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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: Lars.Gille@vetmeduni.ac.at
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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 μm; while IC50 values for cytotoxicity against peritoneal macrophages from BALB/c mice were of 29·5 ± 3·7 and 9·2 ± 0·9 μm, 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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References

Almeida, A. M., Bechara, E. J., Vercesi, A. E. and Nantes, I. L. (1999). Diphenylacetaldehyde-generated excited states promote damage to isolated rat liver mitochondrial DNA, phospholipids, and proteins. Free Radical Biology and Medicine 27, 744–751.Google Scholar
Bodley, A.L., McGarry, M.W. and Shapiro, T.A. (1995). Drug cytotoxicity assay for African Trypanosomes and Leishmania Species. Journal of Infection Diseases 172, 1157–1159.Google Scholar
Borra, R. C., Lotufo, M. A., Gagioti, S. M., Barros, F. M. and Andrade, P. M. (2009). A simple method to measure cell viability in proliferation and cytotoxicity assays. Brazilian Oral Research 23, 255–262.Google Scholar
Cuesta-Rubio, O., Frontana-Uribe, B. A., Ramirez-Apan, T. and Cardenas, J. (2002). Polyisoprenylated benzophenones in cuban propolis; biological activity of nemorosone. Zeitschrift Für Naturforschung C 57, 372–378.Google Scholar
Diaz-Carballo, D., Ueberla, K., Kleff, V., Ergun, S., Malak, S., Freistuehler, M., Somogyi, S., Kucherer, C., Bardenheuer, W. and Strumberg, D. (2010). Antiretroviral activity of two polyisoprenylated acylphloroglucinols, 7-epi-nemorosone and plukenetione A, isolated from Caribbean propolis. International Journal of Clinical Pharmacology and Therapeutics 48, 670–677.Google Scholar
Diaz-Carballo, D., Gustmann, S., Acikelli, A. H., Bardenheuer, W., Buehler, H., Jastrow, H., Ergun, S. and Strumberg, D. (2012). 7-epi-nemorosone from Clusia rosea induces apoptosis, androgen receptor down-regulation and dysregulation of PSA levels in LNCaP prostate carcinoma cells. Phytomedicine 19, 1298–1306.Google Scholar
Filho, V. C., Meyre-Silva, C., Niero, R., Bolda Mariano, L. N., Gomes do Nascimento, F., Vicente, F. I., Gazoni, V. F., Dos Santos Silva, B., Gimenez, A., Gutierrez-Yapu, D., Salamanca, E. and Malheiros, A. (2013). Evaluation of antileishmanial activity of selected Brazilian plants and identification of the active principles. Evidence-Based Complementary and Alternative Medicine 2013, 265025.CrossRefGoogle ScholarPubMed
Fritsche, C., Sitz, M., Weiland, N., Breitling, R. and Pohl, H. D. (2007). Characterization of the growth behavior of Leishmania tarentolae: a new expression system for recombinant proteins. Journal of Basic Microbiology 47, 384–393.CrossRefGoogle ScholarPubMed
Fromentin, Y., Gaboriaud-Kolar, N., Lenta, B. N., Wansi, J. D., Buisson, D., Mouray, E., Grellier, P., Loiseau, P. M., Lallemand, M. C. and Michel, S. (2013). Synthesis of novel guttiferone A derivatives: in-vitro evaluation toward Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani . European Journal of Medicinal Chemistry 65, 284–294.Google Scholar
George, S., Bishop, J. V., Titus, R. G. and Selitrennikoff, C. P. (2006). Novel compounds active against Leishmania major . Antimicrobial Agents and Chemotherapy 50, 474–479.Google Scholar
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.Google Scholar
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
Halliwell, B. and Gutteridge, J. M. (1990). Role of free radicals and catalytic metal ions in human disease: an overview. Methods in Enzymology 186, 1–85.Google Scholar
Ishii, N., Ishii, T. and Hartman, P. S. (2007). The role of the electron transport SDHC gene on lifespan and cancer. Mitochondrion 7, 24–28.Google Scholar
Kumar, S., Sharma, S. and Chattopadhyay, S. K. (2013). The potential health benefit of polyisoprenylated benzophenones from Garcinia and related genera: ethnobotanical and therapeutic importance. Fitoterapia 89, 86–125.CrossRefGoogle ScholarPubMed
Lenta, B. N., Vonthron-Senecheau, C., Weniger, B., Devkota, K. P., Ngoupayo, J., Kaiser, M., Naz, Q., Choudhary, M. I., Tsamo, E. and Sewald, N. (2007). Leishmanicidal and cholinesterase inhibiting activities of phenolic compounds from Allanblackia monticola and Symphonia globulifera . Molecules 12, 1548–1557.Google Scholar
