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Engineering >> 2019, Volume 5, Issue 1 doi: 10.1016/j.eng.2018.11.011

Artemisinin, the Magic Drug Discovered from Traditional Chinese Medicine

a Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
b Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
c Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
d Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore

Received: 2018-06-08 Revised: 2018-08-01 Accepted: 2018-11-12 Available online: 2018-12-18

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Abstract

Artemisinin and its derivatives represent the most important and influential class of drugs in the fight against malaria. Since the discovery of artemisinin in the early 1970s, the global community has made great strides in characterizing and understanding this remarkable phytochemical and its unique chemical and pharmacological properties. Today, even as artemisinin continues to serve as the foundation for antimalarial therapy, numerous challenges have surfaced in the continued application and development of this family of drugs. These challenges include the emergence of delayed treatment responses to artemisinins in malaria and efforts to apply artemisinins for non-malarial indications. Here, we provide an overview of the story of artemisinin in terms of its past, present, and future. In particular, we comment on the current understanding of the mechanism of action (MOA) of artemisinins, and emphasize the importance of relating mechanistic studies to therapeutic outcomes, both in malarial and non-malarial contexts.

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References

[ 1 ] Tu Y. Artemisinin—a gift from traditional Chinese medicine to the world (Nobel lecture). Angew Chem Int Ed 2016;55(35):10210–26. link1

[ 2 ] Cox FE. History of the discovery of the malaria parasites and their vectors. Parasit Vectors 2010;3(1):5. link1

[ 3 ] Krishna S, Bustamante L, Haynes RK, Staines HM. Artemisinins: their growing importance in medicine. Trends Pharmacol Sci 2008;29(10):520–7. link1

[ 4 ] World Health Organization. World malaria report 2017. Geneva: World Health Organization; 2017. link1

[ 5 ] Ding XC, Beck HP, Raso G. Plasmodium sensitivity to artemisinins: magic bullets hit elusive targets. Trends Parasitol 2011;27(2):73–81. link1

[ 6 ] Efferth T, Romero MR, Bilia AR, Osman AG, Sohly ME, et al. Expanding the therapeutic spectrum of artemisinin: activity against infectious diseases beyond malaria and novel pharmaceutical developments. World J Tradit Chin Med 2016;2(2):1–23. link1

[ 7 ] D’Alessandro U, Buttiëns H. History and importance of antimalarial drug resistance. Trop Med Int Health 2001;6(11):845–8. link1

[ 8 ] Tu Y. The discovery of artemisinin (Qinghaosu) and gifts from Chinese medicine. Nat Med 2011;17(10):1217–20. link1

[ 9 ] Liao F. Discovery of artemisinin (Qinghaosu). Molecules 2009;14(12):5362–6. link1

[10] Collaboration Research Group for Qinghaosu. A new sesquiterpene lactone— Qinghaosu. Chin Sci Bull 1997;3:142. Chinese.

[11] Wang MY. Publication process involving the discovery of artemisinin (Qinghaosu) before 1985. Asian Pac J Trop Biomed 2016;6(6):461–7. link1

[12] China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials. Chemical studies on Qinghaosu (artemisinine). J Tradit Chin Med 1982;2(1):3–8. Chinese.

[13] Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science 1985;228(4703):1049–55. link1

[14] Jiang JB, Li GQ, Guo XB, Kong YC, Arnold K. Antimalarial activity of mefloquine and Qinghaosu. Lancet 1982;2(8293):285–8. link1

[15] Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Suntharasamai P, Charoenlarp P, et al. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet 1992;339 (8797):821–4. link1

[16] Nosten F, Luxemburger C, ter Kuile FO, Woodrow C, Eh JP, Chongsuphajaisiddhi T, et al. Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. J Infect Dis 1994;170(4):971–7. link1

[17] Tran TH, Day NP, Nguyen HP, Nguyen TH, Tran TH, Pham PL, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996;335(2):76–83. link1

[18] Looareesuwan S, Wilairatana P, Viravan C, Vanijanonta S, Pitisuttithum P, Kyle DE. Open randomized trial of oral artemether alone and a sequential combination with mefloquine for acute uncomplicated falciparum malaria. Am J Trop Med Hyg 1997;56(6):613–7. link1

[19] Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N, et al; International Artemisinin Study Group. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 2004;363(9402):9–17. link1

