Artemisinins: their growing importance in medicine

Sanjeev Krishna, Leyla Bustamante, Richard K Haynes, Henry M Staines, Sanjeev Krishna, Leyla Bustamante, Richard K Haynes, Henry M Staines

Abstract

Artemisinins are derived from extracts of sweet wormwood (Artemisia annua) and are well established for the treatment of malaria, including highly drug-resistant strains. Their efficacy also extends to phylogenetically unrelated parasitic infections such as schistosomiasis. More recently, they have also shown potent and broad anticancer properties in cell lines and animal models. In this review, we discuss recent advances in defining the role of artemisinins in medicine, with particular focus on their controversial mechanisms of action. This safe and cheap drug class that saves lives at risk from malaria can also have important potential in oncology.

Figures

Figure 1
Figure 1
Chemical structures of artemisinins. Artemisinin (a) isolated in crystalline form in 1973 from Artemisia annua and derivatives dihydroartemisinin (DHA) (b), artemether (c), artesunate (d) and arteether (f) were first prepared by Chinese scientists in the 1970s . Artemisone (e), representative of a new class of artemisinin known as amino-artemisinins, is curative in clinical trials at one-third the dose regimen of artesunate. It is characterized by low toxicity . Artelinate (g) was prepared at the Walter Reed Army Institute of Research (http://wrair-www.army.mil), but was withdrawn because of toxicity concerns . Deoxyartemisinin (h), lacking the peroxide bridge, is biologically inert.
Figure I
Figure I
Diagram showing the complex life cycle of Plasmodium falciparum. Abbreviations: AA, amino acids; Ap, apicoplast; ART, artemisinins; DV, digestive vacuole; ER, endoplasmic reticulum; G, Golgi apparatus; Hb, haemoglobin; Hz, haemozoin; M, mitochondrion; N, nucleus; RBC, red blood cell; TCTP, translationally controlled tumour protein.

