Parasites, Hosts and Diseases

The Korea Society for Parasitology and Tropical Medicine (대한기생충학·열대의학회)
권호 표지
DOI QR코드

DOI QR Code

Effect of Farnesyltransferase Inhibitor R115777 on Mitochondria of Plasmodium falciparum

  • Ha, Young Ran (Division of Integrative Bioscience and Bioengineering, Center for Biofluid and Biomimic Research, Pohang University of Science and Technology) ;
  • Hwang, Bae-Geun (Department of Mechanical Engineering, Center for Biofluid and Biomimic Research, Pohang University of Science and Technology) ;
  • Hong, Yeonchul (Department of Parasitology, Kyungpook National University School of Medicine) ;
  • Yang, Hye-Won (Department of Parasitology, Kyungpook National University School of Medicine) ;
  • Lee, Sang Joon (Department of Mechanical Engineering, Center for Biofluid and Biomimic Research, Pohang University of Science and Technology)
  • Received : 2015.03.16
  • Accepted : 2015.07.05
  • Published : 2015.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

The parasite Plasmodium falciparum causes severe malaria and is the most dangerous to humans. However, it exhibits resistance to their drugs. Farnesyltransferase has been identified in pathogenic protozoa of the genera Plasmodium and the target of farnesyltransferase includes Ras family. Therefore, the inhibition of farnesyltransferase has been suggested as a new strategy for the treatment of malaria. However, the exact functional mechanism of this agent is still unknown. In addition, the effect of farnesyltransferase inhibitor (FTIs) on mitochondrial level of malaria parasites is not fully understood. In this study, therefore, the effect of a FTI R115777 on the function of mitochondria of P. falciparum was investigated experimentally. As a result, FTI R115777 was found to suppress the infection rate of malaria parasites under in vitro condition. It also reduces the copy number of mtDNA-encoded cytochrome c oxidase III. In addition, the mitochondrial membrane potential (${\Delta}{\Psi}m$) and the green fluorescence intensity of MitoTracker were decreased by FTI R115777. Chloroquine and atovaquone were measured by the mtDNA copy number as mitochondrial non-specific or specific inhibitor, respectively. Chloroquine did not affect the copy number of mtDNA-encoded cytochrome c oxidase III, while atovaquone induced to change the mtDNA copy number. These results suggest that FTI R115777 has strong influence on the mitochondrial function of P. falciparum. It may have therapeutic potential for malaria by targeting the mitochondria of parasites.

