Increased trypanocidal activity of the salinomycin derivative ironomycin is due to ROS production and iron uptake impairment

Steverding, Dietmar, Rushworth, Stuart A., Hurle, Georgina R. ORCID: https://orcid.org/0000-0003-0033-2585, Antoszczak, Michał, Sulik, Michał, Huczyński, Adam and Tyler, Kevin M. ORCID: https://orcid.org/0000-0002-0647-8158 (2024) Increased trypanocidal activity of the salinomycin derivative ironomycin is due to ROS production and iron uptake impairment. Molecules, 29 (23). ISSN 1420-3049

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Abstract

Salinomycin and its derivatives display promising anti-proliferating activity against bloodstream forms of Trypanosoma brucei. The mechanism of trypanocidal action of these compounds is due to their ionophoretic activity inducing an influx of sodium cations followed by osmotic water uptake, leading to massive swelling of bloodstream-form trypanosomes. Generally, higher trypanocidal activities of salinomycin derivatives are associated with higher cell swelling activities. Although ironomycin (C20-propargylamine derivative of salinomycin) and salinomycin showed identical cell swelling activities, ironomycin was 6 times more trypanocidal than salinomycin, the 50% growth inhibition (GI50) values were 0.034 μM and 0.20 μM, respectively. However, when bloodstream-form trypanosomes were incubated with ironomycin in the presence of vitamin E and ammonium ferric citrate, the trypanocidal activity of the compound was reduced to that of salinomycin (GI50 = 0.21 μM vs GI50 = 0.20 μM). In addition, vitamin E was found to decrease the trypanocidal activity of ironomycin much more than ammonium ferric citrate (GI50 = 0.18 μM vs GI50 = 0.042 μM). Moreover, ironomycin caused a reduction in the uptake of the iron-carrier protein transferrin mediated by a downregulation of the transferrin receptor and led to the accumulation and sequestering of iron(II) in the parasite’s lysosome triggering an increase production of reactive oxygen species (ROS). These results suggest that the increased trypanocidal activity of ironomycin can be mainly attributed to an increased ROS production and, to a lesser extent, an impairment in iron uptake.

Item Type:	Article
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	28 Nov 2024 01:37
Last Modified:	04 Dec 2024 01:42
URI:	https://ueaeprints.uea.ac.uk/id/eprint/97798
DOI:

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