1. Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
2. Central People’s Hospital of Zhanjiang, Zhanjiang 524045, China
3. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
4. Department of Geriatrics, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People’s Hospital, Shenzhen 518020, China
qyguo@icmm.ac.cn
ccxu@icmm.ac.cn
jgwang@icmm.ac.cn
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History+
Received
Accepted
Published Online
2021-04-06
2021-09-23
2022-01-28
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Abstract
Malaria is an ancient infectious disease that threatens millions of lives globally even today. The discovery of artemisinin, inspired by traditional Chinese medicine (TCM), has brought in a paradigm shift and been recognized as the “best hope for the treatment of malaria” by World Health Organization. With its high potency and low toxicity, the wide use of artemisinin effectively treats the otherwise drug-resistant parasites and helps many countries, including China, to eventually eradicate malaria. Here, we will first review the initial discovery of artemisinin, an extraordinary journey that was in stark contrast with many drugs in western medicine. We will then discuss how artemisinin and its derivatives could be repurposed to treat cancer, inflammation, immunoregulation-related diseases, and COVID-19. Finally, we will discuss the implications of the “artemisinin story” and how that can better guide the development of TCM today. We believe that artemisinin is just a starting point and TCM will play an even bigger role in healthcare in the 21st century.
TuYY. Artemisinin—a gift from traditional Chinese medicine to the world (Nobel Lecture). Angew Chem Int Ed Eng, 2016, l55( 35): 10210– 10226
[2]
World Health Organization. World malaria report 2020: 20 years of global progress and challenges. Geneva: World Health Organization, 2020
[3]
YoshidaGJ. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol, 2017, 10( 1): 67
[4]
EfferthT. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol, 2017, 46 : 65– 83
YangJ, HeY, LiY, ZhangX, WongYK, ShenS, ZhongT, ZhangJ, LiuQ, WangJ. Advances in the research on the targets of anti-malaria actions of artemisinin. Pharmacol Ther, 2020, 216 : 107697
WangJ, XuC, LiaoFL, JiangT, KrishnaS, TuY. A temporizing solution to “artemisinin resistance”. N Engl J Med, 2019, 380( 22): 2087– 2089
[12]
Strategic Advisory Group on Malaria Eradication. Malaria eradication: benefits, future scenarios and feasibility. A report of the Strategic Advisory Group on Malaria Eradication. Geneva: World Health Organization, 2020
[13]
MaN, ZhangZ, LiaoF, JiangT, TuY. The birth of artemisinin. Pharmacol Ther, 2020, 216 : 107658
[14]
TuY. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med, 2011, 17( 10): 1217– 1220
[15]
World Health Organization. Guidelines for the treatment of malaria. 1st ed. Geneva: World Health Organization, 2006
[16]
EfferthT, KainaB. Toxicity of the antimalarial artemisinin and its dervatives. Crit Rev Toxicol, 2010, 40( 5): 405– 421
[17]
The Nobel Prize. The Nobel Prize in Physiology or Medicine. 2015.
[18]
World Health Organization. World Health Organization Model List of Essential Medicines. 21st List. Geneva: World Health Organization, 2019
[19]
EastmanRT, FidockDA. Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nat Rev Microbiol, 2009, 7( 12): 864– 874
[20]
SunX, YanP, ZouC, WongYK, ShuY, LeeYM, ZhangC, YangND, WangJ, ZhangJ. Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives. Med Res Rev, 2019, 39( 6): 2172– 2193
LaiHC, SinghNP, SasakiT. Development of artemisinin compounds for cancer treatment. Invest New Drugs, 2013, 31( 1): 230– 246
[23]
KingD, YeomansonD, BryantHE. PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. J Pediatr Hematol Oncol, 2015, 37( 4): 245– 251
[24]
WangJ, ZhangJ, ShiY, XuC, ZhangC, WongYK, LeeYM, KrishnaS, HeY, LimTK, SimW, HuaZC, ShenHM, LinQ. 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– 750
[25]
YangND, TanSH, NgS, ShiY, ZhouJ, TanKSW, WongWSF, ShenHM. Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin. J Biol Chem, 2014, 289( 48): 33425– 33441
