The molecular mechanism of action of artemisinin - The debate continues

Molecules

Volumn 15, Issue 3, 2010, Pages 1705-1721

  O'Neill, Paul M ^a   Barton, Victoria E ^a   Ward, Stephen A ^b  

^a UNIVERSITY OF LIVERPOOL   (United Kingdom)

^b LIVERPOOL SCHOOL OF TROPICAL MEDICINE   (United Kingdom)

Author keywords

Antimalarial; Antitumor agent; Artemisinin; Bioactivation; Molecular targets

Indexed keywords

ANTIMALARIAL AGENT; ARTEMISININ; ARTEMISININ DERIVATIVE;

ANIMAL; ARTICLE; DRUG EFFECT; PLASMODIUM FALCIPARUM; POLYACRYLAMIDE GEL ELECTROPHORESIS;

ANIMALS; ANTIMALARIALS; ARTEMISININS; ELECTROPHORESIS, POLYACRYLAMIDE GEL; PLASMODIUM FALCIPARUM;

EID: 77950362015     PISSN: None     EISSN: 14203049     Source Type: Journal    
DOI: 10.3390/molecules15031705     Document Type: Article

References (78)

1. World Heath Organisation. The World Malaria Report; World Heath Organisation: Geneva, Switzerland, 2008.
2. Woodrow, C. J.; Haynes, R. K.; Krishna, S. Artemisinins. Postgrad. Med. J. 2005, 81, 71-78.
3. Zhang, J.-F. A Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin).), Yang Cheng Evening News Publishing Company, 2005.
4. Terkuile, F.; White, N. J.; Holloway, P.; Pasvol, G.; Krishna, S. Plasmodium falciparum: In Vitro Studies of the Pharmacodynamic Properties of Drugs Used for the Treatment of Severe Malaria. Exp. Parasitol. 1993, 76, 85-95.
5. Kumar, N.; Zheng, H. Stage-specific gametocytocidal effect in vitro of the antimalaria drug qinghaosu on Plasmodium falciparum. Parasitol. Res. 1990, 76, 214-218.
6. Posner, G. W.; O'Neill, P. M. Knowledge of the proposed chemical mechanism of action and cytochrome p450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides. Acc. Chem. Res. 2004, 37, 397-404.
7. Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu, F. C. K.; Chollet, J.; Dong, Y. X.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam, M.; Tomas, J. S.; Scheurer, C.; Scorneaux, B.; Tang, Y. Q.; Urwyler, H.; Wittlin, S.; Charman, W. N. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 2004, 430, 900-904.
8. Kim, H.-S.; Shibata, Y.; Wataya, U.; Tsuchiya, K.; Masuyama, A.; Nojima, M. Synthesis and antimalarial activity of cyclic peroxides 1, 2, 4,5,7-pentoxocanes and 1, 2,4,5-tetraoxanes. J. Med. Chem. 1999, 42, 2604-2606.
9. Krishna, S.; Bustamante, L.; Haynes, R. K.; Staines, H. M. Artemisinins: their growing importance in medicine. Trends Pharmacol. Sci. 2008, 29, 520-527.
10. Singh, N. P.; Panwar, V. K. Case report of a pituitary macroadenoma treated with artemether. Integr. Cancer Ther. 2006, 5, 391-394.
11. Efferth, T. Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin-from bench to bedside. Planta Medica 2007, 73, 299-309.
12. Pagola, S.; Stephens, P. W.; Bohle, D. S.; Kosar, A. D.; Madsen, S. K. Nature 2000, 404, 307.
13. Egan, T. J. Recent advances in understanding the mechanism of hemozoin (malaria pigment) formation. J. Inorg. Biochem. 2008, 102, 1288-1299.
14. Meshnick, S. R.; Thomas, A.; Ran, A.; Xy, C. M.; Pan, H. Z. Artemisinin (qinghaosu) : the role of intracellular hemin in its mechanism of antimalarial action. Mol. Biochem. Parasitol. 1991, 49, 181-189.
15. Posner, G. H.; Wang, D.; Cumming, J. N.; Oh, C. H.; French, A. N.; Bodley, A. L.; Shapiro, T. A. Further evidence supporting the importance of and the restrictions on a carbon-centered radical for high antimalarial activity of 1,2,4-trioxanes like artemisinin. J. Med. Chem. 1995, 38, 2273-2275.