References

    1. Zhang J.-F. Yang Cheng Evening News Publishing Company; 2005. A Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin)
    1. Kremsner P.G., Krishna S. Antimalarial combinations. Lancet. 2004;364:285–294.
    1. White N.J. Antimalarial drug resistance. J. Clin. Invest. 2004;113:1084–1092.
    1. Haynes R.K. The Fe2+-mediated decomposition, PfATP6 binding, and antimalarial activities of artemisone and other artemisinins: the unlikelihood of C-centered radicals as bioactive intermediates. Chem. Med. Chem. 2007;2:1480–1497.
    1. Vennerstrom J.L. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature. 2004;430:900–904.
    1. Gelb M.H. Drug discovery for malaria: a very challenging and timely endeavor. Curr. Opin. Chem. Biol. 2007;11:440–445.
    1. Golenser J. Current perspectives on the mechanism of action of artemisinins. Int. J. Parasitol. 2006;36:1427–1441.
    1. Jefford C.W. New developments in synthetic peroxidic drugs as artemisinin mimics. Drug Discov. Today. 2007;12:487–495.
    1. Krishna S. Re-evaluation of how artemisinins work in light of emerging evidence of in vitro resistance. Trends Mol. Med. 2006;12:200–205.
    1. Yuthavong Y. Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors. Parasitology. 2005;130:249–259.
    1. Yuvaniyama J. Insights into antifolate resistance from malarial DHFR-TS structures. Nat. Struct. Biol. 2003;10:357–365.
    1. Peters W., Richards W.H.G. 2nd edn. Vol. 1. Springer-Verlag; 1984. (Handbook of Experimental Therapeutics Antimalarial Drugs).
    1. Peters W., Richards W.H.G. 2nd edn. Vol. 2. Springer-Verlag; 1984. (Handbook of Experimental Therapeutics. Antimalarial Drugs).
    1. Hunt P. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites. Mol. Microbiol. 2007;65:27–40.
    1. Afonso A. 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.
    1. Ferrer-Rodriguez I. Plasmodium yoelii: identification and partial characterization of an MDR1 gene in an artemisinin-resistant line. J. Parasitol. 2004;90:152–160.
    1. Puri S.K., Chandra R. Plasmodium vinckei: selection of a strain exhibiting stable resistance to arteether. Exp. Parasitol. 2006;114:129–132.
    1. Walker D.J. Mechanisms of artemisinin resistance in the rodent malaria pathogen Plasmodium yoelii. Antimicrob. Agents Chemother. 2000;44:344–347.
    1. Bray P.G. Quinolines and artemisinin: chemistry, biology and history. Curr. Top. Microbiol. Immunol. 2005;295:3–38.
    1. Haynes R.K. Artemisinin antimalarials do not inhibit hemozoin formation. Antimicrob. Agents Chemother. 2003;47:1175.
    1. Eckstein-Ludwig U. Artemisinins target the SERCA of Plasmodium falciparum. Nature. 2003;424:957–961.
    1. Ellis D.S. The chemotherapy of rodent malaria, XXXIX. Ultrastructural changes following treatment with artemisinine of Plasmodium berghei infection in mice, with observations of the localization of [3H]-dihydroartemisinine in P. falciparum in vitro. Ann. Trop. Med. Parasitol. 1985;79:367–374.
    1. Stocks P.A. Evidence for a common non-heme chelatable-iron-dependent activation mechanism for semisynthetic and synthetic endoperoxide antimalarial drugs. Angew. Chem. Int. Ed. Engl. 2007;46:6278–6283.
    1. Uhlemann A.C. Mechanism of antimalarial action of the synthetic trioxolane RBX11160 (OZ277) Antimicrob. Agents Chemother. 2007;51:667–672.
    1. Creek D.J. Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials. Antimicrob. Agents Chemother. 2008;52:1291–1296.
    1. Creek D.J. Kinetics of iron-mediated artemisinin degradation: effect of solvent composition and iron salt. J. Pharm. Sci. 2005;94:1820–1829.
    1. Charman S.A. Second generation synthetic peroxide antimalarials. Am. J. Trop. Med. Hyg. 2007;77(Suppl. 5):95.
    1. Kreidenweiss A. Antimalarial activity of a synthetic endoperoxide (RBx-11160/OZ277) against Plasmodium falciparum isolates from Gabon. Antimicrob. Agents Chemother. 2006;50:1535–1537.
    1. Kannan R. Reaction of artemisinin with haemoglobin: implications for antimalarial activity. Biochem. J. 2005;385:409–418.
    1. ter Kuile F. Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria. Exp. Parasitol. 1993;76:85–95.
    1. Desakorn V. Stage-dependent production and release of histidine-rich protein 2 by Plasmodium falciparum. Trans. R. Soc. Trop. Med. Hyg. 2005;99:517–524.
    1. Charoenteeraboon J. Inactivation of artemisinin by thalassemic erythrocytes. Biochem. Pharmacol. 2000;59:1337–1344.
    1. Ittarat W. Effects of α-thalassemia on pharmacokinetics of the antimalarial agent artesunate. Antimicrob. Agents Chemother. 1998;42:2332–2335.
    1. Hutagalung R. Influence of hemoglobin E trait on the antimalarial effect of artemisinin derivatives. J. Infect. Dis. 2000;181:1513–1516.
    1. Monti D. Does chloroquine really act through oxidative stress? FEBS Lett. 2002;522:3–5.
    1. Parapini S. Evidence that haem iron in the malaria parasite is not needed for the antimalarial effects of artemisinin. FEBS Lett. 2004;575:91–94.
    1. Jambou R. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet. 2005;366:1960–1963.
