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The antileishmanial activity of xanthohumol is mediated by mitochondrial inhibition

Published online by Cambridge University Press:  12 December 2016

LIANET MONZOTE ,
ALEXANDRA LACKOVA ,
KATRIN STANIEK ,
SILVIA STEINBAUER ,
GERALD PICHLER ,
WALTER JÄGER  and
LARS GILLE Open the ORCID record for LARS GILLE [Opens in a new window]
LIANET MONZOTE
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, A-1210 Vienna, Veterinärplatz 1, Austria Parasitology Department, Institute of Tropical Medicine ‘Pedro Kouri’, 11500 Havana, Marianao 13, PO Box 601, Cuba
ALEXANDRA LACKOVA
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, A-1210 Vienna, Veterinärplatz 1, Austria Department of Pharmaceutical Chemistry, Division of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Althanstraße 14, Austria
KATRIN STANIEK
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, A-1210 Vienna, Veterinärplatz 1, Austria
SILVIA STEINBAUER
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, A-1210 Vienna, Veterinärplatz 1, Austria
GERALD PICHLER
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, A-1210 Vienna, Veterinärplatz 1, Austria
WALTER JÄGER
Affiliation:
Department of Pharmaceutical Chemistry, Division of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Althanstraße 14, Austria
LARS GILLE*
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, A-1210 Vienna, Veterinärplatz 1, Austria
*
*Corresponding author: Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, A-1210 Vienna, Veterinärplatz 1, Austria. E-mail: [email protected]
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Summary

Xanthohumol (Xan) is a natural constituent of human nutrition. Little is known about its actions on leishmanial parasites and their mitochondria as putative target. Therefore, we determined the antileishmanial activity of Xan and resveratrol (Res, as alternative compound with antileishmanial activity) with respect to mitochondria in Leishmania amazonensis promastigotes/amastigotes (LaP/LaA) in comparison with their activity in peritoneal macrophages from mouse (PMM) and macrophage cell line J774A.1 (J774). Mechanistic studies were conducted in Leishmania tarentolae promastigotes (LtP) and mitochondrial fractions isolated from LtP. Xan and Res demonstrated antileishmanial activity in LaA [half inhibitory concentration (IC50): Xan 7 µm, Res 14 µm]; while they had less influence on the viability of PMM (IC50: Xan 70 µm, Res >438 µm). In contrast to Res, Xan strongly inhibited oxygen consumption in Leishmania (LtP) but not in J774 cells. This was based on the inhibition of the mitochondrial electron transfer complex II/III by Xan, which was less pronounced with Res. Neither Xan nor Res increased mitochondrial superoxide release in LtP, while both decreased the mitochondrial membrane potential in LtP. Bioenergetic studies showed that LtP mitochondria have no spare respiratory capacity in contrast to mitochondria in J774 cells and can therefore much less adapt to stress by mitochondrial inhibitors, such as Xan. These data show that Xan may have antileishmanial activity, which is mediated by mitochondrial inhibition.

Keywords

LeishmaniamitochondriaESR spectroscopyxanthohumolresveratrol
Type
Research Article
Information
Parasitology , Volume 144 , Issue 6 , May 2017 , pp. 747 - 759
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Copyright
Copyright © Cambridge University Press 2016 

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