Hostname: page-component-76fb5796d-skm99 Total loading time: 0 Render date: 2024-04-26T09:52:19.769Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  05 November 2018

Sritama De Sarkar ,
Deblina Sarkar ,
Avijit Sarkar ,
Aishwarya Dighal ,
Sasanka Chakrabarti ,
Katrin Staniek ,
Lars Gille Open the ORCID record for Lars Gille [Opens in a new window]  and
Mitali Chatterjee Open the ORCID record for Mitali Chatterjee [Opens in a new window]
Sritama De Sarkar
Affiliation:
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
Deblina Sarkar
Affiliation:
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
Avijit Sarkar
Affiliation:
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
Aishwarya Dighal
Affiliation:
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
Sasanka Chakrabarti
Affiliation:
Department of Biochemistry, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
Katrin Staniek
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
Lars Gille*
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
Mitali Chatterjee
Affiliation:
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
*
Author for correspondence: Lars Gille, E-mail: Lars.Gille@vetmeduni.ac.at and Mitali Chatterjee, E-mail: ilatim@vsnl.net
Get access Rights & Permissions [Opens in a new window]

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.

Keywords

ArtemisininendoperoxidesLeishmaniamitochondriamitochondrial membrane potentialreactive oxygen species (ROS)
Type
Research Article
Information
Parasitology , Volume 146 , Issue 4 , April 2019 , pp. 511 - 520
Check for updates
Copyright
Copyright © Cambridge University Press 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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, 1005–1016.Google Scholar
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, 4244–4258.Google Scholar
Blum, JJ (1994) Energy metabolism in Leishmania. Journal of Bioenergetics and Biomembranes 26, 147–155.Google Scholar
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, 2023–2029.Google Scholar
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, 36027–36031.Google Scholar
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, 462–465.Google Scholar
Croft, SL, Sundar, S and Fairlamb, AH (2006) Drug resistance in leishmaniasis. Clinical Microbiology Reviews 19, 111–126.Google Scholar
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, 629–641.Google Scholar
Dong, Y and Vennerstrom, JL (2003) Mechanisms of in situ activations for peorxidic antimalarials. Redox Report 8, 284–288.Google Scholar
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.Google Scholar
Fidalgo, LM and Gille, L (2011) Mitochondria and trypanosomatids: targets and drugs. Pharmacological Research 28, 2758–2770.Google Scholar
Flohé, L, Hecht, HJ and Steinert, P (1999) Glutathione and trypanothione in parasitic hydroperoxide metabolism. Free Radical Biology and Medicine 27, 966–984.Google Scholar
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, 48–62.Google Scholar
Gottlieb, RA (2001) Mitochondria and apoptosis. Biological Signals and Receptors 10, 147–161.Google Scholar
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, H1747–H1755.Google Scholar
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, 417–430.Google Scholar
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, 3697–3710.Google Scholar
König, J and Fairlamb, AH (2007) A comparative study of type I and type II tryparedoxin peroxidases in Leishmania major. The FEBS Journal 274, 5643–5658.Google Scholar
Krauth-Siegel, RL and Comini, MA (2008) Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochimica et Biophysica Acta 1780, 1236–1248.Google Scholar
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, 53–64.Google Scholar
Luque-Ortega, JR and Rivas, L (2007) Miltefosine (hexadecylphosphocholine) inhibits cytochrome c oxidase in Leishmania donovani promastigotes. Antimicrobial Agents and Chemotherapy 51, 1327–1332.Google Scholar
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, 1679–1687.Google Scholar
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, 9372–9382.Google Scholar
Monzote, L and Gille, L (2010) Mitochondria as a promising antiparasitic target. Current Clinical Pharmacology 5, 55–60.Google Scholar
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, 20–26.Google Scholar
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, 1239–1248.Google Scholar
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, 747–759.Google Scholar
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, 1788–1797.Google Scholar
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, 233–240.Google Scholar
Nohl, H, Gille, L and Kozlov, A (2003) Are mitochondria a spontaneous source of reactive oxygen species? Redox Report 8, 135–141.Google Scholar
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, 225–250.Google Scholar
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.Google Scholar
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, 1292–1307.Google Scholar
Sen, R and Chatterjee, M (2011) Plant derived therapeutics for the treatment of Leishmaniasis. Phytomedicine 18, 1056–1069.Google Scholar
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, 839–846.Google Scholar
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, 52366–52375.Google Scholar
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, 1213–1218.Google Scholar
Sen, R, Ganguly, S, Saha, P and Chatterjee, M (2010 a) Efficacy of artemisinin in experimental visceral leishmaniasis. International Journal of Antimicrobial Agents 36, 43–49.Google Scholar
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, 1289–1295.Google Scholar
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.Google Scholar
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, 381–387.Google Scholar
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, 44784–44790.Google Scholar
Sundar, S and Singh, A (2016) Recent developments and future prospects in the treatment of visceral leishmaniasis. Therapeutic Advances in Infectious Diseases 3, 98–109.Google Scholar
Torres-Guerrero, E, Quintanilla-Cedillo, MR, Ruiz-Esmenjaud, J and Arenas, R (2017) Leishmaniasis: a review. F1000Research 6, 750.Google Scholar
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, 337–351.Google Scholar
Verma, NK, Singh, G and Dey, CS (2007) Miltefosine induces apoptosis in arsenite-resistant Leishmania donovani promastigotes through mitochondrial dysfunction. Experimental Parasitology 116, 1–13.Google Scholar
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, 131–138.Google Scholar
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.Google Scholar
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, 2189–2204.Google Scholar
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).Google Scholar
Yang, DM and Liew, FY (1993) Effects of qinghaosu (artemisinin) and its derivatives on experimental cutaneous leishmaniasis. Parasitology 106, 7–11.Google Scholar