Skip to main content
SpringerLink
Log in

Novel Developments on Artemisinin and Its Derivatives for Cancer Therapy

  • Chapter
  • First Online:
Supportive Cancer Care with Chinese Medicine

Abstract

The lack of effective long-term anticancer therapy highlights the necessity to identify new potent anticancer compounds. Many biocompounds of naturally occurring medicinal plants have pharmacological activities and, thus, represent a source of molecules that may have anti-proliferative effects on a variety of cancers. During the past 10 years, we have systematically analyzed medicinal plants used in traditional Chinese medicine and focused our interest on Artemisia annua (sweet wormwood herb). The active principle of sweet wormwood herb is Artemisinin, a sesquiterpene, which exerts not only anti-malarial activity but also profound cytotoxicity against tumour cells. The anti-tumour mechanism shares similarities to the anti-malarial mechanism: the Artemisinin molecule contains an endoperoxide bridge that reacts with an iron atom to form free radicals causing macromolecular damage and cell death. The anticancer activity of artesunate, a semi-synthetic derivative of Artemisinin, has also been shown in human xenograft tumours in mice and dogs. First encouraging experience in the clinical treatment of patients suffering from laryngeal carcinoma, uveal melanoma, pituitary macroadenoma and non-small cell lung cancer calls for comprehensive clinical trials with artesunate for cancer treatment in the near future. In this chapter, we summarize novel developments on Artemisinin and its derivatives concerning mode of action, metabolism, toxicity, in vivo effects, clinical application and biotechnological production methods.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abdin MZ, Israr M, Rehman RU et al. Artemisinin, a novel antimalarial drug: biochemical and molecular approaches for enhanced production. Planta Med. 2003;69:289–99.

    Article  CAS  PubMed  Google Scholar 

  • Achen MG, Jeltsch M, Kukk E et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A. 1998;95:548–53.

    Article  CAS  PubMed  Google Scholar 

  • Adjuik M, Babiker A, Garner P et al. Artesunate combinations for treatment of malaria: meta-analysis. Lancet. 2004;363:9–17.

    Article  CAS  PubMed  Google Scholar 

  • Anfosso L, Efferth T, Albini A et al. Microarray expression profiles of angiogenesis-related genes predict tumor cell response to Artemisinins. Pharmacogenomics J. 2006;6:269–78.

    CAS  PubMed  Google Scholar 

  • Asimus S, Elsherbiny D, Hai TN et al. Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects. Fundam Clin Pharmacol. 2007;21:307–16.

    Article  CAS  PubMed  Google Scholar 

  • Asimus S, Hai TN, Van Huong N et al. Artemisinin and CYP2A6 activity in healthy subjects. Eur J Clin Pharmacol. 2008;64:283–92.

    Article  CAS  PubMed  Google Scholar 

  • Bapiro TE, Andersson TB, Otter C et al. Cytochrome P450 1A1/2 induction by antiparasitic drugs: dose-dependent increase in ethoxyresorufin O-deethylase activity and mRNA caused by quinine, primaquine and albendazole in HepG2 cells. Eur J Clin Pharmacol. 2002;58:537–42.

    Article  CAS  PubMed  Google Scholar 

  • Bapiro TE, Sayi J, Hasler JA et al. Artemisinin and thiabendazole are potent inhibitors of cytochrome P450 1A2 (CYP1A2) activity in humans. Eur J Clin Pharmacol. 2005;61:755–61.

    Article  CAS  PubMed  Google Scholar 

  • Berger TG, Dieckmann D, Efferth T et al. Artesunate in the treatment of metastatic uveal melanoma – first experiences. Oncol Rep. 2005;14:1599–603.

    CAS  PubMed  Google Scholar 

  • Bertea CM, Freije JR, van der Woude H et al. Identification of intermediates and enzymes involved in the early steps of Artemisinin biosynthesis in Artemisia annua. Planta Med. 2005;71:40–7.

    Article  CAS  PubMed  Google Scholar 

  • Boik J. Natural compounds in cancer therapy. Portland: Oregon Medical Press; 2001.

    Google Scholar 

  • Brewer TG, Grate SJ, Peggins JO et al. Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg. 1994a;51:251–9.

    CAS  PubMed  Google Scholar 

  • Brewer TG, Peggins JO, Grate SJ et al. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg. 1994b;88 Suppl 1:S33–S36.

    Article  PubMed  Google Scholar 

  • Broxterman HJ, Lankelma J, Hoekman K. Resistance to cytotoxic and anti-angiogenic anticancer agents: similarities and differences. Drug Resist Updat. 2003;6:111–27.