16. Posner, G. H.; Oh, C. H. Regiospecifically oxygen-18 labeled 1,2,4-trioxane: a simple chemical model system to probe the mechanism (s) for the antimalarial activity of artemisinin (qinghaosu). J. Am. Chem. Soc. 1992, 114, 8328-8329.
17. Posner, G. H.; Oh, C. W.; Wang, D. S.; Gerena, L.; Milhous, W. K.; Meshnick, S. R.; Asawamahasadka, W. Mechanism-Based Design, Synthesis, and in vitro Antimalarial Testing of New 4-Methylated Trioxanes Structurally Related to Artemisinin: The Importance of a Carbon-Centered Radical for Antimalarial Activity. J. Med. Chem. 1994, 37, 1256-1258.
18. Jefford, C. W.; Favarger, F.; Vicente, M.; Jacquier, Y. The Decomposition of Cis-Fused Cyclopenteno-1, 2, 4-Trioxanes Induced by Ferrous Salts and Some Oxophilic Reagents. Helv. Chim. Acta 1995, 78, 452-458.
19. Jefford, C. W.; Vicente, M. G. H.; Jacquier, Y.; Favarger, F.; Mareda, J.; Millasson-Schmidt, P.; Brunner, G.; Burger, U. The deoxygenation and isomerization of artemisinin and artemether and their relevance to antimalarial action. Helv. Chim. Acta 1996, 79, 1475-1487.
20. Butler, A. R.; Gilbert, B. C.; Hulme, P.; Irvine, L. R.; Renton, L.; Whitwood, A. C. EPR Evidence for the Involvement of Free Radicals in the Iron-Catalysed Decomposition of Qinghaosu (Artemisinin) and Some Derivatives; Antimalarial Action of Some Polycyclic Endoperoxides. Free Radical Res. 1998, 28, 471-476.
21. O'Neill, P. M.; Bishop, L. P. D.; Searle, N. L.; Maggs, J. L.; Storr, R. S.; Ward, S. A.; Park, B. K.; Mabbs, F. Biomimetic Fe (II) -Mediated Degradation of Arteflene (Ro-42-1611). The First EPR Spin-Trapping Evidence for the Previously Postulated Secondary Carbon-Centered Cyclohexyl Radical. J. Org. Chem. 2000, 65, 1578-1582. (Pubitemid 30145998)
22. Wu, W. M.; Wu, Y.; Wu, Y. L.; Yao, Z. J.; Zhou, C. M.; Li, Y.; Shan, F. Unified Mechanistic Framework for the Fe (II) -Induced Cleavage of Qinghaosu and Derivatives/Analogues. The First Spin-Trapping Evidence for the Previously Postulated Secondary C-4 Radical. J. Am. Chem. Soc. 1998, 120, 3316-3325. (Pubitemid 28289067)
23. Haynes, R. K.; Chan, W. C.; Lung, C. M.; Uhlemann, A. C.; Eckstein, U.; Taramelli, D.; Parapini, S.; Monti, D.; Krishna, S. The Fe2+-mediated decomposotion, PfATP6 binding, and antimalarial activities of artemisone and other arteminisins: The unlikehood of C-centered radicals as bioactive intermediates. Chem Med Chem 2007, 2, 1480-1497.
24. Haynes, R. K.; Vonwiller, S. C. The behaviour of qinghaosu (artemisinin) in the presence of heme iron (II) and (III). Tetrahedron Lett. 1996, 37, 253-256.
25. Haynes, R. K.; Pai, H. H.-O.; Voerste, A. Ring opening of artemisinin (qinghaosu) and dihydroartemisinin and interception of the open hydroperoxides with Formation of N-oxides - a chemical model for antimalarial mode of action. Tetrahedron Lett. 1999, 40, 4715-4718. (Pubitemid 29274043)
26. Haynes, R. K.; Vonwiller, S. C. The behaviour of qinghaosu (artemisinin) in the presence of nonheme iron (II) and (III). Tetrahedron Lett. 1996, 37, 257-260.
27. Stocks, P. A.; Bray, P. G.; Barton, V. E.; Al-Helal, M.; Jones, M.; Araujo, N. C.; Gibbons, P.; Ward, S. A.; Hughes, R. H.; Biagini, G. A.; Davies, J.; Amewu, R.; Mercer, A. E.; Ellis, G.; O'Neill, P. M. Evidence for a common non-heme chelatable-iron-dependent activation mechanism for semisynthetic and synthetic endoperoxide antimalarial drugs. Angew. Chem. Int. Ed. 2007, 119, 6394-6399. (Pubitemid 47329416)
28. Eckstein-Ludwig, U.; Webb, R. J.; van Goethem, L. D. A.; East, J. M.; Lee, A. G.; Kimura, M.; O'Neill, P. M.; Bray, P. G.; Ward, S. A.; Krishna, S. Artemisinins target the SERCA of plasmodium falciparum. Nature 2003, 424, 957-961. (Pubitemid 37051688)