[20] Von Seidlein L, Jaffar S, Pinder M, Haywood M, Snounou G, Gemperli B, et al. Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697. J Infect Dis 1997;176(4):1113–6. link1

[21] Von Seidlein L, Bojang K, Jones P, Jaffar S, Pinder M, Obaro S, et al. A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children. Am J Trop Med Hyg 1998;58 (5):638–44. link1

[22] Doherty JF, Sadiq AD, Bayo L, Alloueche A, Olliaro P, Milligan P, et al. A randomized safety and tolerability trial of artesunate plus sulfadoxine— pyrimethamine versus sulfadoxine-pyrimethamine alone for the treatment of uncomplicated malaria in Gambian children. Trans R Soc Trop Med Hyg 1999;93(5):543–6. link1

[23] Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, et al; AQUAMAT Group. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010;376(9753):1647–57. link1

[24] WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group. Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data. BMC Med 2015;13:212. link1

[25] Efferth T, Kaina B. Toxicity of the antimalarial artemisinin and its derivatives. Crit Rev Toxicol 2010;40(5):405–21. link1

[26] World Health Organization. Guidelines for the treatment of malaria. Geneva: World Health Organization; 2006. link1

[27] Luo XD, Shen CC. The chemistry, pharmacology, and clinical applications of Qinghaosu (artemisinin) and its derivatives. Med Res Rev 1987;7(1):29–52. link1

[28] White NJ. Clinical pharmacokinetics and pharmacodynamics of artemisinin and derivatives. Trans R Soc Trop Med Hyg 1994;88(Suppl 1):S41–3. link1

[29] De Vries PJ, Dien TK. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs 1996;52 (6):818–36. link1

[30] German PI, Aweeka FT. Clinical pharmacology of artemisinin-based combination therapies. Clin Pharmacokinet 2008;47(2):91–102. link1

[31] Robert A, Dechy-Cabaret O, Cazelles J, Meunier B. From mechanistic studies on artemisinin derivatives to new modular antimalarial drugs. Acc Chem Res 2002;35(3):167–74. link1

[32] Li J, Zhou B. Biological actions of artemisinin: insights from medicinal chemistry studies. Molecules 2010;15(8):1378–97. link1

[33] Van Agtmael MA, Eggelte TA, van Boxtel CJ. Artemisinin drugs in the treatment of malaria: from medicinal herb to registered medication. Trends Pharmacol Sci 1999;20(5):199–205. link1

[34] Meshnick SR, Taylor TE, Kamchonwongpaisan S. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev 1996;60(2):301–15. link1

[35] Posner GH, O’Neill PM. 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(6):397–404. link1

[36] O’Neill PM, Barton VE, Ward SA. The molecular mechanism of action of artemisinin—the debate continues. Molecules 2010;15(3):1705–21. link1

[37] Lew VL, Tiffert T, Ginsburg H. Excess hemoglobin digestion and the osmotic stability of Plasmodium falciparum-infected red blood cells. Blood 2003;101 (10):4189–94. link1

[38] Klonis N, Crespo-Ortiz MP, Bottova I, Abu-Bakar N, Kenny S, Rosenthal PJ, et al. Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. Proc Natl Acad Sci USA 2011;108(28):11405–10. link1

[39] Xie SC, Dogovski C, Hanssen E, Chiu F, Yang T, Crespo MP, et al. Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins. J Cell Sci 2016;129(2):406–16. link1

[40] Zhang F, Gosser DK Jr, Meshnick SR. Hemin-catalyzed decomposition of artemisinin (Qinghaosu). Biochem Pharmacol 1992;43(8):1805–9. link1

[41] Posner GH, Oh CH, Wang D, Gerena L, Milhous WK, Meshnick SR, et al. 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 (9):1256–8. link1

[42] Wu WM, Wu Y, Wu YL, Yao ZJ, Zhou CM, Li Y, et al. 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(14):3316–25. link1

[43] Stocks PA, Bray PG, Barton VE, Al-Helal M, Jones M, Araujo NC, et al. Evidence for a common non-heme chelatable-iron-dependent activation mechanism for semisynthetic and synthetic endoperoxide antimalarial drugs. Angew Chem Int Ed 2007;46(33):6278–83. link1

