Tafenoquine, an Antiplasmodial 8-Aminoquinoline, Targets Leishmania Respiratory Complex III and Induces Apoptosis

ABSTRACT Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca2+ levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process.

[1]  V. Yardley,et al.  Antileishmanial and Antitrypanosomal Activities of the 8-Aminoquinoline Tafenoquine , 2010, Antimicrobial Agents and Chemotherapy.

[2]  R. K. Yadav,et al.  Overexpression of Mitochondrial Leishmania major Ascorbate Peroxidase Enhances Tolerance to Oxidative Stress-Induced Programmed Cell Death and Protein Damage , 2009, Eukaryotic Cell.

[3]  J. Alvar,et al.  Developments in the treatment of visceral leishmaniasis , 2009, Expert opinion on emerging drugs.

[4]  M. J. Soares,et al.  Different cell death pathways induced by drugs in Trypanosoma cruzi: an ultrastructural study. , 2009, Micron.

[5]  J. M. Pérez-Victoria,et al.  Sitamaquine Sensitivity in Leishmania Species Is Not Mediated by Drug Accumulation in Acidocalcisomes , 2008, Antimicrobial Agents and Chemotherapy.

[6]  U. Brandt,et al.  The Mechanism of Mitochondrial Superoxide Production by the Cytochrome bc1 Complex* , 2008, Journal of Biological Chemistry.

[7]  F. Opperdoes,et al.  Complex I of Trypanosomatidae: does it exist? , 2008, Trends in parasitology.

[8]  E. Veerman,et al.  Human antimicrobial peptide histatin 5 is a cell‐ penetrating peptide targeting mitochondrial ATP synthesis in Leishmania , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  V. Yardley,et al.  Antiparasitic Activities and Toxicities of Individual Enantiomers of the 8-Aminoquinoline 8-[(4-Amino-1-Methylbutyl)Amino]-6-Methoxy-4-Methyl-5-[3,4-Dichlorophenoxy]Quinoline Succinate , 2008, Antimicrobial Agents and Chemotherapy.

[10]  L. Tetley,et al.  The AP3 adaptor is involved in the transport of membrane proteins to acidocalcisomes of Leishmania , 2008, Journal of Cell Science.

[11]  R. Peeling,et al.  Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? , 2007, Nature Reviews Microbiology.

[12]  R. Radi,et al.  Mitochondrial superoxide radicals mediate programmed cell death in Trypanosoma cruzi: cytoprotective action of mitochondrial iron superoxide dismutase overexpression. , 2007, The Biochemical journal.

[13]  L. Rivas,et al.  Miltefosine (Hexadecylphosphocholine) Inhibits Cytochrome c Oxidase in Leishmania donovani Promastigotes , 2007, Antimicrobial Agents and Chemotherapy.

[14]  M. Ouellette,et al.  A Proteomics Screen Implicates HSP83 and a Small Kinetoplastid Calpain-related Protein in Drug Resistance in Leishmania donovani Clinical Field Isolates by Modulating Drug-induced Programmed Cell Death* , 2007, Molecular & Cellular Proteomics.

[15]  B. Tekwani,et al.  8-Aminoquinolines: future role as antiprotozoal drugs , 2006, Current opinion in infectious diseases.

[16]  Barbara M. Bakker,et al.  The mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase of Trypanosomatidae and the glycosomal redox balance of insect stages of Trypanosoma brucei and Leishmania spp. , 2006, Molecular and biochemical parasitology.

[17]  G. H. Coombs,et al.  Endosome Sorting and Autophagy Are Essential for Differentiation and Virulence of Leishmania major* , 2006, Journal of Biological Chemistry.

[18]  S. Sundar,et al.  Visceral leishmaniasis - current therapeutic modalities. , 2006, The Indian journal of medical research.

[19]  Peter Rohloff,et al.  Acidocalcisomes ? conserved from bacteria to man , 2005, Nature Reviews Microbiology.

[20]  N. Sen,et al.  Camptothecin-induced Imbalance in Intracellular Cation Homeostasis Regulates Programmed Cell Death in Unicellular Hemoflagellate Leishmania donovani* , 2004, Journal of Biological Chemistry.