29. Haynes, R. K.; Monti, D.; Taramelli, D.; Basilico, N.; Parapini, S.; Olliaro, P. Artemisinin antimalarials do not inhibit hemozoin formation. Antimicrob. Agents Chemother. 2003, 47, 1175-1175. (Pubitemid 36254260)
30. Reeder, B. J.; Wilson, M. T. Desferrioxamine Inhibits Production of Cytotoxic Heme to Protein Cross-Linked Myoglobin: A Mechanism to Protect against Oxidative Stress without Iron Chelation. Chem. Res. Toxicol. 2005, 18, 1004-1011.
31. Reeder, B. J.; Hider, R. C.; Wilson, M. T. Iron chelators can protect against oxidative stress through ferryl heme reduction. Free Radical Biol. Med. 2008, 44, 264-273.
32. As commented by a reviewer DFO can potentially act as general antioxidant and therefore this should be taken into consideration when interpreting isobolograms/interactions with artemisinin.
33. Zhang, S.; Gerhard, G. Heme activates artemisinin more efficiently than hemin, inorganic iron, or hemoglobin. Bioorg. Med. Chem. 2008, 16, 7853-7861.
34. Creek, D. J.; Ryan, E.; Charman, W. N.; Chiu, F. C. K.; Prankerd, R. J.; Vennerstrom, J. L.; Charman, S. A. Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin. Antimicrob. Agents Chemother. 2009, 53, 3496-3500.
35. Skinner, T. S.; Manning, L. S.; Johnston, W. A.; Davis, T. M. E. In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs. Int. J. Parasit. 1996, 26, 519-525. (Pubitemid 26244548)
36. Jones-Brando, L.; D'Angelo, J.; Posner, G. H.; Yolken, R. In vitro inhibition of toxoplasma gondii by four new derivatives of artemisinin. Antimicrob. Agents Chemother. 2006, 50, 4206-4208.
37. Kumar, S.; Gupta, A. K.; Pal, Y.; Dwivedi, S. K. In-vivo therapeutic efficacy trial with artemisinin derivative, buparvaquone and imidocarb dipropionate against babesia equi infection in donkeys. J. Vet. Med. Sci. 2003, 65, 1171-1177. (Pubitemid 41380039)
38. Bakar, N. A.; Klonis, N.; Hanssen, E.; Chan, C.; Tilley, L. Digestive-vacuole genesis and endocytic processes in the early intraerythrocytic stages of Plasmodium falciparum. J. Cell Sci. 2010, 123, 441-450.
39. Woerdenbag, H. J.; Moskal, T. A.; Pras, N.; Malingre, T. M.; Elferaly, F. S.; Kampinga, H. H.; Konings, A. W. T. Cytotoxicity of artemisinin-related endoperoxides to ehrlich ascites tumor-cells. J. Nat. Prod. 1993, 56, 849-856.
40. Beekman, A. C.; Woerdenbag, H. J.; Kampinga, H. H.; Konings, A. W. T. Cytotoxicity of artemisinin, a dimer of dihydroartemisinin, artemisitene and eupatoriopicrin as evaluated by the MTT and clonogenic assay. Phytother. Res. 1996, 10, 140-144.
41. Beekman, A. C.; Barentsen, A. R. W.; Woerdenbag, H. J.; Van Uden, W.; Pras, N.; Konings, A. W. T.; ElFeraly, F. S.; Galal, A. M.; Wikstrom, H. V. Stereochemistry-dependent cytotoxicity of some artemisinin derivatives. J. Nat. Prod. 1997, 60, 325-330.
42. Beekman, A. C.; Wierenga, P. K.; Woerdenbag, H. J.; Van Uden, W.; Pras, N.; Konings, A. W. T.; El-Feraly, F. S.; Galal, A. M.; Wikstrom, H. V. Artemisinin-derived sesquiterpene lactones as potential antitumour compounds: Cytotoxic action against bone marrow and tumour cells. Planta Medica 1998, 64, 615-619.
43. Kwok, J. C.; Richardson, D. R. The iron metabolism of neoplastic cells: alterations that facilitate proliferation? Crit. Rev. Oncol. Hematol. 2002, 42, 65-78.
44. Efferth, T.; Sauerbrey, A.; Olbrich, A.; Gebhart, E.; Rauch, P.; Weber, H. O.; Hengstler, J. G.; Halatsch, M. E.; Volm, M.; Tew, K. D.; Ross, D. D.; Funk, J. O. Molecular modes of action of artesunate in tumor cell lines. Mol. Pharmacol. 2003, 64, 382-394.