[44] Haynes RK, Chan WC, Lung CM, Uhlemann AC, Eckstein U, Taramelli D, et al. The Fe2+-mediated decomposition, PfATP6 binding, and antimalarial activities of artemisone and other artemisinins: the unlikelihood of C-centered radicals as bioactive intermediates. ChemMedChem 2007;2(10):1480–97. link1

[45] Meunier B, Robert A. Heme as trigger and target for trioxane-containing antimalarial drugs. Acc Chem Res 2010;43(11):1444–51. link1

[46] Haynes RK, Cheu KW, N’Da D, Coghi P, Monti D. Considerations on the mechanism of action of artemisinin antimalarials: part 1—the ‘carbon radical’ and ‘heme’ hypotheses. Infect Disord Drug Targets 2013;13(4):217–77. link1

[47] Wang J, Zhang CJ, Chia WN, Loh CC, Li Z, Lee YM, et al. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat Commun 2015;6:10111. link1

[48] Zhou Y, Li W, Xiao Y. Profiling of multiple targets of artemisinin activated by hemin in cancer cell proteome. ACS Chem Biol 2016;11(4):882–8. link1

[49] Zhang S, Gerhard GS. Heme activates artemisinin more efficiently than hemin, inorganic iron, or hemoglobin. Bioorg Med Chem 2008;16 (16):7853–61. link1

[50] Li W, Zhou Y, Tang G, Xiao Y. Characterization of the artemisinin binding site for translationally controlled tumor protein (TCTP) by bioorthogonal click chemistry. Bioconjug Chem 2016;27(12):2828–33. link1

[51] Li W, Mo W, Shen D, Sun L, Wang J, Lu S, et al. Yeast model uncovers dual roles of mitochondria in action of artemisinin. PLoS Genet 2005;1(3):e36. link1

[52] Wang J, Huang L, Li J, Fan Q, Long Y, Li Y, et al. Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation. PLoS One 2010;5(3):e9582. link1

[53] Sun C, Li J, Cao Y, Long G, Zhou B. Two distinct and competitive pathways confer the cellcidal actions of artemisinins. Microb Cell 2015;2(1):14–25. link1

[54] Fitch CD, Chevli R, Kanjananggulpan P, Dutta P, Chevli K, Chou AC. Intracellular ferriprotoporphyrin IX is a lytic agent. Blood 1983;62(6):1165–8. link1

[55] Egan TJ. Recent advances in understanding the mechanism of hemozoin (malaria pigment) formation. J Inorg Biochem 2008;102(5–6):1288–99. link1

[56] Cazelles J, Robert A, Meunier B. Alkylation of heme by artemisinin, an antimalarial drug. Acad Sci Chem 2001;4(2):85–9. link1

[57] Robert A, Benoit-Vical F, Claparols C, Meunier B. The antimalarial drug artemisinin alkylates heme in infected mice. Proc Natl Acad Sci USA 2005;102 (38):13676–80. link1

[58] Loup C, Lelièvre J, Benoit-Vical F, Meunier B. Trioxaquines and hemeartemisinin adducts inhibit the in vitro formation of hemozoin better than chloroquine. Antimicrob Agents Chemother 2007;51(10):3768–70. link1

[59] Yang YZ, Little B. Meshnick SR. Alkylation of proteins by artemisinin. Effects of heme, pH, and drug structure. Biochem Pharmacol 1994;48(3):569–73. link1

[60] Meshnick SR. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol 2002;32(13):1655–60. link1

[61] Bhisutthibhan J, Pan XQ, Hossler PA, Walker DJ, Yowell CA, Carlton J, et al. The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin. J Biol Chem 1998;273 (26):16192–8. link1

[62] Eckstein-Ludwig U, Webb RJ, Van Goethem ID, East JM, Lee AG, Kimura M, et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature 2003;424(9651):957–61. link1

[63] Uhlemann AC, Cameron A, Eckstein-Ludwig U, Fischbarg J, Iserovich P, Zuniga FA, et al. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins. Nat Struct Mol Biol 2005;12(7):628–9. link1

[64] Krishna S, Pulcini S, Fatih F, Staines H. Artemisinins and the biological basis for the PfATP6/SERCA hypothesis. Trends Parasitol 2010;26(11):517–23. link1

[65] Arnou B, Montigny C, Morth JP, Nissen P, Jaxel C, Møller JV, et al. The Plasmodium falciparum Ca2+-ATPase PfATP6: insensitive to artemisinin, but a potential drug target. Biochem Soc Trans 2011;39(3):823–31. link1

