Increased Trypanocidal Activity of the Salinomycin Derivative Ironomycin Is Due to ROS Production and Iron Uptake Impairment
Salinomycin and its derivatives display promising anti-proliferating activity against bloodstream forms of <i>Trypanosoma brucei</i>. The mechanism of trypanocidal action of these compounds is due to their ionophoretic activity inducing an influx of sodium cations followed by osmotic wat...
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2024-11-01
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| author | Dietmar Steverding Stuart A. Rushworth Georgina R. Hurle Michał Antoszczak Michał Sulik Adam Huczyński Kevin M. Tyler |
| author_facet | Dietmar Steverding Stuart A. Rushworth Georgina R. Hurle Michał Antoszczak Michał Sulik Adam Huczyński Kevin M. Tyler |
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| description | Salinomycin and its derivatives display promising anti-proliferating activity against bloodstream forms of <i>Trypanosoma brucei</i>. 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, and the 50% growth inhibition (GI<sub>50</sub>) 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 (GI<sub>50</sub> = 0.21 μM vs. GI<sub>50</sub> = 0.20 μM). In addition, vitamin E was found to decrease the trypanocidal activity of ironomycin much more than ammonium ferric citrate (GI<sub>50</sub> = 0.18 μM vs. GI<sub>50</sub> = 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. |
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| spelling | doaj-art-b02ecd5c51fb4334b8f3ed45da12d8112025-08-20T01:55:27ZengMDPI AGMolecules1420-30492024-11-012923559710.3390/molecules29235597Increased Trypanocidal Activity of the Salinomycin Derivative Ironomycin Is Due to ROS Production and Iron Uptake ImpairmentDietmar Steverding0Stuart A. Rushworth1Georgina R. Hurle2Michał Antoszczak3Michał Sulik4Adam Huczyński5Kevin M. Tyler6Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, UKBob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, UKBioMedical Research Centre, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UKDepartment of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, PolandDepartment of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, PolandDepartment of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, PolandBioMedical Research Centre, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UKSalinomycin and its derivatives display promising anti-proliferating activity against bloodstream forms of <i>Trypanosoma brucei</i>. 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, and the 50% growth inhibition (GI<sub>50</sub>) 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 (GI<sub>50</sub> = 0.21 μM vs. GI<sub>50</sub> = 0.20 μM). In addition, vitamin E was found to decrease the trypanocidal activity of ironomycin much more than ammonium ferric citrate (GI<sub>50</sub> = 0.18 μM vs. GI<sub>50</sub> = 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.https://www.mdpi.com/1420-3049/29/23/5597<i>Trypanosoma brucei</i>ironomycinsalinomycintrypanocidal activityreactive oxygen species |
| spellingShingle | Dietmar Steverding Stuart A. Rushworth Georgina R. Hurle Michał Antoszczak Michał Sulik Adam Huczyński Kevin M. Tyler Increased Trypanocidal Activity of the Salinomycin Derivative Ironomycin Is Due to ROS Production and Iron Uptake Impairment Molecules <i>Trypanosoma brucei</i> ironomycin salinomycin trypanocidal activity reactive oxygen species |
| title | Increased Trypanocidal Activity of the Salinomycin Derivative Ironomycin Is Due to ROS Production and Iron Uptake Impairment |
| title_full | Increased Trypanocidal Activity of the Salinomycin Derivative Ironomycin Is Due to ROS Production and Iron Uptake Impairment |
| title_fullStr | Increased Trypanocidal Activity of the Salinomycin Derivative Ironomycin Is Due to ROS Production and Iron Uptake Impairment |
| title_full_unstemmed | Increased Trypanocidal Activity of the Salinomycin Derivative Ironomycin Is Due to ROS Production and Iron Uptake Impairment |
| title_short | Increased Trypanocidal Activity of the Salinomycin Derivative Ironomycin Is Due to ROS Production and Iron Uptake Impairment |
| title_sort | increased trypanocidal activity of the salinomycin derivative ironomycin is due to ros production and iron uptake impairment |
| topic | <i>Trypanosoma brucei</i> ironomycin salinomycin trypanocidal activity reactive oxygen species |
| url | https://www.mdpi.com/1420-3049/29/23/5597 |
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