45. Ramacher, M.; Umansky, V.; Efferth, T. Effect of artesunate on immune cells in ret-transgenic mouse melanoma model. Anti-Cancer Drugs 2009, 20, 910-917.
46. Stockwin, L. H.; Han, B. N.; Yu, S. X.; Hollingshead, M. G.; ElSohly, M. A.; Gul, W.; Slade, D.; Galal, A. M.; Newton, D. L. Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction. Int. J. Cancer 2009, 125, 1266-1275.
47. Efferth, T.; Benakis, A.; Romero, M. R.; Tomicic, M.; Rauh, R.; Steinbach, D.; Häfer, R.; Stamminger, T.; Oesch, F.; Kaina, B.; Marschall, M. Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron. Free Radical Biol. Med. 2004, 37, 998-1009.
48. Efferth, T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr. Drug Targets 2006, 4, 407-421.
49. Mercer, A.; Maggs, J.; Sun, X.; Cohen, G.; Chadwick, J.; O'Neill, P.; Park, B. Evidence for the involvement of carbon-centered radicals in the induction of apoptotic cell death by artemisinin compounds. J. Biol. Chem. 2007, 282, 9372-9382.
50. Kelter, G.; Steinbach, D.; Konkimalla, V. B.; Tahara, T.; Taketani, S.; Fiebig, H.-H.; Efferth, T. Role of Transferrin Receptor and the ABC Transporters ABCB6 and ABCB7 for Resistance and Differentiation of Tumor Cells towards Artesunate. PLoS ONE 2007, 2, e798.
51. Zhang, S.; Gerhard, G. S. Heme Mediates Cytotoxicity from Artemisinin and Serves as a General Anti-Proliferation Target. PLoS ONE 2009, 4, e7472.
52. Meshnick, S. R.; Little, B.; Yang, Y. Z. Alkylation of Proteins by artemisinin. Biochem. Pharm. 1994, 48, 569-573.
53. Meshnick, S. R.; Yang, Y. Z.; Lima, V.; Kuypers, F.; Kamchonwongpaisan, S.; Yuthavong, Y. Antimicrob. Agents Chemother. 1993, 37, 1108-1114.
54. Cazelles, J.; Robert, A.; Meunier, B. Alkylation of heme by artemisinin, an antimalarial drug. Comptes Rendus De L'Academie Des Sciences Serie Ii Fascicule C-Chimie 2001, 4, 85-89.
55. Creek, D. J.; Charman, W. N.; Chiu, F. C. K.; Prankerd, R. J.; Dong, Y.; Vennerstrom, J. L.; Charman, S. A. Relationship between Antimalarial activity and Heme Alkylation. Antimicrob. Agents Chemother. 2008, 52, 1291-1296.
56. Robert, A.; Benoit-Vical, F. O.; Claparols, C.; Meunier, B. The antimalarial drug artemisinin alkylates heme in infected mice. Proc. Nat. Acad. Sci. USA 2005, 102, 13676-13680.
57. Bousejra-El Garah, F.; Claparols, C.; Benoit-Vical, F.; Meunier, B.; Robert, A. The antimalarial trioxaquine du1301 alkylates heme in malaria-infected mice. Antimicrob. Agents Chemother. 2008, 52, 2966-2969.
58. Meshnick, S. R.; Little, B.; Yang, Y. Z. Alkylation of human albumin by the antimalarial artemisinin. Biochem. Pharm. 1993, 46, 336-339.
59. Asawamahasakda, W.; Ittarat, I.; Pu, Y. M.; Ziffer, H.; Meshnick, S. R. Reaction of Antimalarial Endoperoxides with specific parasite proteins. Antimicrob. Agents Chemother. 1994, 38, 1854-1858.
60. Bhisutthibhan, J.; Pan, X.; Hossler, P. A.; Walker, D. J.; Yowell, C. A.; Carlton, J.; Dame, J. B.; Meshnick, S. R. The plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin. J. Biol. Chem. 1998, 273, 16192-16198.
61. Wu, W.-M.; Chen, Y.-L.; Zhai, Z.; Xiao, S.-H.; Wu, Y.-L. Study on the mechanism of action of artemether against schistosomes: the identification of cysteine adducts of both carbon-centred free radicals derived from artemether. Bioorg. Med. Chem. Lett. 2003, 13, 1645-1647.
62. Pandey, A. V.; Tekwani, B. L.; Singh, R. L.; Chauhan, V. S. Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite. J. Biol. Chem. 1999, 27, 19383-19388. (Pubitemid 129519370)