[21]  J. Piñero,et al.  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 , 2004, Antimicrobial Agents and Chemotherapy.

[22]  C. Shaha,et al.  Apoptotic Death in Leishmania donovani Promastigotes in Response to Respiratory Chain Inhibition , 2004, Journal of Biological Chemistry.

[23]  M. Ouellette,et al.  Functional Cloning of the Miltefosine Transporter , 2003, Journal of Biological Chemistry.

[24]  D. Andreu,et al.  Identification of new leishmanicidal peptide lead structures by automated real-time monitoring of changes in intracellular ATP. , 2003, The Biochemical journal.

[25]  R. Docampo,et al.  Calcium regulation in protozoan parasites. , 2003, Current opinion in microbiology.

[26]  C. Shaha,et al.  Increase in Cytosolic Ca2+ Levels through the Activation of Non-selective Cation Channels Induced by Oxidative Stress Causes Mitochondrial Depolarization Leading to Apoptosis-like Death in Leishmania donovaniPromastigotes* , 2002, The Journal of Biological Chemistry.

[27]  M. L. Kennedy,et al.  Chemosensitization of a multidrug-resistant Leishmania tropica line by new sesquiterpenes from Maytenus magellanica and Maytenus chubutensis. , 2001, Journal of medicinal chemistry.

[28]  C. Shaha,et al.  Hydrogen peroxide induces apoptosis-like death in Leishmania donovani promastigotes. , 2001, Journal of cell science.

[29]  Ming Chen,et al.  Inhibition of Fumarate Reductase inLeishmania major and L. donovani by Chalcones , 2001, Antimicrobial Agents and Chemotherapy.

[30]  S. Croft,et al.  In Vivo Monitoring of Intracellular ATP Levels inLeishmania donovani Promastigotes as a Rapid Method To Screen Drugs Targeting Bioenergetic Metabolism , 2001, Antimicrobial Agents and Chemotherapy.

[31]  L. Rivas,et al.  Expression and regulation of mitochondrial uncoupling protein 1 from brown adipose tissue in Leishmania major promastigotes. , 1998, Molecular and biochemical parasitology.

[32]  D. Andreu,et al.  The plasma membrane of Leishmania donovani promastigotes is the main target for CA(1-8)M(1-18), a synthetic cecropin A-melittin hybrid peptide. , 1998, The Biochemical journal.

[33]  K. Chang,et al.  Intracellular Ca2+ Pool Content and Signaling and Expression of a Calcium Pump Are Linked to Virulence in Leishmania mexicana amazonesis Amastigotes* , 1997, The Journal of Biological Chemistry.

[34]  J. J. van Hellemond,et al.  Inhibition of the respiratory chain results in a reversible metabolic arrest in Leishmania promastigotes. , 1997, Molecular and biochemical parasitology.

[35]  A. Vercesi,et al.  Ca2+ transport by digitonin-permeabilized Leishmania donovani. Effects of Ca2+, pentamidine and WR-6026 on mitochondrial membrane potential in situ. , 1992, The Biochemical journal.

[36]  A E Vercesi,et al.  Digitonin permeabilization does not affect mitochondrial function and allows the determination of the mitochondrial membrane potential of Trypanosoma cruzi in situ. , 1991, The Journal of biological chemistry.

[37]  L. Ernster,et al.  AN ELECTRON-TRANSPORT SYSTEM ASSOCIATED WITH THE OUTER MEMBRANE OF LIVER MITOCHONDRIA , 1967, The Journal of cell biology.

[38]  R. Madhubala,et al.  Roles for mitochondria in pentamidine susceptibility and resistance in Leishmania donovani. , 2006, Molecular and biochemical parasitology.

[39]  H. Lanners.  Effect of the 8-aminoquinoline primaquine on culture-derived gametocytes of the malaria parasitePlasmodium falciparum , 2004, Parasitology Research.

[40]  B. Halliwell,et al.  Role of free radicals and catalytic metal ions in human disease: an overview. , 1990, Methods in enzymology.