Keywords

References

  1. Farooq U, Mahajan RC. Drug resistance in malaria. J Vector Borne Dis 2004; 41: 45-53.
  2. Hogg T, Nagarajan K, Herzberg S, Chen L, Shen X, Jiang H, Wecke M, Blohmke C, Hilgenfeld R, Schmidt CL. Structural and functional characterization of falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum. J Biol Chem 2006; 281: 25425-25437. https://doi.org/10.1074/jbc.M603776200
  3. Sidhu AB, Verdier-Pinard D, Fidock DA. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 2002; 298: 210-213. https://doi.org/10.1126/science.1074045
  4. Wang J, Huang L, Li J, Fan Q, Long Y, Li Y, Zhou B. Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation. PLoS One 2010; 5: e9582. https://doi.org/10.1371/journal.pone.0009582
  5. Nallan L, Bauer KD, Bendale P, Rivas K, Yokoyama K, Horney CP, Pendyala PR, Floyd D, Lombardo LJ, Williams DK, Hamilton A, Sebti S, Windsor WT, Weber PC, Buckner FS, Chakrabarti D, Gelb MH, Van Voorhis WC. Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. J Med Chem 2005; 48: 3704-3713. https://doi.org/10.1021/jm0491039
  6. Vigil D, Cherfils J, Rossman KL, Der CJ. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 2010; 10: 842-857. https://doi.org/10.1038/nrc2960
  7. Wiesner J, Kettler K, Sakowski J, Ortmann R, Katzin AM, Kimura EA, Silber K, Klebe G, Jomaa H, Schlitzer M. Farnesyltransferase inhibitors inhibit the growth of malaria parasites in vitro and in vivo. Angew Chem Int Ed Engl 2004; 43: 251-254. https://doi.org/10.1002/anie.200351169
  8. Appels NM, Beijnen JH, Schellens JH. Development of farnesyl transferase inhibitors: a review. Oncologist 2005; 10: 565-578. https://doi.org/10.1634/theoncologist.10-8-565
  9. Kohring K, Wiesner J, Altenkamper M, Sakowski J, Silber K, Hillebrecht A, Haebel P, Dahse HM, Ortmann R, Jomaa H, Klebe G, Schlitzer M. Development of benzophenone-based farnesyltransferase inhibitors as novel antimalarials. ChemMedChem 2008; 3: 1217-1231. https://doi.org/10.1002/cmdc.200800043
  10. Ly JD, Grubb DR, Lawen A. The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 2003; 8: 115-128. https://doi.org/10.1023/A:1022945107762
  11. Vaidya AB, Mather MW. Mitochondrial evolution and functions in malaria parasites. Annu Rev Microbiol 2009; 63: 249-267. https://doi.org/10.1146/annurev.micro.091208.073424
  12. Torrentino-Madamet M, Desplans J, Travaille C, James Y, Parzy D. Microaerophilic respiratory metabolism of Plasmodium falciparum mitochondrion as a drug target. Curr Mol Med 2010; 10: 29-46. https://doi.org/10.2174/156652410791065390
  13. Trager W, Jensen JB. Human malaria parasites in continuous culture. Science 1976; 193: 673-675. https://doi.org/10.1126/science.781840
  14. Lambros C, Vanderberg JP. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol 1979; 65: 418-420. https://doi.org/10.2307/3280287
  15. Salehnia M, Tohonen V, Zavareh S, Inzunza J. Does cryopreservation of ovarian tissue affect the distribution and function of germinal vesicle oocytes mitochondria? Biomed Res Int 2013; 2013: 8.
  16. Kellner K, Liebsch G, Klimant I, Wolfbeis OS, Blunk T, Schulz MB, Gopferich A. Determination of oxygen gradients in engineered tissue using a fluorescent sensor. Biotechnol Bioeng 2002; 80: 73-83. https://doi.org/10.1002/bit.10352
  17. Othman A, Ahmad S, Megyerdi S, Mussell R, Choksi K, Maddipati KR, Elmarakby A, Rizk N, Al-Shabrawey M. 12/15-Lipoxygenase-derived lipid metabolites induce retinal endothelial cell barrier dysfunction: contribution of NADPH oxidase. PLoS One 2013; 8: e57254. https://doi.org/10.1371/journal.pone.0057254
  18. Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A. Does oxidative damage to DNA increase with age? Proc Natl Acad Sci USA 2001; 98: 10469-10474. https://doi.org/10.1073/pnas.171202698
  19. Cunha MG, Medina TS, Oliveira SG, Marinho AN, Povoa MM, Ribeiro-dos-Santos AK. Development of a polymerase chain reaction (PCR) method based on amplification of mitochondrial DNA to detect Plasmodium falciparum and Plasmodium vivax. Acta Trop 2009; 111: 35-38. https://doi.org/10.1016/j.actatropica.2009.02.003
  20. Buckling A, Ranford-Cartwright LC, Miles A, Read AF. Chloroquine increases Plasmodium falciparum gametocytogenesis in vitro. Parasitology 1999; 118 (Part 4): 339-346. https://doi.org/10.1017/S0031182099003960
