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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: Lars.Gille@vetmeduni.ac.at
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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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References

REFERENCES

Bodley, A. L. and Shapiro, T. A. (1995). Molecular and cytotoxic effects of camptothecin, a topoisomerase I inhibitor, on trypanosomes and Leishmania. Proceedings of the National Academy of Sciences of the United States of America 92, 3726–3730.Google Scholar
Brand, M. D. and Nicholls, D. G. (2011). Assessing mitochondrial dysfunction in cells. Biochemical Journal 435, 297–312.Google Scholar
Brodziak-Jarosz, L., Fujikawa, Y., Pastor-Flores, D., Kasikci, S., Jirasek, P., Pitzl, S., Owen, R. W., Gerhäuser, C., Amslinger, S. and Dick, T. P. (2016). A click chemistry approach identifies target proteins of xanthohumol. Molecular Nutrition & Food Research 60, 737–748.CrossRefGoogle ScholarPubMed
Chen, M., Bennedsen, M., Zhai, L. and Kharazmi, A. (2001). Purification and enzymatic activity of an NADH-fumarate reductase and other mitochondrial activities of Leishmania parasites. Acta Pathologica, Microbiologica, Et Immunologica Scandinavica 109, 801–808.Google Scholar
Cottart, C. H., Nivet-Antoine, V. and Beaudeux, J. L. (2014). Review of recent data on the metabolism, biological effects, and toxicity of resveratrol in humans. Molecular Nutrition & Food Research 58, 7–21.Google Scholar
Daum, G., Bohni, P. C. and Schatz, G. (1982). Import of proteins into mitochondria. Cytochrome b2 and cytochrome c peroxidase are located in the intermembrane space of yeast mitochondria. Journal of Biological Chemistry 257, 13028–13033.Google Scholar
de Araujo, V. E., Pinheiro, L. C., Almeida, M. C., de Menezes, F. C., Morais, M. H., Reis, I. A., Assuncao, R. M. and Carneiro, M. (2013). Relative risk of visceral leishmaniasis in Brazil: a spatial analysis in urban area. PLoS Neglected Tropical Diseases 7, e2540.Google Scholar
Delorenzi, J. C., Attias, M., Gattass, C. R., Andrade, M., Rezende, C., da Cunha, P. A., Henriques, A. T., Bou-Habib, D. C. and Saraiva, E. M. (2001). Antileishmanial activity of an indole alkaloid from Peschiera australis. Antimicrobial Agents and Chemotherapy 45, 1349–1354.Google Scholar
Dikalov, S. I., Kirilyuk, I. A., Voinov, M. and Grigor'ev, I. A. (2011). EPR detection of cellular and mitochondrial superoxide using cyclic hydroxylamines. Free Radical Research 45, 417–430.Google Scholar
Ferreira, C., Soares, D. C., Nascimento, M. T., Pinto da Silva, L. H., Sarzedas, C. G., Tinoco, L. W. and Saraiva, E. M. (2014). Resveratrol is active against Leishmania amazonensis: in vitro effect of its association with amphotericin B. Antimicrobial Agents and Chemotherapy 58, 6197–6208.Google Scholar
Fidalgo, L. M. and Gille, L. (2011). Mitochondria and trypanosomatids: targets and drugs. Pharmaceutical Research 28, 2758–2770.Google Scholar
Frölich, S., Schubert, C., Bienzle, U. and Jenett-Siems, K. (2005). In vitro antiplasmodial activity of prenylated chalcone derivatives of hops (Humulus lupulus) and their interaction with haemin. Journal of Antimicrobial Chemotherapy 55, 883–887.Google Scholar
Gerhäuser, C. (2005). Broad spectrum anti-infective potential of xanthohumol from hop (Humulus lupulus L.) in comparison with activities of other hop constituents and xanthohumol metabolites. Molecular Nutrition & Food Research 49, 827–831.CrossRefGoogle ScholarPubMed
Gille, L., Staniek, K. and Nohl, H. (2001). Effects of tocopheryl quinone on the heart: model experiments with xanthine oxidase, heart mitochondria, and isolated perfused rat hearts. Free Radical Biology and Medicine 30, 865–876.CrossRefGoogle ScholarPubMed
Gornall, A. G., Bardawill, C. J. and David, M. M. (1949). Determination of serum proteins by means of the biuret reaction. Journal of Biological Chemistry 177, 751–766.Google Scholar
Lam, J., Herant, M., Dembo, M. and Heinrich, V. (2009). Baseline mechanical characterization of J774 macrophages. Biophysical Journal 96, 248–254.Google Scholar
Legette, L., Ma, L., Reed, R. L., Miranda, C. L., Christensen, J. M., Rodriguez-Proteau, R. and Stevens, J. F. (2012). Pharmacokinetics of xanthohumol and metabolites in rats after oral and intravenous administration. Molecular Nutrition & Food Research 56, 466–474.Google Scholar