[66] Cui L, Wang Z, Jiang H, Parker D, Wang H, Su XZ, et al. Lack of association of the S769N mutation in Plasmodium falciparum SERCA (PfATP6) with resistance to artemisinins. Antimicrob Agents Chemother 2012;56 (5):2546–52. link1

[67] Krishna S, Pulcini S, Moore CM, Teo BH, Staines HM. Pumped up: reflections on PfATP6 as the target for artemisinins. Trends Pharmacol Sci 2014;35(1):4–11. link1

[68] Ismail HM, Barton V, Phanchana M, Charoensutthivarakul S, Wong MH, Hemingway J, et al. Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7. Proc Natl Acad Sci USA 2016;113(8):2080–5. link1

[69] Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al; Tracking Resistance to Artemisinin Collaboration (TRAC). Spread of artemisinin resistance in Plasmodium falciparum malaria. N Eng J Med 2014;371(5):411–23. link1

[70] Dondorp AM, Yeung S, White L, Nguon C, Day NP, Socheat D, et al. Artemisinin resistance: current status and scenarios for containment. Nat Rev Microbiol 2010;8(4):272–80. link1

[71] Paloque L, Ramadani AP, Mercereau-Puijalon O, Augereau JM, Benoit-Vical F. Plasmodium falciparum: multifaceted resistance to artemisinins. Malar J 2016;15:149. link1

[72] Tilley L, Straimer J, Gnädig NF, Ralph SA, Fidock DA. Artemisinin action and resistance in Plasmodium falciparum. Trends Parasitol 2016;32(9):682–96. link1

[73] Wang J, Xu C, Lun ZR, Meshnick SR. Unpacking ‘artemisinin resistance’. Trends Pharmacol Sci 2017;38(6):506–11. link1

[74] Gil JP, Krishna S. pfmdr1 (Plasmodium falciparum multidrug drug resistance gene 1): a pivotal factor in malaria resistance to artemisinin combination therapies. Expert Rev Anti Infect Ther 2017;15(6):527–43. link1

[75] Hanscheid T, Hardisty DW. How ‘‘resistant” is artemisinin resistant malaria?—The risks of ambiguity using the term ‘‘resistant” malaria. Travel Med Infect Dis 2018;24:23–4. link1

[76] Meshnick S. Perspective: artemisinin-resistant malaria and the wolf. Am J Trop Med Hyg 2012;87(5):783–4. link1

[77] World Health Organization. Artemisinin and artemisinin-based combination therapy resistance. Report. Geneva: World Health Organization; 2016 Apr. link1

[78] Ho WE, Peh HY, Chan TK, Wong WS. Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther 2014;142(1):126–39. link1

[79] Firestone GL, Sundar SN. Anticancer activities of artemisinin and its bioactive derivatives. Expert Rev Mol Med 2009;11:e32. link1

[80] Crespo-Ortiz MP, Wei MQ. Antitumor activity of artemisinin and its derivatives: from a well-known antimalarial agent to a potential anticancer drug. J Biomed Biotechnol 2012;2012:247597. link1

[81] Lai HC, Singh NP, Sasaki T. Development of artemisinin compounds for cancer treatment. Invest New Drugs 2013;31(1):230–46. link1

[82] Efferth T. Artemisinin—second career as anticancer drug? World J Tradit Chin Med 2015;1(4):2–25. link1

[83] Woerdenbag HJ, Moskal TA, Pras N, Malingré TM, el-Feraly FS, Kampinga HH, et al. Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells. J Nat Prod 1993;56(6):849–56. link1

[84] Lai H, Singh NP. Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin. Cancer Lett 1995;91(1):41–6. link1

[85] Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR. The anti-malarial artesunate is also active against cancer. Int J Oncol 2001;18(4):767–73. link1

[86] Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber HO, et al. Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol 2003;64(2):382–94. link1

[87] Zhang ZY, Yu SQ, Miao LY, Huang XY, Zhang XP, Zhu YP, et al. Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial. J Chin Integr Med 2008;6 (2):134–8. link1

[88] Jansen FH, Adoubi I, JC KC, DE Cnodder T, Jansen N, Tschulakow A, et al. First study of oral Artenimol-R in advanced cervical cancer: clinical benefit, tolerability and tumor markers. Anticancer Res 2011;31(12):4417–22. link1