    Article  CAS  PubMed  Google Scholar 

  • Burk O, Arnold KA, Nussler AK et al. Antimalarial Artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol. 2005;67:1954–65.

    Article  CAS  PubMed  Google Scholar 

  • Carrara VI, Phyo AP, Nwee P et al. Auditory assessment of patients with acute uncomplicated Plasmodium falciparum malaria treated with three-day mefloquine-artesunate on the north-western border of Thailand. Malar J. 2008;7:233.

    Article  PubMed  Google Scholar 

  • Charles DJ, Simon JE, Wood KV et al. Germplasm variation in Artemisinin content of Artemisia annua L. using an alternative method of Artemisinin analysis from crude plant extracts. J Nat Prod. 1990;53:157–60.

    Article  CAS  Google Scholar 

  • Chen T, Li M, Zhang R et al. Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy. J Cell Mol Med. 2009;13:1358–70.

    Article  PubMed  CAS  Google Scholar 

  • Chen H, Sun B, Pan S et al. Dihydroartemisinin inhibits growth of pancreatic cancer cells in vitro and in vivo. Anticancer Drugs. 2009;20:131–40.

    Article  PubMed  CAS  Google Scholar 

  • Chen HH, Zhou HJ, Fang X. Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by Artemisinin derivatives in vitro. Pharmacol Res. 2003;48:231–6.

    Article  CAS  PubMed  Google Scholar 

  • Chen HH, Zhou HJ, Wang WQ et al. Antimalarial dihydroartemisinin also inhibits angiogenesis. Cancer Chemother Pharmacol. 2004a;53:423–32.

    Article  CAS  PubMed  Google Scholar 

  • Chen HH, Zhou HJ, Wu GD et al. Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacology. 2004b;71:1–9.

    Article  CAS  PubMed  Google Scholar 

  • D’Alessandro S, Gelati M, Basilico N et al. Differential effects on angiogenesis of two antimalarial compounds, dihydroartemisinin and artemisone: implications for embryotoxicity. Toxicology. 2007;241:66–74.

    Article  PubMed  CAS  Google Scholar 

  • Davis TM, Karunajeewa HA, Ilett KF. Artemisinin-based combination therapies for uncomplicated malaria. Med J Aust. 2005;182:181–5.

    PubMed  Google Scholar 

  • De Jesus-Gonzalez L, Weathers PJ. Tetraploid Artemisia annua hairy roots produce more Artemisinin than diploids. Plant Cell Rep. 2003;21:809–13.

    PubMed  Google Scholar 

  • Delabays N, Simonnet X, Gaudin M. The genetics of Artemisinin content in Artemisia annua L. and the breeding of high yielding cultivars. Curr Med Chem. 2001;8:1795–801.

    CAS  PubMed  Google Scholar 

  • Dell’Eva R, Pfeffer U, Vene R et al. Inhibition of angiogenesis in vivo and growth of Kaposi’s sarcoma xenograft tumors by the anti-malarial artesunate. Biochem Pharmacol. 2004;68:2359–66.

    Article  PubMed  CAS  Google Scholar 

  • Disbrow GL, Baege AC, Kierpiec KA et al. Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo. Cancer Res. 2005;65:10854–61.

    Article  CAS  PubMed  Google Scholar 

  • Dondorp A, Nosten F, Stepniewska K et al. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005;366:717–25.

    Article  PubMed  CAS  Google Scholar 

  • Efferth T. Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of Artemisinin – from bench to bedside. Planta Med. 2007;73:299–309.

    Article  CAS  PubMed  Google Scholar 

  • Efferth T, Benakis A, Romero MR et al. Enhancement of cytotoxicity of Artemisinins toward cancer cells by ferrous iron. Free Radic Biol Med. 2004;37:998–1009.

    Article  CAS  PubMed  Google Scholar 

  • Efferth T, Briehl MM, Tome ME. Role of antioxidant genes for the activity of artesunate against tumor cells. Int J Oncol. 2003a;23:1231–5.

    CAS  PubMed  Google Scholar 

  • Efferth T, Davey M, Olbrich A et al. 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. 2002c;28:160–8.

    Article  PubMed  Google Scholar 

  • Efferth T, Dunstan H, Sauerbrey A et al. The anti-malarial artesunate is also active against cancer. Int J Oncol. 2001;18:767–73.

    CAS  PubMed  Google Scholar 

  • Efferth T, Fabry U, Osieka R. Apoptosis and resistance to daunorubicin in human leukemic cells. Leukemia. 1997;11:1180–6.

    Article  CAS  PubMed  Google Scholar 

  • Efferth T, Fabry U, Osieka R. Interleukin-6 affects melphalan-induced DNA damage and repair in human multiple myeloma cells. Anticancer Res. 2002a;22:231–4.

