry , University of Warwick , Coventry CV4 7AL , U.K.
Abstract:
Platinum drugs are widely used for cancer treatment. Other precious metals are promising, but their clinical progress depends on achieving different mechanisms of action to overcome Pt-resistance. Here, we evaluate 13 organo-Os complexes: 16-electron sulfonyl-diamine catalysts [(η6-arene)Os( N, N')], and 18-electron phenylazopyridine complexes [(η6-arene)Os( N, N')Cl/I]+ (arene = p-cymene, biphenyl, or terphenyl). Their antiproliferative activity does not depend on p21 or p53 status, unlike cisplatin, and their selective potency toward cancer cells involves the generation of reactive oxygen species. Evidence of such a mechanism of action has been found both in vitro and in vivo. This work appears to provide the first study of osmium complexes in the zebrafish model, which has been shown to closely model toxicity in humans. A fluorescent osmium complex, derived from a lead compound, was employed to confirm internalization of the complex, visualize in vivo distribution, and confirm colocalization with reactive oxygen species generated in zebrafish.
Insights
New osmium complexes show potent anticancer activity by generating reactive oxygen species, offering a promising alternative to platinum drugs. This study introduces the zebrafish model for evaluating novel metal-based cancer therapies.
Area of Science:
- Inorganic Chemistry
- Medicinal Chemistry
- Cancer Research
Background:
- Platinum-based drugs are mainstays in cancer chemotherapy.
- Drug resistance to platinum agents necessitates novel therapeutic strategies.
- Exploring alternative precious metals like osmium offers potential for new anticancer mechanisms.
Purpose of the Study:
- To evaluate the antiproliferative activity of novel organo-osmium complexes.
- To investigate the mechanism of action, focusing on reactive oxygen species generation.
- To assess the efficacy and distribution of osmium complexes in a zebrafish model.
Main Methods:
- Synthesis and characterization of 13 organo-osmium complexes.
- In vitro antiproliferative assays against cancer cell lines.
- In vivo studies using the zebrafish model, including fluorescent imaging.
- Assessment of reactive oxygen species generation and cellular uptake.
Main Results:
- Osmium complexes exhibited significant antiproliferative activity, independent of p21 or p53 status.
- Selective cancer cell toxicity was mediated by reactive oxygen species generation.
- In vivo studies in zebrafish confirmed complex distribution and colocalization with reactive oxygen species.
- The zebrafish model closely mirrored human toxicity.
Conclusions:
- Organo-osmium complexes represent a promising class of anticancer agents with a distinct mechanism of action.
- Reactive oxygen species generation is a key factor in their selective cytotoxicity.
- The zebrafish model is a valuable tool for preclinical evaluation of metal-based therapeutics.
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