Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-28T05:23:43.709Z Has data issue: false hasContentIssue false
  • English
  • Français

Anticancer activities of artemisinin and its bioactive derivatives

Published online by Cambridge University Press:  30 October 2009

Gary L. Firestone  and
Shyam N. Sundar
Gary L. Firestone*
Affiliation:
Department of Molecular and Cell Biology and The Cancer Research Laboratory, The University of California at Berkeley, CA 94720-3200, USA.
Shyam N. Sundar
Affiliation:
Department of Molecular and Cell Biology and The Cancer Research Laboratory, The University of California at Berkeley, CA 94720-3200, USA.
*
*Corresponding author: Gary Firestone, Department of Molecular and Cell Biology and The Cancer Research Laboratory, 591, Life Sciences Addition, The University of California at Berkeley, Berkeley, CA 94720-3200, USA. Tel: +1 510 642 8319; Fax: +1 510 643 6791; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Artemisinin, a sesquiterpene lactone derived from the sweet wormwood plant Artemisia annua, and its bioactive derivatives exhibit potent anticancer effects in a variety of human cancer cell model systems. The pleiotropic response in cancer cells includes growth inhibition by cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness. These effects of artemisinin and its derivatives result from perturbations of many cellular signalling pathways. This review provides a comprehensive discussion of these cellular responses, and considers the ramifications for the potential development of artemisinin-based compounds in anticancer therapeutic and preventative strategies.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 11 , July 2009 , e32
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Duffy, P.E. and Mutabingwa, T.K. (2004) Drug combinations for malaria: time to ACT? Lancet 363, 3-4Google Scholar
2Meshnick, S.R. (1998) Artemisinin antimalarials: mechanisms of action and resistance. Médecine Tropicale 58, 13-17Google ScholarPubMed
3Efferth, T. (2009) Artemisinin: a versatile weapon from traditional Chinese medicine. In Herbal Drugs: Ethnomedicine to Modern Medicine (Ramawat, K.G., ed.), pp. 173-194, Springer-Verlag Berlin HeidelbergCrossRefGoogle Scholar
4Meshnick, S.R. (2002) Artemisinin: mechanisms of action, resistance and toxicity. International Journal for Parasitology 32, 1655-1660CrossRefGoogle ScholarPubMed
5Rosenthal, P.J. and Meshnick, S.R. (1996) Hemoglobin catabolism and iron utilization by malaria parasites. Molecular and Biochemical Parasitology 83, 131-139CrossRefGoogle ScholarPubMed
6Efferth, T. et al. (2001) The anti-malarial artesunate is also active against cancer. International Journal of Oncology 18, 767-773Google ScholarPubMed
7Paik, I.H. et al. (2006) Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity. Journal of Medicinal Chemistry 49, 2731-2734CrossRefGoogle ScholarPubMed
8Bustos, M.D., Gay, F. and Diquet, B. (1994) In-vitro tests on Philippine isolates of Plasmodium falciparum against four standard antimalarials and four qinghaosu derivatives. Bulletin of the World Health Organization 72, 729-735Google ScholarPubMed
9Kelter, G. et al. (2007) Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate. PLoS One 2, e798CrossRefGoogle ScholarPubMed
10Efferth, T., Olbrich, A. and Bauer, R. (2002) mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether. Biochemical Pharmacology 64, 617-623Google Scholar
11Mukanganyama, S. et al. (2002) Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. International Journal of Cancer 97, 700-705CrossRefGoogle ScholarPubMed
12Nam, W. et al. (2007) Effects of artemisinin and its derivatives on growth inhibition and apoptosis of oral cancer cells. Head and Neck 29, 335-340Google Scholar