    CAS  PubMed  Google Scholar 

  • Efferth T, Grassmann R. Impact of viral oncogenesis on responses to anti-cancer drugs and irradiation. Crit Rev Oncog. 2000;11:165–87.

    CAS  PubMed  Google Scholar 

  • Efferth T, Mattern J, Volm M. Immunohistochemical detection of P glycoprotein, glutathione S transferase and DNA topoisomerase II in human tumors. Oncology. 1992;49:368–75.

    Article  CAS  PubMed  Google Scholar 

  • Efferth T, Oesch F. Oxidative stress response of tumor cells: microarray-based comparison between Artemisinins and anthracyclines. Biochem Pharmacol. 2004;68:3–10.

    Article  CAS  PubMed  Google Scholar 

  • Efferth T, Olbrich A, Bauer R. mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether. Biochem Pharmacol. 2002b;64:617–23.

    Article  CAS  PubMed  Google Scholar 

  • Efferth T, Romero MR, Wolf DG et al. The antiviral activities of Artemisinin and artesunate. Clin Infect Dis. 2008;47:804–11.

    Article  CAS  PubMed  Google Scholar 

  • Efferth T, Rucker G, Falkenberg M et al. Detection of apoptosis in KG-1a leukemic cells treated with investigational drugs. Arzneimittelforschung. 1996;46:196–200.

    CAS  PubMed  Google Scholar 

  • Efferth T, Sauerbrey A, Olbrich A et al. Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol. 2003b;64:382–94.

    Article  CAS  PubMed  Google Scholar 

  • Efferth T, Volm M. Reversal of doxorubicin-resistance in sarcoma 180 tumor cells by inhibition of different resistance mechanisms. Cancer Lett. 1993;70:197–202.

    Article  CAS  PubMed  Google Scholar 

  • Efferth T, Volm M. Pharmacogenetics for individualized cancer chemotherapy. Pharmacol Ther. 2005;107:155–76.

    Article  CAS  PubMed  Google Scholar 

  • Elmarakby SA, el-Feraly FS, Elsohly HN et al. Microbial transformation studies on arteannuin B. J Nat Prod. 1987;50:903–9.

    Article  CAS  PubMed  Google Scholar 

  • Elsherbiny DA, Asimus SA, Karlsson MO et al. A model based assessment of the CYP2B6 and CYP2C19 inductive properties by Artemisinin antimalarials: implications for combination regimens. J Pharmacokinet Pharmacodyn. 2008;35:203–17.

    Article  CAS  PubMed  Google Scholar 

  • Folkman J. The role of angiogenesis in tumor growth. Semin Cancer Biol. 1992;3:65–71.

    CAS  PubMed  Google Scholar 

  • Fujita T, Felix K, Pinkaew D et al. Human fortilin is a molecular target of dihydroartemisinin. FEBS Lett. 2008;582:1055–60.

    Article  CAS  PubMed  Google Scholar 

  • Gallo MA, Kaufman D. Antagonistic and agonistic effects of tamoxifen: significance in human cancer. Semin Oncol. 1997;24:71–80.

    Google Scholar 

  • Genovese RF, Newman DB. Understanding Artemisinin-induced brainstem neurotoxicity. Arch Toxicol. 2008;82:379–85.

    Article  CAS  PubMed  Google Scholar 

  • Genovese RF, Newman DB, Li Q et al. Dose-dependent brainstem neuropathology following repeated arteether administration in rats. Brain Res Bull. 1998b;45:199–202.

    Article  CAS  PubMed  Google Scholar 

  • Genovese RF, Newman DB, Petras JM et al. Behavioral and neural toxicity of arteether in rats. Pharmacol Biochem Behav. 1998a;60:449–58.

    Article  CAS  PubMed  Google Scholar 

  • Giao PT, de Vries PJ. Pharmacokinetic interactions of antimalarial agents. Clin Pharmacokinet. 2001;40:343–73.

    Article  CAS  PubMed  Google Scholar 

  • Gordi T, Lepist EI. Artemisinin derivatives: toxic for laboratory animals, safe for humans? Toxicol Lett. 2004;147:99–107.

    Article  CAS  PubMed  Google Scholar 

  • Gordi T, Xie R, Huong NV et al. A semiphysiological pharmacokinetic model for Artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction. Br J Clin Pharmacol. 2005;59:189–98.

    Article  CAS  PubMed  Google Scholar 

  • Grant S, Qiao L, Dent P. Roles of ERBB family receptor tyrosine kinases, and downstream signaling pathways, in the control of cell growth and survival. Front Biosci. 2002;7:d376–89.

