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The leishmanicidal activity of artemisinin is mediated by cleavage of the endoperoxide bridge and mitochondrial dysfunction

  • Sritama De Sarkar (a1), Deblina Sarkar (a1), Avijit Sarkar (a1), Aishwarya Dighal (a1), Sasanka Chakrabarti (a2), Katrin Staniek (a3), Lars Gille (a3) and Mitali Chatterjee (a1)...
Abstract

Endoperoxides kill malaria parasites via cleavage of their endoperoxide bridge by haem or iron, leading to generation of cytotoxic oxygen-centred radicals. In view of the Leishmania parasites having a relatively compromised anti-oxidant defense and high iron content, this study aims to establish the underlying mechanism(s) accounting for the apoptotic-like death of Leishmania promastigotes by artemisinin, an endoperoxide. The formation of reactive oxygen species was confirmed by flow cytometry and was accompanied by inhibition of mitochondrial complexes I–III and II–III. However, this did not translate into a generation of mitochondrial superoxide or decrease in oxygen consumption, indicating minimal impairment of the electron transport chain. Artemisinin caused depolarization of the mitochondrial membrane along with a substantial depletion of adenosine triphosphatase (ATP), but it was not accompanied by enhancement of ATP hydrolysis. Collectively, the endoperoxide-mediated radical formation by artemisinin in Leishmania promastigotes was the key step for triggering its antileishmanial activity, leading secondarily to mitochondrial dysfunction indicating that endoperoxides represent a promising therapeutic strategy against Leishmania worthy of pharmacological consideration.

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Corresponding author
Author for correspondence: Lars Gille, E-mail: Lars.Gille@vetmeduni.ac.at and Mitali Chatterjee, E-mail: ilatim@vsnl.net
References
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Antoine, T, Fisher, N, Amewu, R, O'Neill, PM, Ward, SA and Biagini, GA (2014) Rapid kill of malaria parasites by artemisinin and semi-synthetic endoperoxides involves ROS-dependent depolarization of the membrane potential. The Journal of Antimicrobial Chemotherapy 69, 10051016.
Avery, MA, Muraleedharan, KM, Desai, PV, Bandyopadhyaya, AK, Furtado, MM and Tekwani, BL (2003) Structure-activity relationships of the antimalarial agent artemisinin. 8. Design, synthesis, and CoMFA studies toward the development of artemisinin-based drugs against leishmaniasis and malaria. Journal of Medicinal Chemistry 46, 42444258.
Blum, JJ (1994) Energy metabolism in Leishmania. Journal of Bioenergetics and Biomembranes 26, 147155.
Chen, M, Zhai, L, Christensen, SB, Theander, TG and Kharazmi, A (2001) Inhibition of fumarate reductase in Leishmania major and L. donovani by chalcones. Antimicrobial Agents and Chemotherapy 45, 20232029.
Chen, Q, Vazquez, EJ, Moghaddas, S, Hoppel, CL and Lesnefsky, EJ (2003) Production of reactive oxygen species by mitochondria: central role of complex III. The Journal of Biological Chemistry 278, 3602736031.
Chollet, C, Crousse, B, Bories, C, Bonnet-Delpon, D and Loiseau, PM (2008) In vitro antileishmanial activity of fluoro-artemisinin derivatives against Leishmania donovani. Biomedicine & Pharmacotherapy 62, 462465.
Croft, SL, Sundar, S and Fairlamb, AH (2006) Drug resistance in leishmaniasis. Clinical Microbiology Reviews 19, 111126.
Das, S, Aich, A and Shaha, C (2015) The complex world of cellular defense in the Leishmania parasite. Proceedings of the Indian National Science Academy 81, 629641.
Dong, Y and Vennerstrom, JL (2003) Mechanisms of in situ activations for peorxidic antimalarials. Redox Report 8, 284288.
Faccenda, D and Campanella, M (2012) Molecular regulation of the mitochondrial F(1)F(0)-ATP synthase: physiological and pathological significance of the inhibitory factor 1 (IF(1)). International Journal of Cell Biology 2012, 367934.
Fidalgo, LM and Gille, L (2011) Mitochondria and trypanosomatids: targets and drugs. Pharmacological Research 28, 27582770.
Flohé, L, Hecht, HJ and Steinert, P (1999) Glutathione and trypanothione in parasitic hydroperoxide metabolism. Free Radical Biology and Medicine 27, 966984.