    1. Legrand E. In vitro monitoring of Plasmodium falciparum drug resistance in French Guiana: a synopsis of continuous assessment from 1994 to 2005. Antimicrob. Agents Chemother. 2008;52:288–298.
    1. Hayward R. pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum. Mol. Microbiol. 2005;55:1285–1295.
    1. Walliker D. Fitness of drug-resistant malaria parasites. Acta Trop. 2005;94:251–259.
    1. Cojean S. Resistance to dihydroartemisinin. Emerg. Infect. Dis. 2006;12:1798–1799.
    1. Legrand E. Resistance to dihydroartemisinin. Emerg. Infect. Dis. 2007;13:808–809.
    1. Toyoshima C. Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 Å resolution. Nature. 2000;405:647–655.
    1. Uhlemann A.C. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins. Nat. Struct. Mol. Biol. 2005;12:628–629.
    1. Price R.N. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004;364:438–447.
    1. Li W. Yeast model uncovers dual roles of mitochondria in action of artemisinin. PLoS Genet. 2005;1:e36.
    1. Alenquer M. Adaptive response to the antimalarial drug artesunate in yeast involves Pdr1p/Pdr3p-mediated transcriptional activation of the resistance determinants TPO1 and PDR5. FEMS Yeast Res. 2006;6:1130–1139.
    1. Schmuck G. Neurotoxic mode of action of artemisinin. Antimicrob. Agents Chemother. 2002;46:821–827.
    1. Dondorp A. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005;366:717–725.
    1. Nealon C. Intramuscular bioavailability and clinical efficacy of artesunate in gabonese children with severe malaria. Antimicrob. Agents Chemother. 2002;46:3933–3939.
    1. Woodrow C.J. Artesunate versus quinine for severe falciparum malaria: a randomised trial. Lancet. 2006;367:110–111.
    1. Gomes M. Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies. BMC Infect. Dis. 2008;8:39.
    1. Krishna S. Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria. Antimicrob. Agents Chemother. 2001;45:509–516.
    1. Campos, M.S. et al. Fatal artesunate toxicity in a child. J. Pediatr. Infect. Dis. (in press)
    1. Woodrow C.J. Artemisinins. Postgrad. Med. J. 2005;81:71–78.
    1. Haynes R.K. Artemisone – a highly active antimalarial drug of the artemisinin class. Angew. Chem. Int. Ed. Engl. 2006;45:2082–2088.
    1. Nagamune K. Artemisinin induces calcium-dependent protein secretion in the protozoan parasite Toxoplasma gondii. Eukaryot. Cell. 2007;6:2147–2156.
    1. Nagamune K. Artemisinin-resistant mutants of Toxoplasma gondii have altered calcium homeostasis. Antimicrob. Agents Chemother. 2007;51:3816–3823.
    1. Vial H.J., Gorenflot A. Chemotherapy against babesiosis. Vet. Parasitol. 2006;138:147–160.
    1. Utzinger J. Artemisinins for schistosomiasis and beyond. Curr. Opin. Investig. Drugs. 2007;8:105–116.
    1. Mishina Y.V. Artemisinins inhibit Trypanosoma cruzi and Trypanosoma brucei rhodesiense in vitro growth. Antimicrob. Agents Chemother. 2007;51:1852–1854.
    1. Xiao S.H. Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins. Acta Trop. 2005;96:153–167.
    1. Chen D.J. Experimental studies on antischistosomal activity of qinghaosu. Zhong Hui Yi Xue Zha Zhi. 1980;60:422–425.
    1. Efferth T. The anti-malarial artesunate is also active against cancer. Int. J. Oncol. 2001;18:767–773.
    1. Kelter G. 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.
    1. Li L.N. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/β-catenin pathway. Int. J. Cancer. 2007;121:1360–1365.
    1. Zhou H.J. Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. Vascul. Pharmacol. 2007;47:131–138.
    1. Wu X.H. Dihydroartemisinin inhibits angiogenesis induced by multiple myeloma RPMI8226 cells under hypoxic conditions via downregulation of vascular endothelial growth factor expression and suppression of vascular endothelial growth factor secretion. Anticancer Drugs. 2006;17:839–848.
    1. Li J., Zhou H.J. Dihydroartemisinin inhibits the expression of vascular endothelial growth factor in K562 cells. Yao Xue Xue Bao. 2005;40:1041–1045.
    1. Anfosso L. Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics J. 2006;6:269–278.
    1. Longo M. Effects of the antimalarial drug dihydroartemisinin (DHA) on rat embryos in vitro. Reprod. Toxicol. 2006;21:83–93.
    1. Dell’Eva R. Inhibition of angiogenesis in vivo and growth of Kaposi's sarcoma xenograft tumors by the anti-malarial artesunate. Biochem. Pharmacol. 2004;68:2359–2366.
    1. Huan-huan C. Artesunate reduces chicken chorioallantoic membrane neovascularisation and exhibits antiangiogenic and apoptotic activity on human microvascular dermal endothelial cell. Cancer Lett. 2004;211:163–173.
    1. Chen H.H. Antimalarial dihydroartemisinin also inhibits angiogenesis. Cancer Chemother. Pharmacol. 2004;53:423–432.
    1. Chen H.H. Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacology. 2004;71:1–9.
    1. Wartenberg M. The antimalaria agent artemisinin exerts antiangiogenic effects in mouse embryonic stem cell-derived embryoid bodies. Lab. Invest. 2003;83:1647–1655.
    1. Chen H.H. Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro. Pharmacol. Res. 2003;48:231–236.
    1. Wu G.D. Apoptosis of human umbilical vein endothelial cells induced by artesunate. Vascul. Pharmacol. 2004;41:205–212.