    Article  CAS  PubMed  Google Scholar 

  • Hampton T. Collaboration hopes microbe factories can supply key antimalaria drug. JAMA. 2005;293:785–7.

    Article  CAS  PubMed  Google Scholar 

  • Haynes RK. Artemisinin and derivatives: the future for malaria treatment? Curr Opin Infect Dis. 2001;14:719–26.

    CAS  PubMed  Google Scholar 

  • He F, Bi HC, Xie ZY et al. Rapid determination of six metabolites from multiple cytochrome P450 probe substrates in human liver microsome by liquid chromatography/mass spectrometry: application to high-throughput inhibition screening of terpenoids. Rapid Commun Mass Spectrom. 2007;21:635–43.

    Article  CAS  PubMed  Google Scholar 

  • Hofheinz W, Burgin H, Gocke E et al. Ro 42-1611 (arteflene), a new effective antimalarial: chemical structure and biological activity. Trop Med Parasitol. 1994;45:261–5.

    CAS  PubMed  Google Scholar 

  • Hou J, Wang D, Zhang R et al. Experimental therapy of hepatoma with Artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res. 2008;14:5519–30.

    Article  CAS  PubMed  Google Scholar 

  • Huan-huan C, Li-Li Y, Shang-Bin L. Artesunate reduces chicken chorioallantoic membrane neovascularisation and exhibits antiangiogenic and apoptotic activity on human microvascular dermal endothelial cell. Cancer Lett. 2004;211:163–73.

    Article  PubMed  CAS  Google Scholar 

  • Huang XJ, Li CT, Zhang WP et al. Dihydroartemisinin potentiates the cytotoxic effect of temozolomide in rat C6 glioma cells. Pharmacology. 2008;82:1–9.

    Article  CAS  PubMed  Google Scholar 

  • Huang XJ, Ma ZQ, Zhang WP et al. Dihydroartemisinin exerts cytotoxic effects and inhibits hypoxia inducible factor-1alpha activation in C6 glioma cells. J Pharm Pharmacol. 2007;59:849–56.

    Article  CAS  PubMed  Google Scholar 

  • Hutagalung R, Htoo H, Nwee P et al. A case-control auditory evaluation of patients treated with artemether-lumefantrine. Am J Trop Med Hyg. 2006;74:211–4.

    CAS  PubMed  Google Scholar 

  • Jiao Y, Ge CM, Meng QH et al. Dihydroartemisinin is an inhibitor of ovarian cancer cell growth. Acta Pharmacol Sin. 2007;28:1045–56.

    Article  CAS  PubMed  Google Scholar 

  • Joukov V, Pajusola K, Kaipainen A et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 1996;15:290–8.

    CAS  PubMed  Google Scholar 

  • Kamchonwongpaisan S, McKeever P, Hossler P et al. Artemisinin neurotoxicity: neuropathology in rats and mechanistic studies in vitro. Am J Trop Med Hyg. 1997;56:7–12.

    CAS  PubMed  Google Scholar 

  • Kelter G, Steinbach D, Konkimalla VB et al. 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.

    Article  PubMed  CAS  Google Scholar 

  • Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2:727–39.

    Article  CAS  PubMed  Google Scholar 

  • Kim SJ, Kim MS, Lee JW et al. Dihydroartemisinin enhances radiosensitivity of human glioma cells in vitro. J Cancer Res Clin Oncol. 2006;132:129–35.

    Article  CAS  PubMed  Google Scholar 

  • Klayman DL. Qinghaosu (Artemisinin): an antimalarial drug from China. Science. 1985;228:1049–55.

    Article  CAS  PubMed  Google Scholar 

  • Konkimalla VB, Blunder M, Korn B et al. Effect of Artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264. 7 mouse macrophage cells. Nitric Oxide. 2008;19:184–91.

    Article  CAS  PubMed  Google Scholar 

  • Konkimalla VB, McCubrey JA, Efferth T. The role of downstream signaling pathways of the epidermal growth factor receptor for Artesunate’s activity in cancer cells. Curr Cancer Drug Targets. 2009;9:72–80.

    Article  CAS  PubMed  Google Scholar 

  • Lai H, Sasaki T, Singh NP. Targeted treatment of cancer with Artemisinin and Artemisinin-tagged iron-carrying compounds. Expert Opin Ther Targets. 2005;9:995–1007.

    Article  CAS  PubMed  Google Scholar 

  • Laughlin JC. Agricultural production of Artemisinin – a review. Trans R Soc Trop Med Hyg. 1994;88 Suppl 1:S.

    Google Scholar 

  • Lee J, Zhou HJ, Wu XH. Dihydroartemisinin downregulates vascular endothelial growth factor expression and induces apoptosis in chronic myeloid leukemia K562 cells. Cancer Chemother Pharmacol. 2006;57:213–20.

