title: The antileishmanial activity of xanthohumol is mediated by mitochondrial inhibition.
abstract: 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 µ m, Res 14 µ m]; while they had less influence on the viability of PMM (IC50: Xan 70 µ m, Res >438 µ m). 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.
authors.affiliation: Department of Biomedical Sciences,Institute of Pharmacology and Toxicology,University of Veterinary Medicine,A-1210 Vienna,Veterinärplatz 1,Austria.
authors.forename: Lianet
authors.initials: L
authors.lastname: Monzote
authors.affiliation: Department of Biomedical Sciences,Institute of Pharmacology and Toxicology,University of Veterinary Medicine,A-1210 Vienna,Veterinärplatz 1,Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lackova
authors.affiliation: Department of Biomedical Sciences,Institute of Pharmacology and Toxicology,University of Veterinary Medicine,A-1210 Vienna,Veterinärplatz 1,Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Staniek
authors.affiliation: Department of Biomedical Sciences,Institute of Pharmacology and Toxicology,University of Veterinary Medicine,A-1210 Vienna,Veterinärplatz 1,Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Steinbauer
authors.affiliation: Department of Biomedical Sciences,Institute of Pharmacology and Toxicology,University of Veterinary Medicine,A-1210 Vienna,Veterinärplatz 1,Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Pichler
authors.affiliation: Department of Pharmaceutical Chemistry, Division of Clinical Pharmacy and Diagnostics,University of Vienna,A-1090 Vienna, Althanstraße 14,Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
authors.affiliation: Department of Biomedical Sciences,Institute of Pharmacology and Toxicology,University of Veterinary Medicine,A-1210 Vienna,Veterinärplatz 1,Austria.
authors.forename: Lars
authors.identifier: 0000-0003-1223-0201
authors.initials: L
authors.lastname: Gille
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D004579:Electron Transport / Q000187:drug effects; D014450:Electron Transport Complex III / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D017737:Macrophages, Peritoneal / Q000469:parasitology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D015003:Yeasts / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D000981:Antiprotozoal Agents; D005419:Flavonoids; D011427:Propiophenones; D013267:Stilbenes; D013481:Superoxides; D014450:Electron Transport Complex III; D000077185:Resveratrol; C104536:xanthohumol
keywords: 
                 Leishmania
              ; ESR spectroscopy; mitochondria; resveratrol; xanthohumol