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Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A

Published online by Cambridge University Press:  01 June 2015

LIANET MONZOTE ,
ALEXANDRA LACKOVA ,
KATRIN STANIEK ,
OSMANY CUESTA-RUBIO  and
LARS GILLE
LIANET MONZOTE
Affiliation:
Parasitology Department, Institute of Tropical Medicine ‘Pedro Kouri’, Havana, Cuba
ALEXANDRA LACKOVA
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
KATRIN STANIEK
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
OSMANY CUESTA-RUBIO
Affiliation:
Faculty of Chemical Sciences and Health, Technical University of Machala, Machala, El Oro, Ecuador
LARS GILLE*
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
*
* Corresponding author. Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinärplatz 1, A-1210 Vienna, Austria. Tel: +43-1-25077-2907. Fax: +43-1-25077-2990. E-mail: [email protected]
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Summary

Nemorosone (Nem) and guttiferone A (GutA) are acyl phloroglucinol derivatives (APD) that are present in different natural products. For both compounds anti-cancer and anti-microbial properties have been reported. In particular, an anti-leishmanial activity of both compounds was demonstrated. The aim of this study was to explore the possible role of mitochondria in the anti-leishmanial activity of Nem and GutA in comparison with their action on mammalian mitochondria. Both APD inhibited the growth of promastigotes of Leishmania tarentolae (LtP) with half maximal inhibitory concentration (IC50) values of 0·67 ± 0·17 and 6·2 ± 2·6 μ m; while IC50 values for cytotoxicity against peritoneal macrophages from BALB/c mice were of 29·5 ± 3·7 and 9·2 ± 0·9 μ m, respectively. Nemorosone strongly inhibited LtP oxygen consumption, caused species-specific inhibition (P < 0·05) of succinate:ubiquinone oxidoreductase (complex II) from LtP-mitochondria and significantly increased (P < 0·05) the mitochondrial superoxide production. In contrast, GutA caused only a moderate reduction of respiration in LtP and triggered less superoxide radical production in LtP compared with Nem. In addition, GutA inhibited mitochondrial complex III in bovine heart submitochondrial particles, which is possibly involved in its mammalian toxicity. Both compounds demonstrated at low micromolar concentrations an effect on the mitochondrial membrane potential in LtP. The present study suggests that Nem caused its anti-leishmanial action due to specific inhibition of complexes II/III of mitochondrial respiratory chain of Leishmania parasites that could be responsible for increased production of reactive oxygen species that triggers parasite death.

Keywords

Leishmania tarentolaemitochondriaacyl phloroglucinol derivativesnemorosoneguttiferone A
Type
Research Article
Information
Parasitology , Volume 142 , Issue 9 , August 2015 , pp. 1239 - 1248
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Copyright
Copyright © Cambridge University Press 2015 

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