Geroldinger, G, Tonner, M, Hettegger, H, Bacher, M, Monzote, L, Walter, M, Staniek, K, Rosenau, T and Gille, L (2017) Mechanism of ascaridole activation in Leishmania. Biochemical Pharmacology 132, 4862.
Gottlieb, RA (2001) Mitochondria and apoptosis. Biological Signals and Receptors 10, 147161.
Grover, GJ, Atwal, KS, Sleph, PG, Wang, FL, Monshizadegan, H, Monticello, T and Green, DW (2004) Excessive ATP hydrolysis in ischemic myocardium by mitochondrial F 1F 0-ATPase: effect of selective pharmacological inhibition of mitochondrial ATPase hydrolase activity. American Journal of Physiology. Heart and Circulatory Physiology 287, H1747H1755.
Hermans, N, Cos, P, Maes, L, De Bruyne, T, Vanden Berghe, D, Vlietinck, AJ and Pieters, L (2007) Challenges and pitfalls in antioxidant research. Current Medicinal Chemistry 14, 417430.
Jiang, LH, Mousawi, F, Yang, X and Roger, S (2017) ATP-induced Ca2+-signalling mechanisms in the regulation of mesenchymal stem cell migration. Cellular and Molecular Life Sciences 74, 36973710.
König, J and Fairlamb, AH (2007) A comparative study of type I and type II tryparedoxin peroxidases in Leishmania major. The FEBS Journal 274, 56435658.
Krauth-Siegel, RL and Comini, MA (2008) Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochimica et Biophysica Acta 1780, 12361248.
Lee, N, Bertholet, S, Debrabant, A, Muller, J, Duncan, R and Nakhasi, HL (2002) Programmed cell death in the unicellular protozoan parasite Leishmania. Cell Death and Differentiation 9, 5364.
Luque-Ortega, JR and Rivas, L (2007) Miltefosine (hexadecylphosphocholine) inhibits cytochrome c oxidase in Leishmania donovani promastigotes. Antimicrobial Agents and Chemotherapy 51, 13271332.
Mandal, G, Wyllie, S, Singh, N, Sundar, S, Fairlamb, AH and Chatterjee, M (2007) Increased levels of thiols protect antimony unresponsive Leishmania donovani field isolates against reactive oxygen species generated by trivalent antimony. Parasitology 134, 16791687.
Mercer, AE, Maggs, JL, Sun, XM, Cohen, GM, Chadwick, J, O'Neill, PM and Park, BK (2007) Evidence for the involvement of carbon-centered radicals in the induction of apoptotic cell death by artemisinin compounds. The Journal of Biological Chemistry 282, 93729382.
Monzote, L and Gille, L (2010) Mitochondria as a promising antiparasitic target. Current Clinical Pharmacology 5, 5560.
Monzote, L, García, 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, 2026.
Monzote, L, Lackova, A, Staniek, K, Cuesta-Rubio, O and Gille, L (2015) Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A. Parasitology 142, 12391248.
Monzote, L, Lackova, A, Staniek, K, Steinbauer, S, Pichler, G, Jäger, W and Gille, L (2017) The antileishmanial activity of xanthohumol is mediated by mitochondrial inhibition. Parasitology 144, 747759.
Mookerjee Basu, J, Mookerjee, A, Sen, P, Bhaumik, S, Sen, P, Banerjee, S, Naskar, K, Choudhuri, SK, Saha, B, Raha, S and Roy, S (2006) Sodium antimony gluconate induces generation of reactive oxygen species and nitric oxide via phosphoinositide 3-kinase and mitogen-activated protein kinase activation in Leishmania donovani-infected macrophages. Antimicrobial Agents and Chemotherapy 50, 17881797.
Mukhopadhyay, S, Bhattacharyya, S, Majhi, R, De, T, Naskar, K, Majumdar, S and Roy, S (2000) Use of an attenuated leishmanial parasite as an immunoprophylactic and immunotherapeutic agent against murine visceral leishmaniasis. Clinical and Diagnostic Laboratory Immunology 7, 233240.
Nohl, H, Gille, L and Kozlov, A (2003) Are mitochondria a spontaneous source of reactive oxygen species? Redox Report 8, 135141.
Polster, BM, Nicholls, DG, Ge, SX and Roelofs, BA (2014) Use of potentiometric fluorophores in the measurement of mitochondrial reactive oxygen species. Methods in Enzymology 547, 225250.