    Article  CAS  PubMed  Google Scholar 

  • Lenihan JR, Tsuruta H, Diola D et al. Developing an industrial artemisinic acid fermentation process to support the cost-effective production of antimalarial Artemisinin-based combination therapies. Biotechnol Prog. 2008;24:1026–32.

    Article  CAS  PubMed  Google Scholar 

  • Li H, van Berlo D, Shi T et al. Curcumin protects against cytotoxic and inflammatory effects of quartz particles but causes oxidative DNA damage in a rat lung epithelial cell line. Toxicol Appl Pharmacol. 2008;227:115–24.

    Article  CAS  PubMed  Google Scholar 

  • Li LN, Zhang HD, Yuan SJ et al. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer. 2007;121:1360–5.

    Article  CAS  PubMed  Google Scholar 

  • Li QG, Mog SR, Si YZ et al. Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents. Am J Trop Med Hyg. 2002;66:516–25.

    CAS  PubMed  Google Scholar 

  • Li XQ, Bjorkman A, Andersson TB et al. Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003;59:429–42.

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Wu YL. How Chinese scientists discovered Qinghaosu ngHaoSu (Artemisinin) and developed its derivatives? What are the future perspectives? Med Trop (Mars). 1998;58:9–12.

    CAS  Google Scholar 

  • Lindahl AL, Olsson ME, Mercke P et al. Production of the Artemisinin precursor amorpha-4,11-diene by engineered Saccharomyces cerevisiae. Biotechnol Lett. 2006;28:571–80.

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Zhao Y, Wang Y. Artemisinin: current state and perspectives for biotechnological production of an antimalarial drug. Appl Microbiol Biotechnol. 2006;72:11–20.

    Article  CAS  PubMed  Google Scholar 

  • Lotem J, Sachs L. Control of apoptosis in hematopoiesis and leukemia by cytokines, tumor suppressor and oncogenes. Leukemia. 1996;10:925–31.

    CAS  PubMed  Google Scholar 

  • Martin VJ, Pitera DJ, Withers ST et al. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat Biotechnol. 2003;21:796–802.

    Article  CAS  PubMed  Google Scholar 

  • McCarty MF. Turning an ‘Achilles’ Heel’ into an asset – activation of HIF-1alpha during angiostatic therapy will increase tumor sensitivity to iron-catalyzed oxidative damage. Med Hypotheses. 2003;61:509–11.

    Article  CAS  PubMed  Google Scholar 

  • McColl BK, Loughran SJ, Davydova N et al. Mechanisms of lymphangiogenesis: targets for blocking the metastatic spread of cancer. Curr Cancer Drug Targets. 2005;5:561–71.

    Article  CAS  PubMed  Google Scholar 

  • McCubrey JA, Steelman LS, Chappell WH et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773:1263–84.

    Article  CAS  PubMed  Google Scholar 

  • Mihara K, Svensson US, Tybring G et al. Stereospecific analysis of omeprazole supports Artemisinin as a potent inducer of CYP2C19. Fundam Clin Pharmacol. 1999;13:671–5.

    Article  CAS  PubMed  Google Scholar 

  • Moore JC, Lai H, Li JR et al. Oral administration of dihydroartemisinin and ferrous sulfate retarded implanted fibrosarcoma growth in the rat. Cancer Lett. 1995;98:83–7.

    CAS  PubMed  Google Scholar 

  • Mu D, Chen W, Yu B et al. Calcium and survivin are involved in the induction of apoptosis by dihydroartemisinin in human lung cancer SPC-A-1 cells. Methods Find Exp Clin Pharmacol. 2007;29:33–8.

    Article  CAS  PubMed  Google Scholar 

  • Mu D, Zhang W, Chu D et al. The role of calcium, P38 MAPK in dihydroartemisinin-induced apoptosis of lung cancer PC-14 cells. Cancer Chemother Pharmacol. 2008;61:639–45.

    Article  CAS  PubMed  Google Scholar 

  • Nair MS, Acton N, Klayman DL et al. Production of Artemisinin in tissue cultures of Artemisia annua. J Nat Prod. 1986;49:504–07.

    Article  CAS  PubMed  Google Scholar 

  • Nakase I, Gallis B, Takatani-Nakase T et al. Transferrin receptor-dependent cytotoxicity of Artemisinin-transferrin conjugates on prostate cancer cells and induction of apoptosis. Cancer Lett. 2009;274:290–8.

    Article  CAS  PubMed  Google Scholar 

  • Nakase I, Lai H, Singh NP et al. Anticancer properties of Artemisinin derivatives and their targeted delivery by transferrin conjugation. Int J Pharm. 2008;354:28–33.