[26]
FengFB, QiuHY. Effects of artesunate on chondrocyte proliferation, apoptosis and autophagy through the PI3K/AKT/mTOR signaling pathway in rat models with rheumatoid arthritis. Biomed Pharmacother, 2018, 102 : 1209– 1220
[27]
WangYS, YuP, WangY, ZhangJ, HangW, YinZX, LiuG, ChenJ, WerleKD, QuanCS, GaoH, ZengQ, CuiR, LiangJ, DingQ, LiYL, XuZX. AMP-activated protein kinase protects against necroptosis via regulation of Keap1-PGAM5 complex. Int J Cardiol, 2018, 259 : 153– 162
[28]
CarlingD. AMPK signalling in health and disease. Curr Opin Cell Biol, 2017, 45 : 31– 37
[29]
ChoiYK, ParkKG. Metabolic roles of AMPK and metformin in cancer cells. Mol Cells, 2013, 36( 4): 279– 287
[30]
DuJ, WangT, LiY, ZhouY, WangX, YuX, RenX, AnY, WuY, SunW, FanW, ZhuQ, WangY, TongX. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med, 2019, 131 : 356– 369
[31]
ZhouX, ChenY, WangF, WuH, ZhangY, LiuJ, CaiY, HuangS, HeN, HuZ, JinX. Artesunate induces autophagy dependent apoptosis through upregulating ROS and activating AMPK-mTOR-ULK1 axis in human bladder cancer cells. Chem Biol Interact, 2020, 331 : 109273
[32]
ChengC, WangT, SongZ, PengL, GaoM, HermineO, RousseauxS, KhochbinS, MiJQ, WangJ. Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044. Cancer Med, 2018, 7( 2): 380– 396
[33]
OrlovaA, WagnerC, deAraujo ED, BajuszD, NeubauerHA, HerlingM, GunningPT, KeserűGM, MorigglR. Direct targeting options for STAT3 and STAT5 in cancer. Cancers (Basel), 2019, 11( 12): 1930
[34]
YanX, LiP, ZhanY, QiM, LiuJ, AnZ, YangW, XiaoH, WuH, QiY, ShaoH. Dihydroartemisinin suppresses STAT3 signaling and Mcl-1 and survivin expression to potentiate ABT-263-induced apoptosis in non-small cell lung cancer cells harboring EGFR or RAS mutation. Biochem Pharmacol, 2018, 150 : 72– 85
[35]
WangW, SunY, LiX, ShiX, LiZ, LuX. Dihydroartemisinin prevents distant metastasis of laryngeal carcinoma by inactivating STAT3 in cancer stem cells. Med Sci Monit, 2020, 26 : e922348
[36]
IlamathiM, PrabuPC, AyyappaKA, SivaramakrishnanV. Artesunate obliterates experimental hepatocellular carcinoma in rats through suppression of IL-6-JAK-STAT signalling. Biomed Pharmacother, 2016, 82 : 72– 79
WeiY, SinhaS, LevineB. Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation. Autophagy, 2008, 4( 7): 949– 951
[42]
YaoGD, GeMY, LiDQ, ChenL, HayashiT, TashiroSI, OnoderaS, GuoC, SongSJ, IkejimaT. L-A03, a dihydroartemisinin derivative, promotes apoptotic cell death of human breast cancer MCF-7 cells by targeting c-Jun N-terminal kinase. Biomed Pharmacother, 2018, 105 : 320– 325
[43]
OrlowskiRZ, BaldwinAS Jr. NF-κB as a therapeutic target in cancer. Trends Mol Med, 2002, 8( 8): 385– 389
[44]
BaldwinAS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB. J Clin Invest, 2001, 107( 3): 241– 246
[45]
ChenX, WongYK, LimTK, LimWH, LinQS, WangJG, HuaZC. Artesunate activates the intrinsic apoptosis of HCT116 cells through the suppression of fatty acid synthesis and the NF-κB pathway. Molecules, 2017, 22( 8): 1272
[46]
HuW, ChenSS, ZhangJL, LouXE, ZhouHJ. Dihydroartemisinin induces autophagy by suppressing NF-κB activation. Cancer Lett, 2014, 343( 2): 239– 248
[47]
LiB, BuS, SunJ, GuoY, LaiD. Artemisinin derivatives inhibit epithelial ovarian cancer cells via autophagy-mediated cell cycle arrest. Acta Biochim Biophys Sin (Shanghai), 2018, 50( 12): 1227– 1235
[48]
LinY, JiangM, ChenW, ZhaoT, WeiY. Cancer and ER stress: mutual crosstalk between autophagy, oxidative stress and inflammatory response. Biomed Pharmacother, 2019, 118 : 109249
[49]
XiaoR, DingC, ZhuH, LiuX, GaoJ, LiuQ, LuD, ZhangN, ZhangA, ZhouH. Suppression of asparagine synthetase enhances the antitumor potency of ART and artemalogue SOMCL-14-221 in non-small cell lung cancer. Cancer Lett, 2020, 475 : 22– 33
ShiC, LiH, YangY, HouL. Anti-inflammatory and immunoregulatory functions of artemisinin and its derivatives. Mediators Inflamm, 2015, 2015 : 435713
[53]
ZhouWL, WuJM, WuQL, WangJX, ZhouY, ZhouR, HePL, LiXY, YangYF, ZhangY, LiY, ZuoJP. A novel artemisinin derivative, 3-(12-β-artemisininoxy) phenoxyl succinic acid (SM735), mediates immunosuppressive effects in vitro and in vivo. Acta Pharmacol Sin, 2005, 26( 11): 1352– 1358