13Chen, H. et al. (2009) Dihydroartemisinin inhibits growth of pancreatic cancer cells in vitro and in vivo. Anti-Cancer Drugs 20, 131-140CrossRefGoogle ScholarPubMed
14Lu, Y.Y. et al. (2009) Dihydroartemisinin (DHA) induces caspase-3-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells. Journal of Biomedical Science 16, 16Google Scholar
15Hou, J. et al. (2008) Experimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clinical Cancer Research 14, 5519-5530Google Scholar
16Jiao, Y. et al. (2007) Dihydroartemisinin is an inhibitor of ovarian cancer cell growth. Acta Pharmacologica Sinica 28, 1045-1056CrossRefGoogle ScholarPubMed
17Sundar, S.N. et al. (2008) Artemisinin selectively decreases functional levels of estrogen receptor-alpha and ablates estrogen-induced proliferation in human breast cancer cells. Carcinogenesis 29, 2252-2258CrossRefGoogle ScholarPubMed
18Willoughby, J.A. Sr et al. (2009) 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. Journal of Biological Chemistry 284, 2203-2213Google Scholar
19Dong, L. et al. (1999) Mechanisms of transcriptional activation of bcl-2 gene expression by 17beta-estradiol in breast cancer cells. Journal of Biological Chemistry 274, 32099-32107Google Scholar
20Lee, S.K. et al. (2006) p38 and ERK MAP kinase mediates iron chelator-induced apoptosis and-suppressed differentiation of immortalized and malignant human oral keratinocytes. Life Sciences 79, 1419-1427Google Scholar
21Petersen, C. et al. (2005) The p38 MAPK pathway mediates interleukin-1-induced Sertoli cell proliferation. Cytokine 32, 51-59CrossRefGoogle ScholarPubMed
22Mu, D. et al. (2008) The role of calcium, P38 MAPK in dihydroartemisinin-induced apoptosis of lung cancer PC-14 cells. Cancer Chemotherapy and Pharmacology 61, 639-645Google Scholar
23Riganti, C. et al. (2009) Artemisinin induces doxorubicin resistance in human colon cancer cells via calcium-dependent activation of HIF-1alpha and P-glycoprotein overexpression. British Journal of Pharmacology 156, 1054-1066CrossRefGoogle ScholarPubMed
24Genovese, R.F. and Newman, D.B. (2008) Understanding artemisinin-induced brainstem neurotoxicity. Archives of Toxicology 82, 379-385CrossRefGoogle ScholarPubMed
25Mu, D. et al. (2007) Calcium and survivin are involved in the induction of apoptosis by dihydroartemisinin in human lung cancer SPC-A-1 cells. Methods and Findings in Experimental and Clinical Pharmacology 29, 33-38Google Scholar
26Mita, A.C. et al. (2008) Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clinical Cancer Research. 14, 5000-5005Google Scholar
27Maruyama, J. et al. (2009) Stress-activated MAP kinase cascades in cellular senescence. Current Medicinal Chemistry 16, 1229-1235CrossRefGoogle ScholarPubMed
28Efferth, T. et al. (2003) Molecular modes of action of artesunate in tumor cell lines. Molecular Pharmacology 64, 382-394Google Scholar
29Gautam, A. et al. (2009) Pharmacokinetics and pharmacodynamics of endoperoxide antimalarials. Current Drug Metabolism 10, 289-306CrossRefGoogle ScholarPubMed
30Efferth, T. et al. (2004) Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron. Free Radical Biology and Medicine 37, 998-1009CrossRefGoogle ScholarPubMed
31Nakase, I. et al. (2009) Transferrin receptor-dependent cytotoxicity of artemisinin-transferrin conjugates on prostate cancer cells and induction of apoptosis. Cancer Letters 274, 290-298Google Scholar
32Mauriz, J.L., Tunon, M.J. and Gonzalez-Gallego, J. (2008) Apoptotic signaling pathways as a target for the treatment of liver diseases. Mini Reviews in Medicinal Chemistry 8, 1485-1493CrossRefGoogle ScholarPubMed
33Li, P.C. et al. (2008) Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Research 68, 4347-4351CrossRefGoogle ScholarPubMed
34Huang, X.J. et al. (2008) Dihydroartemisinin potentiates the cytotoxic effect of temozolomide in rat C6 glioma cells. Pharmacology 82, 1-9CrossRefGoogle ScholarPubMed