[89] Krishna S, Ganapathi S, Ster IC, Saeed ME, Cowan M, Finlayson C, et al. A randomised, double blind, placebo-controlled pilot study of oral artesunate therapy for colorectal cancer. EBioMedicine 2014;2(1):82–90. link1

[90] Efferth T, Rücker G, Falkenberg M, Manns D, Olbrich A, Fabry U, et al. Detection of apoptosis in KG-1a leukemic cells treated with investigational drugs. Arzneimittelforschung 1996;46(2):196–200. link1

[91] Willoughby JA Sr, Sundar SN, Cheung M, Tin AS, Modiano J, Firestone GL. Artemisinin blocks prostate cancer growth and cell cycle progression by disrupting Sp1 interactions with the cyclin-dependent kinase-4 (CDK4) promoter and inhibiting CDK4 gene expression. J Biol Chem 2009;284 (4):2203–13. link1

[92] Steinbrück L, Pereira G, Efferth T. Effects of artesunate on cytokinesis and G2/M cell cycle progression of tumour cells and budding yeast. Cancer Genomics Proteomics 2010;7(6):337–46. link1

[93] Hamacher-Brady A, Stein HA, Turschner S, Toegel I, Mora R, Jennewein N, et al. Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem 2011;286(8):6587–601. link1

[94] Anfosso L, Efferth T, Albini A, Pfeffer U. Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics J 2006;6(4):269–78. link1

[95] Button RW, Lin F, Ercolano E, Vincent JH, Hu B, Hanemann CO, et al. Artesunate induces necrotic cell death in schwannoma cells. Cell Death Dis 2014;5:e1466. link1

[96] Buommino E, Baroni A, Canozo N, Petrazzuolo M, Nicoletti R, Vozza A, et al. Artemisinin reduces human melanoma cell migration by down-regulating aVb3 integrin and reducing metalloproteinase 2 production. Invest New Drugs 2009;27(5):412–8. link1

[97] Chen T, Li M, Zhang R, Wang H. Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy. J Cell Mol Med 2009;13(7):1358–70. link1

[98] Li PC, Lam E, Roos WP, Zdzienicka MZ, Kaina B, Efferth T. Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Res 2008;68(11):4347–51. link1

[99] Hou J, Wang D, Zhang R, Wang H. Experimental therapy of hepatoma with artemisinin and its derivatives:in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res 2008;14(17):5519–30. link1

[100] Berdelle N, Nikolova T, Quiros S, Efferth T, Kaina B. Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ ATR damage response in cancer cells. Mol Cancer Ther 2011;10(12):2224–33. link1

[101] Huang C, Ba Q, Yue Q, Li J, Li J, Chu R, et al. Artemisinin rewires the protein interaction network in cancer cells: network analysis, pathway identification, and target prediction. Mol Biosyst 2013;9(12):3091–100. link1

[102] Li X, Ba Q, Liu Y, Yue Q, Chen P, Li J, et al. Dihydroartemisinin selectively inhibits PDGFR a-positive ovarian cancer growth and metastasis through inducing degradation of PDGFR a protein. Cell Discov 2017;3:17042. link1

[103] Efferth T, Benakis A, Romero MR, Tomicic M, Rauh R, Steinbach D, et al. Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron. Free Radic Biol Med 2004;37(7):998–1009. link1

[104] Ba Q, Zhou N, Duan J, Chen T, Hao M, Yang X, et al. Dihydroartemisinin exerts its anticancer activity through depleting cellular iron via transferrin receptor- 1. PLoS One 2012;7(8):e42703. link1

[105] Zhang S, Gerhard GS. Heme mediates cytotoxicity from artemisinin and serves as a general anti-proliferation target. PLoS One 2009;4(10):e7472. link1

[106] Stockwin LH, Han B, Yu SX, Hollingshead MG, ElSohly MA, Gul W, et al. Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction. Int J Cancer 2009;125(6):1266–75. link1

[107] Zhang S, Chen H, Gerhard GS. Heme synthesis increases artemisinin-induced radical formation and cytotoxicity that can be suppressed by superoxide scavengers. Chem Biol Interact 2010;186(1):30–5. link1

[108] Mercer AE, Copple IM, Maggs JL, O’Neill PM, Park BK. The role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarials. J Biol Chem 2011;286 (2):987–96. link1