    Article  CAS  PubMed  Google Scholar 

  • Nam W, Tak J, Ryu JK et al. Effects of Artemisinin and its derivatives on growth inhibition and apoptosis of oral cancer cells. Head Neck. 2007;29:335–40.

    Article  PubMed  Google Scholar 

  • Navolanic PM, Steelman LS, McCubrey JA. EGFR family signaling and its association with breast cancer development and resistance to chemotherapy (Review. Int J Oncol. 2003;22:237–52.

    CAS  PubMed  Google Scholar 

  • Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs over the period 1981–2002. J Nat Prod. 2003;66:1022–37.

    Article  CAS  PubMed  Google Scholar 

  • Newman JD, Marshall J, Chang M et al. High-level production of amorpha-4,11-diene in a two-phase partitioning bioreactor of metabolically engineered Escherichia coli. Biotechnol Bioeng. 2006;95:684–91.

    Article  CAS  PubMed  Google Scholar 

  • Nontprasert A, Pukrittayakamee S, Dondorp AM et al. Neuropathologic toxicity of Artemisinin derivatives in a mouse model. Am J Trop Med Hyg. 2002;67:423–9.

    CAS  PubMed  Google Scholar 

  • Oh S, Jeong IH, Ahn CM et al. Synthesis and antiangiogenic activity of thioacetal Artemisinin derivatives. Bioorg Med Chem. 2004;12:3783–90.

    Article  CAS  PubMed  Google Scholar 

  • Oh S, Kim BJ, Singh NP et al. Synthesis and anti-cancer activity of covalent conjugates of Artemisinin and a transferrin-receptor targeting peptide. Cancer Lett. 2009;274:33–9.

    Article  CAS  PubMed  Google Scholar 

  • Panossian LA, Garga NI, Pelletier D. Toxic brainstem encephalopathy after Artemisinin treatment for breast cancer. Ann Neurol. 2005;58:812–3.

    Article  PubMed  Google Scholar 

  • Petras JM, Kyle DE, Gettayacamin M et al. Arteether: risks of two-week administration in Macaca mulatta. Am J Trop Med Hyg. 1997;56:390–6.

    CAS  PubMed  Google Scholar 

  • Petras JM, Young GD, Bauman RA et al. Arteether-induced brain injury in Macaca mulatta. I. The precerebellar nuclei: the lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei. Anat Embryol (Berl). 2000;201:383–97.

    Article  CAS  Google Scholar 

  • Pommier Y, Sordet O, Antony S et al. Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene. 2004;23:2934–49.

    Article  CAS  PubMed  Google Scholar 

  • Reizenstein P. Iron, free radicals and cancer. Med Oncol Tumor Pharmacother. 1991;8:229–33.

    CAS  PubMed  Google Scholar 

  • Relf M, LeJeune S, Scott PA et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997;57:963–9.

    CAS  PubMed  Google Scholar 

  • Reungpatthanaphong P, Mankhetkorn S. Modulation of multidrug resistance by Artemisinin, artesunate and dihydroartemisinin in K562/adr and GLC4/adr resistant cell lines. Biol Pharm Bull. 2002;25:1555–61.

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro IR, Olliaro P. Safety of Artemisinin and its derivatives. A review of published and unpublished clinical trials. Med Trop (Mars). 1998;58:50–3.

    CAS  Google Scholar 

  • Ro DK, Paradise EM, Ouellet M et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature. 2006;440:940–3.

    Article  CAS  PubMed  Google Scholar 

  • Segditsas S, Tomlinson I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene. 2006;25:7531–7.

    Article  CAS  PubMed  Google Scholar 

  • Shaul YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta. 2007;1773:1213–26.

    Article  CAS  PubMed  Google Scholar 

  • Shiba Y, Paradise EM, Kirby J et al. Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae for high-level production of isoprenoids. Metab Eng. 2007;9:160–8.

    Article  CAS  PubMed  Google Scholar 

  • Shimizu K, Oku N. Cancer anti-angiogenic therapy. Biol Pharm Bull. 2004;27:599–605.

    Article  CAS  PubMed  Google Scholar 

  • Simonsson US, Lindell M, Raffalli-Mathieu F et al. In vivo and mechanistic evidence of nuclear receptor CAR induction by Artemisinin. Eur J Clin Invest. 2006;36:647–53.

    Article  CAS  PubMed  Google Scholar 

  • Singh NP, Lai H. Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Life Sci. 2001;70:49–56.

    Article  CAS  PubMed  Google Scholar 

  • Singh NP, Lai HC. Artemisinin induces apoptosis in human cancer cells. Anticancer Res. 2004;24:2277–80.