    1. Efferth T., Oesch F. Oxidative stress response of tumor cells: microarray-based comparison between artemisinins and anthracyclines. Biochem. Pharmacol. 2004;68:3–10.
    1. Efferth T. Role of antioxidant genes for the activity of artesunate against tumor cells. Int. J. Oncol. 2003;23:1231–1235.
    1. Singh N.P., Lai H.C. Synergistic cytotoxicity of artemisinin and sodium butyrate on human cancer cells. Anticancer Res. 2005;25:4325–4331.
    1. Kim S.J. Dihydroartemisinin enhances radiosensitivity of human glioma cells in vitro. J. Cancer Res. Clin. Oncol. 2006;132:129–135.
    1. Efferth T. Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron. Free Radic. Biol. Med. 2004;37:998–1009.
    1. Singh N.P., Lai H.C. Artemisinin induces apoptosis in human cancer cells. Anticancer Res. 2004;24:2277–2280.
    1. Sadava D. Transferrin overcomes drug resistance to artemisinin in human small-cell lung carcinoma cells. Cancer Lett. 2002;179:151–156.
    1. Singh N.P., Lai H. Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Life Sci. 2001;70:49–56.
    1. Lai H., Singh N.P. Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin. Cancer Lett. 1995;91:41–46.
    1. Berger T.G. Artesunate in the treatment of metastatic uveal melanoma – first experiences. Oncol. Rep. 2005;14:1599–1603.
    1. Singh N.P., Panwar V.K. Case report of a pituitary macroadenoma treated with artemether. Integr. Cancer Ther. 2006;5:391–394.
    1. Zhang Z.Y. Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial. Zhong Xi Yi Jie He Xue Bao. 2008;6:134–138.
    1. Paeshuyse J. Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin. Biochem. Biophys. Res. Commun. 2006;348:139–144.
    1. Romero M.R. Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an “in vitro” replicative system. Antiviral Res. 2005;68:75–83.
    1. Efferth T. Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses. J. Mol. Med. 2002;80:233–242.
    1. Kaptein S.J. The anti-malaria drug artesunate inhibits replication of cytomegalovirus in vitro and in vivo. Antiviral Res. 2006;69:60–69.
    1. Naesens L. Antiviral activity of diverse classes of broad-acting agents and natural compounds in HHV-6-infected lymphoblasts. J. Clin. Virol. 2006;37(Suppl. 1):S69–S75.
    1. Efferth T. Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrug-resistant human CCRF-CEM leukemia cells. Blood Cells Mol. Dis. 2002;28:160–168.
    1. Qian R.S. The immunologic and antiviral effect of qinghaosu. J. Tradit. Chin. Med. 1982;2:271–276.
    1. Romero M.R. Antiviral effect of artemisinin from Artemisia annua against a model member of the Flaviviridae family, the bovine viral diarrhoea virus (BVDV) Planta Med. 2006;72:1169–1174.
    1. Shapira M.Y. Artesunate as a potent antiviral agent in a patient with late drug-resistant cytomegalovirus infection after hematopoietic stem cell transplantation. Clin. Infect. Dis. 2008;46:1455–1457.
    1. Merali S., Meshnick S.R. Susceptibility of Pneumocystis carinii to artemisinin in vitro. Antimicrob. Agents Chemother. 1991;35:1225–1227.
    1. Ni X., Chen Y. In vitro study of the anti-pneumocystis carinii effect of arteminsin derivatives. Zhonghua Jie He He Hu Xi Za Zhi. 2001;24:164–167.
    1. Brun-Pascaud M. Lack of activity of artemether for prophylaxis and treatment of Toxoplasma gondii and Pneumocystis carinii infections in rat. Parasite. 1996;3:187–189.
    1. Chen Y.T. An experimental trial of artemether in treatment of Pneumocystis carinii in immunosuppressed rats. Chin. Med. J. (Engl.) 1994;107:673–677.
    1. Xu H. Anti-malarial agent artesunate inhibits TNF-α-induced production of proinflammatory cytokines via inhibition of NF-κB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology (Oxford) 2007;46:920–926.
    1. Mirshafiey A. Design of a new line in treatment of experimental rheumatoid arthritis by artesunate. Immunopharmacol. Immunotoxicol. 2006;28:397–410.
    1. Cuzzocrea S. Artemether: a new therapeutic strategy in experimental rheumatoid arthritis. Immunopharmacol. Immunotoxicol. 2005;27:615–630.
    1. Razavi A. Treatment of experimental nephrotic syndrome with artesunate. Int. J. Toxicol. 2007;26:373–380.
    1. Zhao M. Induction of apoptosis by artemisinin relieving the severity of inflammation in caerulein-induced acute pancreatitis. World J. Gastroenterol. 2007;13:5612–5617.
    1. Li W.D. Dihydroarteannuin ameliorates lupus symptom of BXSB mice by inhibiting production of TNF-α and blocking the signaling pathway NF-κB translocation. Int. Immunopharmacol. 2006;6:1243–1250.
    1. Dong Y.J. Effect of dihydro-qinghaosu on auto-antibody production. TNFα secretion and pathologic change of lupus nephritis in BXSB mice. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2003;23:676–679.
    1. Lu L. Study on effect of Cordyceps sinensis and artemisinin in preventing recurrence of lupus nephritis. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2002;22:169–171.
    1. Li Q. Toxicokinetics and hydrolysis of artelinate and artesunate in malaria-infected rats. Int. J. Toxicol. 2005;24:241–250.

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