[109] Hooda J, Cadinu D, Alam MM, Shah A, Cao TM, Sullivan LA, et al. Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells. PLoS One 2013;8(5):e63402. link1

[110] Hooda J, Shah A, Zhang L. Heme, an essential nutrient from dietary proteins, critically impacts diverse physiological and pathological processes. Nutrients 2014;6(3):1080–102. link1

[111] Hooda J, Alam M, Zhang L. Measurement of heme synthesis levels in mammalian cells. J Vis Exp 2015;101:e51579. link1

[112] Zhang X, Ba Q, Gu Z, Guo D, Zhou Y, Xu Y, et al. Fluorescent coumarinartemisinin conjugates as mitochondria-targeting theranostic probes for enhanced anticancer activities. Chemistry 2015;21(48):17415–21. link1

[113] Zhang CJ, Wang J, Zhang J, Lee YM, Feng G, Lim TK, et al. Mechanism-guided design and synthesis of a mitochondria-targeting artemisinin analogue with enhanced anticancer activity. Angew Chem Int Ed 2016;55(44):13770–4. link1

[114] Wang J, Zhang J, Shi Y, Xu C, Zhang C, Wong YK, et al. Mechanistic investigation of the specific anticancer property of artemisinin and its combination with aminolevulinic acid for enhanced anticolorectal cancer activity. ACS Cent Sci 2017;3(7):743–50. link1

[115] Wong YK, Xu C, Kalesh KA, He Y, Lin Q, Wong WSF, et al. Artemisinin as an anticancer drug: recent advances in target profiling and mechanisms of action. Med Res Rev 2017;37(6):1492–517. link1

[116] Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012;149(5):1060–72. link1

[117] Eling N, Reuter L, Hazin J, Hamacher-Brady A, Brady NR. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience 2015;2(5):517–32. link1

[118] Ooko E, Saeed ME, Kadioglu O, Sarvi S, Colak M, Elmasaoudi K, et al. Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells. Phytomedicine 2015;22(11):1045–54. link1

[119] Yang ND, Tan SH, Ng S, Shi Y, Zhou J, Tan KS, et al. Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin. J Biol Chem 2014;289(48):33425–41. link1

[120] Efferth T. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol 2017;46:65–83. link1

[121] Abba ML, Patil N, Leupold JH, Saeed MEM, Efferth T, Allgayer H. Prevention of carcinogenesis and metastasis by artemisinin-type drugs. Cancer Lett 2018;429:11–8. link1

[122] Noori S, Hassan ZM. Dihydroartemisinin shift the immune response towards Th1, inhibit the tumor growth in vitro and in vivo. Cell Immunol 2011;271 (1):67–72. link1

[123] Farsam V, Hassan ZM, Zavaran-Hosseini A, Noori S, Mahdavi M, Ranjbar M. Antitumor and immunomodulatory properties of artemether and its ability to reduce CD4+ CD25+ FoxP3+ T reg cells in vivo. Int Immunopharmacol 2011;11(11):1802–8. link1

[124] Zhang LX, Liu ZN, Ye J, Sha M, Qian H, Bu XH, et al. Artesunate exerts an antiimmunosuppressive effect on cervical cancer by inhibiting PGE2 production and Foxp3 expression. Cell Biol Int 2014;38(5):639–46. link1

[125] Cui C, Feng H, Shi X, Wang Y, Feng Z, Liu J, et al. Artesunate down-regulates immunosuppression from colorectal cancer Colon26 and RKO cells in vitro by decreasing transforming growth factor b1 and interleukin-10. Int Immunopharmacol 2015;27(1):110–21. link1

[126] Reiter C, Fröhlich T, Gruber L, Hutterer C, Marschall M, Voigtländer C, et al. Highly potent artemisinin-derived dimers and trimers: synthesis and evaluation of their antimalarial, antileukemia and antiviral activities. Bioorg Med Chem 2015;23(17):5452–8. link1

[127] Fröhlich T, Çapcı Karagöz A, Reiter C, Tsogoeva SB. Artemisinin-derived dimers: potent antimalarial and anticancer agents. J Med Chem 2016;59 (16):7360–88. link1