[54]
YangZS, WangJX, ZhouY, ZuoJP, LiY. Synthesis and immunosuppressive activity of new artemisinin derivatives. Part 2: 2-[12(β or α)-dihydroartemisinoxymethyl(or 1′-ethyl)]phenoxyl propionic acids and esters. Bioorg Med Chem, 2006, 14( 23): 8043– 8049
[55]
Zhang JX, Wang JX, Zhang Y, Zuo JP, Wu JM, Sui Y, Li Y. Synthesis and immunosuppressive activity of new artemisinin derivatives containing polyethylene glycol group. Acta Pharmaceutica Sinica (Yao Xue Xue Bao)2006; 41(1): 65–70 (in Chinese)
[56]
HouLF, HeSJ, WangJX, YangY, ZhuFH, ZhouY, HePL, ZhangY, YangYF, LiY, TangW, ZuoJP. SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivo. Int Immunopharmacol, 2009, 9( 13–14): 1509– 1517
[57]
HouL, BlockKE, HuangH. Artesunate abolishes germinal center B cells and inhibits autoimmune arthritis. PLoS One, 2014, 9( 8): e104762
[58]
HeY, FanJ, LinH, YangX, YeY, LiangL, ZhanZ, DongX, SunL, XuH. The anti-malaria agent artesunate inhibits expression of vascular endothelial growth factor and hypoxia-inducible factor-1α in human rheumatoid arthritis fibroblast-like synoviocyte. Rheumatol Int, 2011, 31( 1): 53– 60
[59]
HouLF, HeSJ, LiX, YangY, HePL, ZhouY, ZhuFH, YangYF, LiY, TangW, ZuoJP. Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses. Arthritis Rheum, 2011, 63( 8): 2445– 2455
[60]
LiWD, DongYJ, TuYY, LinZB. Dihydroarteannuin ameliorates lupus symptom of BXSB mice by inhibiting production of TNF-alpha and blocking the signaling pathway NF-kappa B translocation. Int Immunopharmacol, 2006, 6( 8): 1243– 1250
[61]
TangY, LiuJ, ZhangD, XuZ, JiJ, WenC. Cytokine storm in COVID-19: the current evidence and treatment strategies. Front Immunol, 2020, 11 : 1708
[62]
GendrotM, DuflotI, BoxbergerM, DelandreO, JardotP, Le BideauM, AndreaniJ, FontaI, MosnierJ, RollandC, HutterS, La ScolaB, PradinesB. Antimalarial artemisinin-based combination therapies (ACT) and COVID-19 in Africa: in vitro inhibition of SARS-CoV-2 replication by mefloquine-artesunate. Int J Infect Dis, 2020, 99 : 437– 440
[63]
LiG, YuanM, LiH, DengC, WangQ, TangY, ZhangH, YuW, XuQ, ZouY, YuanY, GuoJ, JinC, GuanX, XieF, SongJ. Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: an open-label, non-randomised and controlled trial. Int J Antimicrob Agents, 2021, 57( 1): 106216
ChenK, HuaH, ZhuZ, WuT, JiaZ, LiuQ. Artemisinin and dihydroartemisinin promote β-cell apoptosis induced by palmitate via enhancing ER stress. Apoptosis, 2020, 25( 3–4): 192– 204
[66]
Xue X, Dong Z, Deng Y, Yin S, Wang P, Liao Y, Hu G, Chen Y. Dihydroartemisinin alleviates atopic dermatitis in mice by inhibiting mast cell infiltration. J South Med Univ (Nan Fang Yi Ke Da Xue Xue Bao)2020; 40(10): 1480–1487 (in Chinese)
[67]
NongX, RajbanshiG, ChenL, LiJ, LiZ, LiuT, ChenS, WeiG, LiJ. Effect of artesunate and relation with TGF-β1 and SMAD3 signaling on experimental hypertrophic scar model in rabbit ear. Arch Dermatol Res, 2019, 311( 10): 761– 772
[68]
YangFM, FanD, YangXQ, ZhuFH, ShaoMJ, LiQ, LiuYT, LinZM, CaoSQ, TangW, HeSJ, ZuoJP. The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-κB/NLRP3 signaling. Acta Pharmacol Sin, 2021, 42( 4): 593– 603
[69]
LiuJ, ManheimerE, ShiY, GluudC. Chinese herbal medicine for severe acute respiratory syndrome: a systematic review and meta-analysis. J Altern Complement Med, 2004, 10( 6): 1041– 1051
[70]
World Health Organization. SARS: clinical trials on treatment using a combination of traditional Chinese medicine and Western medicine. Geneva: World Health Organization, 2004
[71]
National Administration of Traditional Chinese Medicine . The Traditional Chinese Medicine Prevention Program of Influenza A (H1N1) (2009). National Administration of Traditional Chinese Medicine, 2009 (in Chinese)
[72]
LuoH, TangQL, ShangYX, LiangSB, YangM, RobinsonN, LiuJP. Can Chinese medicine be used for prevention of corona virus disease 2019 (COVID-19)? A review of historical classics, research evidence and current prevention programs.. Chin J Integr Med, 2020, 26( 4): 243– 250