35Wang, J.X. et al. (2007) Investigation of the immunosuppressive activity of artemether on T-cell activation and proliferation. British Journal of Pharmacology 150, 652-661CrossRefGoogle ScholarPubMed
36Wang, Z. et al. (2007) Anti-inflammatory properties and regulatory mechanism of a novel derivative of artemisinin in experimental autoimmune encephalomyelitis. Journal of Immunology 179, 5958-5965CrossRefGoogle ScholarPubMed
37McEwan, I.J. (2009) Nuclear receptors: one big family. Methods in Molecular Biology 505, 3-18CrossRefGoogle ScholarPubMed
38Kerkhofs, S. et al. (2009) Androgen receptor knockout and knock-in mouse models. Journal of Molecular Endocrinology 42, 11-17Google Scholar
39McDevitt, M.A. et al. (2008) New insights into the classical and non-classical actions of estrogen: evidence from estrogen receptor knock-out and knock-in mice. Molecular and Cellular Endocrinology 290, 24-30Google Scholar
40Santen, R. et al. (2009) Estrogen mediation of breast tumor formation involves estrogen receptor-dependent, as well as independent, genotoxic effects. Annals of the New York Academy of Sciences 1155, 132-140Google Scholar
41Fox, E.M., Davis, R.J. and Shupnik, M.A. (2008) ERbeta in breast cancer–onlooker, passive player, or active protector? Steroids 73, 1039-1051Google Scholar
42Paruthiyil, S. et al. (2004) Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Research 64, 423-428CrossRefGoogle ScholarPubMed
43Strom, A. et al. (2004) Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proceedings of the National Academy of Sciences of the United States of America 101, 1566-1571CrossRefGoogle ScholarPubMed
44Roger, P. et al. (2001) Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors. Cancer Research 61, 2537-2541Google Scholar
45Shaaban, A.M. et al. (2003) Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia. American Journal of Surgical Pathology 27, 1502-1512Google Scholar
46Lai, H. and Singh, N.P. (2006) Oral artemisinin prevents and delays the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in the rat. Cancer Letters 231, 43-48CrossRefGoogle Scholar
47Cheng, J. et al. (2007) Tamoxifen induction of CCAAT enhancer-binding protein alpha is required for tamoxifen-induced apoptosis. Journal of Biological Chemistry 282, 30535-30543Google Scholar
48Eeckhoute, J. et al. (2007) Positive cross-regulatory loop ties GATA-3 to estrogen receptor alpha expression in breast cancer. Cancer Research 67, 6477-6483CrossRefGoogle ScholarPubMed
49Kerdelhue, B. and Jolette, J. (2002) The influence of the route of administration of 17beta-estradiol, intravenous (pulsed) versus oral, upon DMBA-induced mammary tumour development in ovariectomised rats. Breast Cancer Research and Treatment 73, 13-22CrossRefGoogle ScholarPubMed
50Hung, H. (2004) Inhibition of estrogen receptor alpha expression and function in MCF7 cells by kaempferol. Journal of Cellular Physiology 198, 197-208Google Scholar
51Sundar, S.N. et al. (2006) Indole-3-carbinol selectively uncouples expression and activity of estrogen receptor subtypes in human breast cancer cells. Molecular Endocrinology 20, 3070-3082Google Scholar
52Staka, C.M., Nicholson, R.I. and Gee, J.M. (2005) Acquired resistance to oestrogen deprivation: role for growth factor signalling kinases/oestrogen receptor cross-talk revealed in new MCF-7X model. Endocrine-Related Cancer 12 (Suppl 1), S85-97CrossRefGoogle ScholarPubMed
53Crawford, E.D. (2009) Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology 73, S4-10CrossRefGoogle ScholarPubMed
54Ghosh, P.M. et al. (2005) Signal transduction pathways in androgen-dependent and-independent prostate cancer cell proliferation. Endocrine-Related Cancer 12, 119-134CrossRefGoogle ScholarPubMed