  21. Painter HJ, Morrisey JM, Mather MW, Vaidya AB. Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature 2007; 446: 88-91. https://doi.org/10.1038/nature05572
  22. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate parkin. PLoS Biol 2010; 8: e1000298. https://doi.org/10.1371/journal.pbio.1000298
  23. Chazotte B. Labeling mitochondria with MitoTracker dyes. Cold Spring Harb Protoc 2011; 2011: 990-992.
  24. Lancet JE, Gojo I, Gotlib J, Feldman EJ, Greer J, Liesveld JL, Bruzek LM, Morris L, Park Y, Adjei AA, Kaufmann SH, Garrett-Mayer E, Greenberg PL, Wright JJ, Karp JE. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 2007; 109: 1387-1394. https://doi.org/10.1182/blood-2006-04-014357
  25. Zhu KC, Gerbino E, Beaupre DM, Mackley PA, Muro-Cacho C, Beam C, Hamilton AD, Lichtenheld MG, Kerr WG, Dalton W, Alsina M, Sebti SM. Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells. Blood 2005; 105: 4759-4766. https://doi.org/10.1182/blood-2004-11-4307
  26. Balabaskaran Nina P, Morrisey JM, Ganesan SM, Ke H, Pershing AM, Mather MW, Vaidya AB. ATP synthase complex of Plasmodium falciparum: dimeric assembly in mitochondrial membranes and resistance to genetic disruption. J Biol Chem 2011; 286: 41312-41322. https://doi.org/10.1074/jbc.M111.290973
  27. Kataoka M, Fukura Y, Shinohara Y, Baba Y. Analysis of mitochondrial membrane potential in the cells by microchip flow cytometry. Electrophoresis 2005; 26: 3025-3031. https://doi.org/10.1002/elps.200410402
  28. Rousset S, Alves-Guerra MC, Mozo J, Miroux B, Cassard-Doulcier AM, Bouillaud F, Ricquier D. The biology of mitochondrial uncoupling proteins. Diabetes 2004; 53 (suppl 1): S130-S135. https://doi.org/10.2337/diabetes.53.2007.S130
  29. Shen J, Khan N, Lewis LD, Armand R, Grinberg O, Demidenko E, Swartz H. Oxygen consumption rates and oxygen concentration in molt-4 cells and their mtDNA depleted (rho0) mutants. Biophys J 2003; 84: 1291-1398. https://doi.org/10.1016/S0006-3495(03)74944-3
  30. Goncalves RL, Oliveira JH, Oliveira GA, Andersen JF, Oliveira MF, Oliveira PL, Barillas-Mury C. Mitochondrial reactive oxygen species modulate mosquito susceptibility to Plasmodium infection. PLoS One 2012; 7: e41083. https://doi.org/10.1371/journal.pone.0041083
  31. Molina-Cruz A, DeJong RJ, Charles B, Gupta L, Kumar S, Jaramillo-Gutierrez G, Barillas-Mury C. Reactive oxygen species modulate Anopheles gambiae immunity against bacteria and Plasmodium. J Biol Chem 2008; 283: 3217-3223. https://doi.org/10.1074/jbc.M705873200
  32. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y, Shadel GS, Ghosh S. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011; 472: 476-480. https://doi.org/10.1038/nature09973
  33. Pabon A, Carmona J, Burgos LC, Blair S. Oxidative stress in patients with non-complicated malaria. Clin Biochem 2003; 36: 71-78. https://doi.org/10.1016/S0009-9120(02)00423-X
  34. Krungkrai J, Krungkrai SR, Suraveratum N, Prapunwattana P. Mitochondrial ubiquinol-cytochrome c reductase and cytochrome c oxidase: chemotherapeutic targets in malarial parasites. Biochem Mol Biol Int 1997; 42: 1007-1014.
  35. Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan MS, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DM, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, Barrell B. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 2002; 419: 498-511. https://doi.org/10.1038/nature01097
  36. Sullivan SKD. Malaria: Drugs, Disease and Post-gemonic Biology. New York, USA. Springer. 2010.
  37. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 1997; 275: 1129-1132. https://doi.org/10.1126/science.275.5303.1129
  38. Srivastava IK, Rottenberg H, Vaidya AB. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J Biol Chem 1997; 272: 3961-3966. https://doi.org/10.1074/jbc.272.7.3961

Cited by

  1. Exploring the putative self-binding property of the human farnesyltransferase alpha-subunit vol.591, pp.21, 2015, https://doi.org/10.1002/1873-3468.12862
  2. Live and Let Dye: Visualizing the Cellular Compartments of the Malaria Parasite Plasmodium falciparum vol.97, pp.7, 2015, https://doi.org/10.1002/cyto.a.23927
  3. Disentangling the therapeutic tactics in GBM: From bench to bedside and beyond vol.45, pp.1, 2015, https://doi.org/10.1002/cbin.11484