    CAS  PubMed  Google Scholar 

  • Singh NP, Lai HC. Synergistic cytotoxicity of Artemisinin and sodium butyrate on human cancer cells. Anticancer Res. 2005;25:4325–31.

    CAS  PubMed  Google Scholar 

  • Singh NP, Panwar VK. Case report of a pituitary macroadenoma treated with artemether. Integr Cancer Ther. 2006;5:391–4.

    Google Scholar 

  • Singh NP, Verma KB. Case report of a laryngeal squamous cell carcinoma treated with artesunate. Arch Oncol. 2002;10:279–80.

    Google Scholar 

  • Souret FF, Kim Y, Wyslouzil BE et al. Scale-up of Artemisia annua L. hairy root cultures produces complex patterns of terpenoid gene expression. Biotechnol Bioeng. 2003;83:653–67.

    Article  CAS  PubMed  Google Scholar 

  • Stepniewska K, Day N, Babiker A et al. A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg. 2001;95:637–50.

    Article  CAS  Google Scholar 

  • Sukhija M, Medhi B, Pandhi P. Effects of Artemisinin, artemether, arteether on the pharmacokinetics of carbamazepine. Pharmacology. 2006;76:110–6.

    Article  CAS  PubMed  Google Scholar 

  • Sundar SN, Marconett CN, Doan VB et al. Artemisinin selectively decreases functional levels of estrogen receptor-alpha and ablates estrogen-induced proliferation in human breast cancer cells. Carcinogenesis. 2008;29:2252–8.

    Article  CAS  PubMed  Google Scholar 

  • Svensson US, Ashton M. Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of Artemisinin. Br J Clin Pharmacol. 1999;48:528–35.

    Article  CAS  PubMed  Google Scholar 

  • Svensson US, Maki-Jouppila M, Hoffmann KJ et al. Characterisation of the human liver in vitro metabolic pattern of Artemisinin and auto-induction in the rat by use of nonlinear mixed effects modelling. Biopharm Drug Dispos. 2003;24:71–85.

    Article  CAS  PubMed  Google Scholar 

  • Taketani S, Kakimoto K, Ueta H et al. Involvement of ABC7 in the biosynthesis of heme in erythroid cells: interaction of ABC7 with ferrochelatase. Blood. 2003;101:3274–80.

    Article  CAS  PubMed  Google Scholar 

  • Tan RX, Zheng WF, Tang HQ. Biologically active substances from the genus Artemisia. Planta Med. 1998;64:295–302.

    Article  CAS  PubMed  Google Scholar 

  • Tang W, Hemm I, Bertram B. Recent development of antitumor agents from Chinese herbal medicines. Part II. High molecular compounds(3). Planta Med. 2003a;69:193–201.

    Article  CAS  PubMed  Google Scholar 

  • Tang W, Hemm I, Bertram B. Recent development of antitumor agents from Chinese herbal medicines; part I. Low molecular compounds. Planta Med. 2003b;69:97–108.

    Article  CAS  PubMed  Google Scholar 

  • Toovey S. Are currently deployed Artemisinins neurotoxic? Toxicol Lett. 2006;166:95–104.

    Article  CAS  PubMed  Google Scholar 

  • Toovey S, Jamieson A. Audiometric changes associated with the treatment of uncomplicated falciparum malaria with co-artemether. Trans R Soc Trop Med Hyg. 2004;98:261–9.

    Article  PubMed  Google Scholar 

  • Tuttle TM. Technical advances in sentinel lymph node biopsy for breast cancer. Am Surg. 2004;70:407–13.

    PubMed  Google Scholar 

  • 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;20:199–205.

    Article  PubMed  Google Scholar 

  • van Geldre E, Vergauwe A, van den Eeckhout E. State of the art of the production of the antimalarial compound Artemisinin in plants. Plant Mol Biol. 1997;33:199–209.

    Article  PubMed  Google Scholar 

  • van Hensbroek MB, Onyiorah E, Jaffar S et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med. 1996;335:69–75.

    Article  PubMed  Google Scholar 

  • Volm M, Kastel M, Mattern J et al. Expression of resistance factors (P-glycoprotein, glutathione S-transferase-pi, and topoisomerase II) and their interrelationship to proto-oncogene products in renal cell carcinomas. Cancer. 1993;71:3981–7.

    Article  CAS  PubMed  Google Scholar 

  • Volm M, Koomagi R, Mattern J et al. Expression profile of genes in non-small cell lung carcinomas from long-term surviving patients. Clin Cancer Res. 2002a;8:1843–8.