Ponte-Sucre, A, Gamarro, F, Dujardin, JC, Barrett, MP, López-Vélez, R, García-Hernández, R, Pountain, AW, Mwenechanya, R and Papadopoulou, B (2017) Drug resistance and treatment failure in leishmaniasis: a 21st century challenge. PLoS Neglected Tropical Diseases 11, e0006052.
Roy, A, Ganguly, A, Bose Dasgupta, S, Das, BB, Pal, C, Jaisankar, P and Majumder, HK (2008) Mitochondria-dependent reactive oxygen species-mediated programmed cell death induced by 3,3′-diindolylmethane through inhibition of F 0F 1-ATP synthase in unicellular protozoan parasite Leishmania donovani. Molecular Pharmacology 74, 12921307.
Sen, R and Chatterjee, M (2011) Plant derived therapeutics for the treatment of Leishmaniasis. Phytomedicine 18, 10561069.
Sen, N and Majumder, HK (2008) Mitochondrion of protozoan parasite emerges as potent therapeutic target: exciting drugs are on the horizon. Current Pharmaceutical Design 14, 839846.
Sen, N, Das, BB, Ganguly, A, Mukherjee, T, Bandyopadhyay, S and Majumder, HK (2004) Camptothecin-induced imbalance in intracellular cation homeostasis regulates programmed cell death in unicellular hemoflagellate Leishmania donovani. The Journal of Biological Chemistry 279, 5236652375.
Sen, R, Bandyopadhyay, S, Dutta, A, Mandal, G, Ganguly, S, Saha, P and Chatterjee, M (2007) Artemisinin triggers induction of cell-cycle arrest and apoptosis in Leishmania donovani promastigotes. Journal of Medical Microbiology 56, 12131218.
Sen, R, Ganguly, S, Saha, P and Chatterjee, M (2010 a) Efficacy of artemisinin in experimental visceral leishmaniasis. International Journal of Antimicrobial Agents 36, 4349.
Sen, R, Saha, P, Sarkar, A, Ganguly, S and Chatterjee, M (2010 b) Iron enhances generation of free radicals by artemisinin causing a caspase-independent, apoptotic death in Leishmania donovani promastigotes. Free Radical Research 44, 12891295.
Shadab, M, Jha, B, Asad, M, Deepthi, M, Kamran, M and Ali, N (2017) Apoptosis-like cell death in Leishmania donovani treated with KalsomeTM10, a new liposomal amphotericin B. PLoS ONE 12, e0171306.
Staniek, K, Gille, L and Kozlov, AV (2002) Mitochondrial superoxide radical formation is controlled by electron bifurcation to the high and low potential pathways. Free Radical Research 36, 381387.
St-Pierre, J, Buckingham, JA, Roebuck, SJ and Brand, MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. The Journal of Biological Chemistry 277, 4478444790.
Sundar, S and Singh, A (2016) Recent developments and future prospects in the treatment of visceral leishmaniasis. Therapeutic Advances in Infectious Diseases 3, 98109.
Torres-Guerrero, E, Quintanilla-Cedillo, MR, Ruiz-Esmenjaud, J and Arenas, R (2017) Leishmaniasis: a review. F1000Research 6, 750.
van Assche, T, Deschacht, M, da Luz, RA, Maes, L and Cos, P (2011) Leishmania-macrophage interactions: insights into the redox biology. Free Radical Biology & Medicine 51, 337351.
Verma, NK, Singh, G and Dey, CS (2007) Miltefosine induces apoptosis in arsenite-resistant Leishmania donovani promastigotes through mitochondrial dysfunction. Experimental Parasitology 116, 113.
Wan, CP, Myung, E and Lau, BH (1993) An automated micro-fluorometric assay for monitoring oxidative burst activity of phagocytes. Journal of Immunological Methods 159, 131138.
Wang, J, Huang, L, Li, J, Fan, Q, Long, Y, Li, Y and Zhou, B (2010) Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation. PLoS ONE 5, e9582.
Want, MY, Islammudin, M, Chouhan, G, Ozbak, HA, Hemeg, HA, Chattopadhyay, AP and Afrin, F (2017) Nanoliposomal artemisinin for the treatment of murine visceral Leishmaniasis. International Journal of Nanomedicine 12, 21892204.
World Health Organization. Overview of malaria treatment. Retrieved from World Health Organization Available at http://www.who.int/malaria/areas/treatment/overview/en/ (Accessed 21 June 2018).
Yang, DM and Liew, FY (1993) Effects of qinghaosu (artemisinin) and its derivatives on experimental cutaneous leishmaniasis. Parasitology 106, 711.
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Parasitology
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