Luque-Ortega, J. R., Martinez, S., Saugar, J. M., Izquierdo, L. R., Abad, T., Luis, J. G., Pinero, J., Valladares, B. and Rivas, L. (2004). Fungus-elicited metabolites from plants as an enriched source for new leishmanicidal agents: antifungal phenyl-phenalenone phytoalexins from the banana plant (Musa acuminata) target mitochondria of Leishmania donovani promastigotes. Antimicrobial Agents and Chemotherapy 48, 1534–1540.Google Scholar
Luque-Ortega, J. R., Reuther, P., Rivas, L. and Dardonville, C. (2010). New benzophenone-derived bisphosphonium salts as leishmanicidal leads targeting mitochondria through inhibition of respiratory complex II. Journal of Medicinal Chemistry 53, 1788–1798.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
Monzote, L., Cuesta-Rubio, O., Matheeussen, A., Van Assche, T., Maes, L. and Cos, P. (2011). Antimicrobial evaluation of the polyisoprenylated benzophenones nemorosone and guttiferone A. Phytotherapy Research 25, 458–462.CrossRefGoogle ScholarPubMed
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
Murphy, M. P. (2009). How mitochondria produce reactive oxygen species. Biochemical Journal 417, 1–13.Google Scholar
Nohl, H. and Hegner, D. (1978). Do mitochondria produce oxygen radicals in vivo? European Journal of Biochemistry 82, 563–567.Google Scholar
Nunez-Figueredo, Y., Garcia-Pupo, L., Ramirez-Sanchez, J., Alcantara-Isaac, Y., Cuesta-Rubio, O., Hernandez, R. D., Naal, Z., Curti, C. and Pardo-Andreu, G. L. (2012). Neuroprotective action and free radical scavenging activity of guttiferone-A, a naturally occurring prenylated benzophenone. Arzneimittelforschung 62, 583–589.Google Scholar
Pan, M. H., Chang, W. L., Lin-Shiau, S. Y., Ho, C. T. and Lin, J. K. (2001). Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells. Journal of Agricultural and Food Chemistry 49, 1464–1474.Google Scholar
Pardo-Andreu, G. L., Nunez-Figueredo, Y., Tudella, V. G., Cuesta-Rubio, O., Rodrigues, F. P., Pestana, C. R., Uyemura, S. A., Leopoldino, A. M., Alberici, L. C. and Curti, C. (2011 a). The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: ensuing energetic and oxidative stress implications. Toxicology and Applied Pharmacology 253, 282–289.Google Scholar
Pardo-Andreu, G. L., Nunez-Figueredo, Y., Tudella, V. G., Cuesta-Rubio, O., Rodrigues, F. P., Pestana, C. R., Uyemura, S. A., Leopoldino, A. M., Alberici, L. C. and Curti, C. (2011 b). The anti-cancer agent nemorosone is a new potent protonophoric mitochondrial uncoupler. Mitochondrion 11, 255–263.Google Scholar
Popolo, A., Piccinelli, A. L., Morello, S., Sorrentino, R., Osmany, C. R., Rastrelli, L. and Pinto, A. (2011). Cytotoxic activity of nemorosone in human MCF-7 breast cancer cells. Canadian Journal of Physiology and Pharmacology 89, 50–57.Google Scholar
Protiva, P., Hopkins, M. E., Baggett, S., Yang, H., Lipkin, M., Holt, P. R., Kennelly, E. J. and Bernard, W. I. (2008). Growth inhibition of colon cancer cells by polyisoprenylated benzophenones is associated with induction of the endoplasmic reticulum response. International Journal of Cancer 123, 687–694.Google Scholar
Reis, F. H., Pardo-Andreu, G. L., Nunez-Figueredo, Y., Cuesta-Rubio, O., Marin-Prida, J., Uyemura, S. A., Curti, C. and Alberici, L. C. (2014). Clusianone, a naturally occurring nemorosone regioisomer, uncouples rat liver mitochondria and induces HepG2 cell death. Chemico-Biological Interactions 212, 20–29.Google Scholar
Roux, D., Hadi, H. A., Thoret, S., Guenard, D., Thoison, O., Pais, M. and Sevenet, T. (2000). Structure-activity relationship of polyisoprenyl benzophenones from Garcinia pyrifera on the tubulin/microtubule system. Journal of Natural Products 63, 1070–1076.Google Scholar
Roy, A., Das, B. B., Ganguly, A., Bose, D. S., Khalkho, N. V., Pal, C., Dey, S., Giri, V. S., Jaisankar, P., Dey, S. and Majumder, H. K. (2008). An insight into the mechanism of inhibition of unusual bi-subunit topoisomerase I from Leishmania donovani by 3,3′-di-indolylmethane, a novel DNA topoisomerase I poison with a strong binding affinity to the enzyme. Biochemical Journal 409, 611–622.Google Scholar
Santhamma, K. R. and Bhaduri, A. (1995). Characterization of the respiratory chain of Leishmania donovani promastigotes. Molecular and Biochemical Parasitology 75, 43–53.Google Scholar
Singh, A. K., Papadopoulou, B. and Ouellette, M. (2001). Gene amplification in amphotericin B-resistant Leishmania tarentolae . Experimental Parasitology 99, 141–147.Google Scholar
Terrazas, P. M., de Souza, M. E., Mariano, L. N., Cechinel-Filho, V., Niero, R., Andrade, S. F. and Maistro, E. L. (2013). Benzophenone guttiferone A from Garcinia achachairu Rusby (Clusiaceae) presents genotoxic effects in different cells of mice. PLoS ONE 8, e76485.Google Scholar