Lenaz, G. and Genova, M. L. (2007). Kinetics of integrated electron transfer in the mitochondrial respiratory chain: random collisions vs solid state electron channeling. American Journal of Physiology: Cell Physiology 292, C1221–C1239.CrossRefGoogle ScholarPubMed
Liu, J., Burdette, J. E., Xu, H., Gu, C., van Breemen, R. B., Bhat, K. P., Booth, N., Constantinou, A. I., Pezzuto, J. M., Fong, H. H., Farnsworth, N. R. and Bolton, J. L. (2001 a). Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. Journal of Agricultural and Food Chemistry 49, 2472–2479.Google Scholar
Liu, M., Wilairat, P. and Go, M. L. (2001 b). Antimalarial alkoxylated and hydroxylated chalcones: structure-activity relationship analysis. Journal of Medicinal Chemistry 44, 4443–4452.Google Scholar
Liu, L., Wang, Y., Lam, K. S. and Xu, A. (2008). Moderate wine consumption in the prevention of metabolic syndrome and its related medical complications. Endocrine Metabolic & Immune Disorders – Drug Targets 8, 89–98.Google Scholar
Lucas, I. K. and Kolodziej, H. (2013). In vitro antileishmanial activity of resveratrol originates from its cytotoxic potential against host cells. Planta Medica 79, 20–26.Google ScholarPubMed
Madan, E., Prasad, S., Roy, P., George, J. and Shukla, Y. (2008). Regulation of apoptosis by resveratrol through JAK/STAT and mitochondria mediated pathway in human epidermoid carcinoma A431 cells. Biochemical and Biophysical Research Communications 377, 1232–1237.Google Scholar
Magalhaes, P. J., Carvalho, D. O., Cruz, J. M., Guido, L. F. and Barros, A. A. (2009). Fundamentals and health benefits of xanthohumol, a natural product derived from hops and beer. Natural Product Communications 4, 591–610.Google Scholar
Mehta, A. and Shaha, C. (2004). Apoptotic death in Leishmania donovani promastigotes in response to respiratory chain inhibition: complex II inhibition results in increased pentamidine cytotoxicity. Journal of Biological Chemistry 279, 11798–11813.Google Scholar
Milligan, S. R., Kalita, J. C., Heyerick, A., Rong, H., De Cooman, L. and De Keukeleire, D. (1999). Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. Journal of Clinical Endocrinology and Metabolism 84, 2249–2252.Google Scholar
Miranda, C. L., Stevens, J. F., Helmrich, A., Henderson, M. C., Rodriguez, R. J., Yang, Y. H., Deinzer, M. L., Barnes, D. W. and Buhler, D. R. (1999). Antiproliferative and cytotoxic effects of prenylated flavonoids from hops (Humulus lupulus) in human cancer cell lines. Food and Chemical Toxicology 37, 271–285.CrossRefGoogle ScholarPubMed
Monzote, L. and Gille, L. (2010). Mitochondria as a promising antiparasitic target. Current Clinical Pharmacology 5, 55–66.CrossRefGoogle ScholarPubMed
Monzote, L., Garcia, M., Pastor, J., Gil, L., Scull, R., Maes, L., Cos, P. and Gille, L. (2014). Essential oil from Chenopodium ambrosioides and main components: activity against Leishmania, their mitochondria and other microorganisms. Experimental Parasitology 136, 20–26.Google Scholar
Müllebner, A., Patel, A., Stamberg, W., Staniek, K., Rosenau, T., Netscher, T. and Gille, L. (2010). Modulation of the mitochondrial cytochrome bc1 complex activity by chromanols and related compounds. Chemical Research in Toxicology 23, 193–202.Google Scholar
Murias, M., Jäger, W., Handler, N., Erker, T., Horvath, Z., Szekeres, T., Nohl, H. and Gille, L. (2005). Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure-activity relationship. Biochemical Pharmacology 69, 903–912.Google Scholar
Nabavi, S. F., Li, H., Daglia, M. and Nabavi, S. M. (2014). Resveratrol and stroke: from chemistry to medicine. Current Neurovascular Research 11, 390–397.CrossRefGoogle ScholarPubMed
Nohl, H. and Hegner, D. (1978). Do mitochondria produce oxygen radicals in vivo? European Journal of Biochemistry 82, 563–567.Google Scholar
Rossignol, R., Malgat, M., Mazat, J. P. and Letellier, T. (1999). Threshold effect and tissue specificity. Implication for mitochondrial cytopathies. Journal of Biological Chemistry 274, 33426–33432.Google Scholar
Schempp, H., Vogel, S., Huckelhoven, R. and Heilmann, J. (2010). Re-evaluation of superoxide scavenging capacity of xanthohumol. Free Radical Research 44, 1435–1444.Google Scholar
Staniek, K., Rosenau, T., Gregor, W., Nohl, H. and Gille, L. (2005). The protection of bioenergetic functions in mitochondria by new synthetic chromanols. Biochemical Pharmacology 70, 1361–1370.Google Scholar