    CAS  PubMed  Google Scholar 

  • Volm M, Koomagi R, Mattern J et al. Protein expression profiles indicative for drug resistance of non-small cell lung cancer. Br J Cancer. 2002b;87:251–7.

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Guo Y, Zhang BC et al. Induction of apoptosis and inhibition of cell migration and tube-like formation by dihydroartemisinin in murine lymphatic endothelial cells. Pharmacology. 2007a;80:207–18.

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Zhang B, Guo Y et al. Artemisinin inhibits tumor lymphangiogenesis by suppression of vascular endothelial growth factor C. Pharmacology. 2008;82:148–55.

    Article  CAS  PubMed  Google Scholar 

  • Wang JX, Tang W, Shi LP et al. Investigation of the immunosuppressive activity of artemether on T-cell activation and proliferation. Br J Pharmacol. 2007b;150:652–61.

    Article  CAS  PubMed  Google Scholar 

  • Wang JX, Tang W, Yang ZS et al. Suppressive effect of a novel water-soluble Artemisinin derivative SM905 on T cell activation and proliferation in vitro and in vivo. Eur J Pharmacol. 2007c;564:211–8.

    Article  CAS  PubMed  Google Scholar 

  • Wartenberg M, Wolf S, Budde P et al. The antimalaria agent Artemisinin exerts antiangiogenic effects in mouse embryonic stem cell-derived embryoid bodies. Lab Invest. 2003;83:1647–55.

    Article  CAS  PubMed  Google Scholar 

  • White NJ. Qinghaosu ngHaoSu (Artemisinin): the price of success. Science. 2008;320:330–4.

    Article  CAS  PubMed  Google Scholar 

  • Willoughby JA, Sr, Sundar SN, Cheung M et al. 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;284:2203–13.

    Article  CAS  PubMed  Google Scholar 

  • Woerdenbag HJ, Moskal TA, Pras N et al. Cytotoxicity of Artemisinin-related endoperoxides to Ehrlich ascites tumor cells. J Nat Prod. 1993;56:849–56.

    Article  CAS  PubMed  Google Scholar 

  • Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J. 2005;81:71–8.

    Article  CAS  PubMed  Google Scholar 

  • Wouters BG, van den Beucken T, Magagnin MG et al. Targeting hypoxia tolerance in cancer. Drug Resist Updat. 2004;7:25–40.

    Article  CAS  PubMed  Google Scholar 

  • Wu XH, Zhou HJ, Lee J. 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;17:839–48.

    Article  CAS  PubMed  Google Scholar 

  • Yamachika E, Habte T, Oda D. Artemisinin: an alternative treatment for oral squamous cell carcinoma. Anticancer Res. 2004;24:2153–60.

    CAS  PubMed  Google Scholar 

  • Yeung S, Pongtavornpinyo W, Hastings IM et al. Antimalarial drug resistance, Artemisinin-based combination therapy, and the contribution of modeling to elucidating policy choices. Am J Trop Med Hyg. 2004;71:179–86.

    PubMed  Google Scholar 

  • Yu JL, Coomber BL, Kerbel RS. A paradigm for therapy-induced microenvironmental changes in solid tumors leading to drug resistance. Differentiation. 2002;70:599–609.

    Article  PubMed  Google Scholar 

  • Zhang ZY, Yu SQ, Miao LY et al. [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;6:134–8.

    Article  CAS  PubMed  Google Scholar 

  • Zhou HJ, Wang WQ, Wu GD et al. Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. Vascul Pharmacol. 2007;47:131–8.

    Article  CAS  PubMed  Google Scholar 

  • Zhou HJ, Wang Z, Li A. Dihydroartemisinin induces apoptosis in human leukemia cells HL60 via downregulation of transferrin receptor expression. Anticancer Drugs. 2008;19:247–55.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Otorhinolaryngology, Head and Neck Surgery, University Heidelberg, Heidelberg, Germany

    Serkan Sertel & Peter K. Plinkert

  2. German Cancer Research Centre (DKFZ), Pharmaceutical Biology (C015), Heidelberg, Germany

    Serkan Sertel

  3. University of Mainz, Mainz, Germany

    Thomas Efferth

Authors
  1. Serkan Sertel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter K. Plinkert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Efferth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Efferth .

Editor information

Editors and Affiliations

  1. Dept. Clinical Oncology, Queen Elizabeth Hospital, Gascoigne Road 30, Kowloon, Hong Kong/PR China

    William C.S. Cho

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Sertel, S., Plinkert, P.K., Efferth, T. (2010). Novel Developments on Artemisinin and Its Derivatives for Cancer Therapy. In: Cho, W. (eds) Supportive Cancer Care with Chinese Medicine. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3555-4_9

Download citation

Publish with us

Policies and ethics

Search

Navigation