63. Jefford, C. W. New developments in synthetic peroxidic drugs as artemisinin mimics. Drug Discovery Today 2007, 12, 487-495.
64. Jung, M.; Kim, H.; Ki, Y. N.; Kyoung, T. N. Three-dimensional structure of Plasmodium falciparum Ca2+-ATPase (PfATP6) and docking of artemisinin derivatives to PfATP6. Bioorg. Med. Chem. Lett. 2005, 15, 2994-2997. (Pubitemid 40755184)
65. Uhlemann, A. C.; Cameron, A.; Eckstein-Ludwig, U.; Fischbarg, J.; Iserovich, P.; Zuniga, F. A.; East, M.; Lee, A.; Brady, L.; Haynes, R. K.; Krishna, S. A single amino acid residue can determine the sensitivity of SERCAs to artemisinin. Nat. Struct. Mol. Biol. 2005, 12, 628-629. (Pubitemid 40980816)
66. Afonso, A.; Hunt, P.; Cheesman, S.; Alves, A. C.; Cunha, C. V.; do Rosario, V.; Cravo, P. Malaria Parasites Can Develop Stable Resistance to Artemisinin but Lack Mutations in Candidate Genes atp6 (Encoding the Sarcoplasmic and Endoplasmic Reticulum Ca2+ ATPase), tctp, mdr1, and cg10. Antimicrob. Agents Chemother. 2006, 50, 480-489. (Pubitemid 43190956)
67. del Pilar Crespo, M.; Avery, T. D.; Hanssen, E.; Fox, E.; Robinson, T. V.; Valente, P.; Taylor, D. K.; Tilley, L. Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology. Antimicrob. Agents Chemother. 2008, 52, 98-109.
68. Uhlemann, A.-C.; Wittlin, S.; Matile, H.; Bustamante, L.; Krishna, S. Mechanism of Antimalarial Action of the Synthetic Trioxolane RBX11160 (OZ277) Antimicrob. Agents Chemother. 2007, 51, 667-672. (Pubitemid 46185288)
69. Bousejra-El Garah, F.; Stigliani, J. L.; Cosledan, F.; Meunier, B.; Robert, A. Docking Studies of Structurally Diverse Antimalarial Drugs Targeting PfATP6: No Correlation between in silico Binding Affinity and in vitro Antimalarial Activity. ChemMedChem 2009, 4, 1469-1479.
70. Hartwig, C. L.; Rosenthal, A. S.; Dangelo, J.; Griffin, C. E.; Posner, G. H.; Cooper, R. A. Accumulation of artemisinin trioxane derivatives within neutral lipids of Plasmodium falciparum malaria parasites is endoperoxide-dependent. Biochem. Pharmacol. 2009, 77, 322-336.
71. Kumura, N.; Furukawa, H.; Onyango, A. N.; Izumi, M.; Nakajima, S.; Ito, H.; Hatano, T.; Kim, H. S.; Wataya, Y.; Baba, N. Different behavior of artemisinin and tetraoxane in the oxidative degradation of phospholipid. Chem. Phys. Lipids 2009, 160, 114-120.
72. Li, W.; Mo, W.; Shen, D.; Sun, L.; Wang, J.; Lu, S.; Gitschier, J. M.; Zhou, B. Yeast model uncovers dual roles of mitochondria in the action of artemisinin. PLoS Genet. 2005, 1, 329-334.
73. Efferth, T.; Oesch, F. Oxidative stress response of tumor cells: microarray-based comparison between artemisinins and anthracyclines. Biochem. Pharmacol. 2004, 68, 3-10. (Pubitemid 38746536)
74. Efferth, T.; Briehl, M. M.; Tome, M. E. Role of antioxidant genes for the activity of artesunate against tumor cells. Int. J. Oncol. 2003, 4, 1231-1235.
75. Efferth, T. Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. Drug Resist Updates 2005, 8, 85-97. (Pubitemid 40797959)
76. Youns, M.; Efferth, T.; Reichling, J.; Fellenberg, K.; Bauer, A.; Hoheisel, J. D. Gene expression profiling identifies novel key players involved in the cytotoxic effect of Artesunate on pancreatic cancer cells. Biochem. Pharmacol. 2009, 78, 273-283.
77. Yang, Y. Z.; Little, B.; Meshnick, S. R. Alkylation proteins by artemisinin. Effect of heme, pH, and drug structure. Biochem. Pharmacol. 1994, 48, 569-573. (Pubitemid 124009658)
78. Li, P. C. H.; Lam, E.; Roos, W. P.; Zdzienicka, M. Z.; Kaina, B.; Efferth, T. Artesunate Derived from Traditional Chinese Medicine Induces DNA Damage and Repair. Cancer Res. 2008, 68, 4347-4351.