55Heinlein, C.A. and Chang, C. (2004) Androgen receptor in prostate cancer. Endocrine Reviews 25, 276-308Google Scholar
56Isbarn, H. et al. Testosterone and prostate cancer: revisiting old paradigms. European Urology (in press)Google Scholar
57Modica, S., Bellafante, E. and Moschetta, A. (2009) Master regulation of bile acid and xenobiotic metabolism via the FXR, PXR and CAR trio. Frontiers in Bioscience 14, 4719-4745CrossRefGoogle ScholarPubMed
58Masi, A.D. et al. Nuclear receptors CAR and PXR: molecular, functional, and biomedical aspects. Molecular Aspects of Medicine (in press)Google Scholar
59Burk, O. et al. (2005) Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Molecular Pharmacology 67, 1954-1965CrossRefGoogle ScholarPubMed
60Haslam, I.S. et al. (2008) Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84). Biochemical Pharmacology 76, 850-861CrossRefGoogle ScholarPubMed
61Wu, X. et al. (2009) Chemokine receptors as targets for cancer therapy. Current Pharmaceutical Design 15, 742-757Google Scholar
62Tischer, E. et al. (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. Journal of Biological Chemistry 266, 11947-11954Google Scholar
63Anfosso, L. et al. (2006) Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics Journal 6, 269-278Google Scholar
64Wartenberg, M. et al. (2003) The antimalaria agent artemisinin exerts antiangiogenic effects in mouse embryonic stem cell-derived embryoid bodies. Laboratory Investigation 83, 1647-1655Google Scholar
65Zhou, H.J. et al. (2007) Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. Vascular Pharmacology 47, 131-138CrossRefGoogle ScholarPubMed
66Chen, T. et al. Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy. Journal of Cellular and Molecular Medicine (in press)Google Scholar
67Kim, M.S. et al. (2000) Anti-angiogenic activity of torilin, a sesquiterpene compound isolated from Torilis japonica. International Journal of Cancer 87, 269-275Google Scholar
68Jeong, S.J. et al. (2002) Costunolide, a sesquiterpene lactone from Saussurea lappa, inhibits the VEGFR KDR/Flk-1 signaling pathway. Cancer Letters 187, 129-133CrossRefGoogle ScholarPubMed
69Longo, M. et al. (2006) Effects of the antimalarial drug dihydroartemisinin (DHA) on rat embryos in vitro. Reproductive Toxicology 21, 83-93CrossRefGoogle ScholarPubMed
70Buommino, E. et al. (2009) Artemisinin reduces human melanoma cell migration by down-regulating alphaVbeta3 integrin and reducing metalloproteinase 2 production. Investigational New Drugs 27, 412-418Google Scholar
71Hung, W.C. and Chang, H.C. (2009) Indole-3-carbinol inhibits Sp1-induced matrix metalloproteinase-2 expression to attenuate migration and invasion of breast cancer cells. Journal of Agricultural and Food Chemistry 57, 76-82Google Scholar
72Fishwick, J. et al. (1995) The toxicity of artemisinin and related compounds on neuronal and glial cells in culture. Chemico-Biological Interactions 96, 263-271CrossRefGoogle ScholarPubMed
73Efferth, T. et al. (2004) Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774. Biochemical Pharmacology 67, 1689-1700CrossRefGoogle ScholarPubMed
74Harichand-Herdt, S., Zelnak, A. and O'Regan, R. (2009) Endocrine therapy for the treatment of postmenopausal women with breast cancer. Expert Review of Anticancer Therapy 9, 187-198CrossRefGoogle ScholarPubMed
75Rau, K.M. et al. (2005) The mechanisms and managements of hormone-therapy resistance in breast and prostate cancers. Endocrine-related Cancer 12, 511-532CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

Efferth, T. (2009) Artemisinin: a versatile weapon from traditional Chinese medicine. In Herbal Drugs: Ethnomedicine to Modern Medicine (Ramawat, K.G. ed.), pp. 173-194, Springer-Verlag Berlin HeidelbergGoogle Scholar
Li, Q., Milhous, W.K. and Weina, P.J. (2007) Artemisinins in Malaria Therapy, Nova Science Publishers, NY, USAGoogle Scholar