Stervbo, U., Vang, O. and Bonnesen, C. (2007). A review of the content of the putative chemopreventive phytoalexin resveratrol in red wine. Food Chemistry 101, 449–457.CrossRefGoogle Scholar
Strathmann, J., Klimo, K., Sauer, S. W., Okun, J. G., Prehn, J. H. and Gerhäuser, C. (2010). Xanthohumol-induced transient superoxide anion radical formation triggers cancer cells into apoptosis via a mitochondria-mediated mechanism. FASEB Journal 24, 2938–2950.Google Scholar
Sun, P., Liang, J. L., Kang, L. Z., Huang, X. Y., Huang, J. J., Ye, Z. W., Guo, L. Q. and Lin, J. F. (2015). Increased resveratrol production in wines using engineered wine strains Saccharomyces cerevisiae EC1118 and relaxed antibiotic or auxotrophic selection. Biotechnology Progress 31, 650–655.Google Scholar
Sushko, I., Novotarskyi, S., Korner, R., Pandey, A. K., Rupp, M., Teetz, W., Brandmaier, S., Abdelaziz, A., Prokopenko, V. V., Tanchuk, V. Y., Todeschini, R., Varnek, A., Marcou, G., Ertl, P., Potemkin, V., Grishina, M., Gasteiger, J., Schwab, C., Baskin, I. I., Palyulin, V. A., Radchenko, E. V., Welsh, W. J., Kholodovych, V., Chekmarev, D., Cherkasov, A., Aires-de-Sousa, J., Zhang, Q. Y., Bender, A., Nigsch, F., Patiny, L. et al. (2011). Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information. Journal of Computer-Aided Molecular Design 25, 533–554.Google Scholar
Szekeres, T., Fritzer-Szekeres, M., Saiko, P. and Jäger, W. (2010). Resveratrol and resveratrol analogues-structure-activity relationship. Pharmaceutical Research 27, 1042–1048.Google Scholar
Taylor, V. M., Munoz, D. L., Cedeno, D. L., Velez, I. D., Jones, M. A. and Robledo, S. M. (2010). Leishmania tarentolae: utility as an in vitro model for screening of antileishmanial agents. Experimental Parasitology 126, 471–475.Google Scholar
Torres-Santos, E. C., Moreira, D. L., Kaplan, M. A., Meirelles, M. N. and Rossi-Bergmann, B. (1999). Selective effect of 2′,6′-dihydroxy-4′-methoxychalcone isolated from Piper aduncum on Leishmania amazonensis . Antimicrobial Agents and Chemotherapy 43, 1234–1241.Google Scholar
Vaidya, A. B. (2004). Mitochondrial and plastid functions as antimalarial drug targets. Current Drug Targets – Infectious Disorders 4, 11–23.Google Scholar
Walker, C. J., Lence, C. F. and Biendl, M. (2008). Investigation into the high levels of xanthohumol found in Stout and Porterstyle beers. Brauwelt International 2, 100–103.Google Scholar
Walle, T. (2011). Bioavailability of resveratrol. Annals of the New York Academy of Sciences 1215, 9–15.Google Scholar
Wunderlich, S., Zurcher, A. and Back, W. (2005). Enrichment of xanthohumol in the brewing process. Molecular Nutrition & Food Research 49, 874–881.Google Scholar
Yang, J. Y., Della-Fera, M. A., Rayalam, S. and Baile, C. A. (2007). Effect of xanthohumol and isoxanthohumol on 3T3-L1 cell apoptosis and adipogenesis. Apoptosis 12, 1953–1963.CrossRefGoogle ScholarPubMed
Yang, X., Li, X. and Ren, J. (2014). From French Paradox to cancer treatment: anti-cancer activities and mechanisms of resveratrol. Anti-Cancer Agents in Medicinal Chemistry 14, 806–825.Google Scholar
Yao, J., Zhang, B., Ge, C., Peng, S. and Fang, J. (2015). Xanthohumol, a polyphenol chalcone present in hops, activating Nrf2 enzymes to confer protection against oxidative damage in PC12 cells. Journal of Agricultural and Food Chemistry 63, 1521–1531.CrossRefGoogle ScholarPubMed
Yatawara, L., Le, T. H., Wickramasinghe, S. and Agatsuma, T. (2008). Maxicircle (mitochondrial) genome sequence (partial) of Leishmania major: gene content, arrangement and composition compared with Leishmania tarentolae . Gene 424, 80–86.Google Scholar
Zanoli, P. and Zavatti, M. (2008). Pharmacognostic and pharmacological profile of Humulus lupulus L. Journal of Ethnopharmacology 116, 383–396.Google Scholar
Zhang, B., Chu, W., Wei, P., Liu, Y. and Wei, T. T. (2015). Xanthohumol induces generation of reactive oxygen species and triggers apoptosis through inhibition of mitochondrial electron transfer chain complex I. Free Radical Biology and Medicine 89, 486–497.Google Scholar
Zheng, J. and Ramirez, V. D. (1999). Piceatannol, a stilbene phytochemical, inhibits mitochondrial F 0 F 1-ATPase activity by targeting the F 1 complex. Biochemical and Biophysical Research Communications 261, 499–503.Google Scholar