[128] Fröhlich T, Ndreshkjana B, Muenzner JK, Reiter C, Hofmeister E, Mederer S, et al. Synthesis of novel hybrids of thymoquinone and artemisinin with high activity and selectivity against colon cancer. ChemMedChem 2017;12 (3):226–34. link1

[129] Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochem Pharmacol 2017;139:56–70. link1

[130] Fröhlich T, Hahn F, Belmudes L, Leidenberger M, Friedrich O, Kappes B, et al. Synthesis of artemisinin-derived dimers, trimers and dendrimers: investigation of their antimalarial and antiviral activities including putative mechanisms of action. Chemistry 2018;24(32):8103–13. link1

[131] Horwedel C, Tsogoeva SB, Wei S, Efferth T. Cytotoxicity of artesunic acid homo- and heterodimer molecules toward sensitive and multidrug-resistant CCRF-CEM leukemia cells. J Med Chem 2010;53(13):4842–8. link1

[132] Reiter C, Herrmann A, Çapci A, Efferth T, Tsogoeva SB. New artesunic acid homodimers: potent reversal agents of multidrug resistance in leukemia cells. Bioorg Med Chem 2012;20(18):5637–41. link1

[133] Reiter C, Capcı Karagöz A, Fröhlich T, Klein V, Zeino M, Viertel K, et al. Synthesis and study of cytotoxic activity of 1,2,4-trioxane- and egonolderived hybrid molecules against Plasmodium falciparum and multidrugresistant human leukemia cells. Eur J Med Chem 2014;75:403–12. link1

[134] Reiter C, Fröhlich T, Zeino M, Marschall M, Bahsi H, Leidenberger M, et al. New efficient artemisinin derived agents against human leukemia cells, human cytomegalovirus and Plasmodium falciparum: 2nd generation 1,2,4- trioxane-ferrocene hybrids. Eur J Med Chem 2015;97:164–72. link1

[135] Leto I, Coronnello M, Righeschi C, Bergonzi MC, Mini E, Bilia AR. Enhanced efficacy of artemisinin loaded in transferrin-conjugated liposomes versus stealth liposomes against HCT-8 colon cancer cells. ChemMedChem 2016;11 (16):1745–51. link1

[136] Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta T. Clinical trial of artesunate and artemether on multidrug resistant falciparum malaria in Thailand. A preliminary report. Southeast Asian J Trop Med Public Health 1991;22(3):380–5. link1

[137] Efferth T, Romero MR, Wolf DG, Stamminger T, Marin JJ, Marschall M. The antiviral activities of artemisinin and artesunate. Clin Infect Dis 2008;47 (6):804–11. link1

[138] Keiser J, Utzinger J. Artemisinins and synthetic trioxolanes in the treatment of helminth infections. Curr Opin Infect Dis 2007;20(6):605–12. link1

[139] Saeed MEM, Krishna S, Greten HJ, Kremsner PG, Efferth T. Antischistosomal activity of artemisinin derivatives in vivo and in patients. Pharmacol Res 2016;110:216–26. link1

[140] Lam NS, Long X, Su XZ, Lu F. Artemisinin and its derivatives in treating helminthic infections beyond schistosomiasis. Pharmacol Res 2018;133:77–100. link1

[141] Efferth T. Beyond malaria: the inhibition of viruses by artemisinin-type compounds. Biotechnol Adv 2018;36(6):1730–7. link1

[142] Li J, Casteels T, Frogne T, Ingvorsen C, Honoré C, Courtney M, et al. Artemisinins target GABAA receptor signaling and impair a cell identity. Cell 2017;168(1–2):86–100.e15. link1

[143] Van der Meulen T, Lee S, Noordeloos E, Donaldson CJ, Adams MW, Noguchi GM, et al. Artemether does not turn a cells into b cells. Cell Metab 2018;27 (1). 218 25.e4. link1

[144] Ho WE, Cheng C, Peh HY, Xu F, Tannenbaum SR, Ong CN, et al. Anti-malarial drug artesunate ameliorates oxidative lung damage in experimental allergic asthma. Free Radic Biol Med 2012;53(3):498–507. link1

[145] Isacchi B, Arrigucci S, la Marca G, Bergonzi MC, Vannucchi MG, Novelli A, et al. Conventional and long-circulating liposomes of artemisinin: preparation, characterization, and pharmacokinetic profile in mice. J Liposome Res 2011;21(3):237–44. link1

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