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Journal of Biomedicine and Biotechnology
Volume 2012 (2012), Article ID 247597, 18 pages
http://dx.doi.org/10.1155/2012/247597
Review Article

Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug

1Department of Biomedical Science, Faculty of Basic and Health Science, Santiago de Cali University, Pampalinda Campus, Cali, Colombia
2Division of Molecular and Gene Therapies, Griffith Health Institute and School of Medical Science, Griffith University, Gold Coast Campus, Southport, QLD 4222, Australia

Received 1 August 2011; Accepted 29 August 2011

Academic Editor: Masa-Aki Shibata

Copyright © 2012 Maria P. Crespo-Ortiz and Ming Q. Wei. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. W. L. W. Hsiao and L. Liu, “The role of traditional Chinese herbal medicines in cancer therapy from TCM theory to mechanistic insights,” Planta Medica, vol. 76, no. 11, pp. 1118–1131, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  2. T. Efferth, H. Dunstan, A. Sauerbrey, H. Miyachi, and C. R. Chitambar, “The anti-malarial artesunate is also active against cancer,” International Journal of Oncology, vol. 18, no. 4, pp. 767–773, 2001. View at Google Scholar · View at Scopus
  3. H. J. Woerdenbag, T. A. Moskal, N. Pras et al., “Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells,” Journal of Natural Products, vol. 56, no. 6, pp. 849–856, 1993. View at Google Scholar · View at Scopus
  4. P. Reungpatthanaphong and S. Mankhetkorn, “Modulation of multidrug resistance by artemisinin, artesunate and dihydroartemisinin in K562/adr and GLC4/adr resistant cell lines,” Biological and Pharmaceutical Bulletin, vol. 25, no. 12, pp. 1555–1561, 2002. View at Publisher · View at Google Scholar · View at Scopus
  5. T. Efferth, A. Saverbrey, A. Olbrich et al., “Molecular modes of action of artesunate in tumour cell lines,” Molecular Pharmacology, vol. 64, no. 2, pp. 382–394, 2003. View at Google Scholar
  6. T. Gordi and E. I. Lepist, “Artemisinin derivatives: toxic for laboratory animals, safe for humans?” Toxicology Letters, vol. 147, no. 2, pp. 99–107, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. A. M. Dondorp, F. Nosten, P. Yi et al., “Artemisinin resistance in Plasmodium falciparum malaria,” New England Journal of Medicine, vol. 361, no. 5, pp. 455–467, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. Qinghaosu Antimalaria Coordinating Research Group, “Antimalaria studies on Qinghaosu,” Chinese Medical Journal, vol. 92, no. 12, pp. 811–816, 1979. View at Google Scholar · View at Scopus
  9. M. Ashton, N. D. Sy, N. van Huong et al., “Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria,” Clinical Pharmacology and Therapeutics, vol. 63, no. 4, pp. 482–493, 1998. View at Publisher · View at Google Scholar · View at Scopus
  10. Q. Li, P. J. Weina, and W. K. Milhous, “Pharmacokinetic and pharmacodynamic profiles of rapid-acting artemisinins in the antimalarial therapy,” Current Drug Therapy, vol. 2, no. 3, pp. 210–223, 2007. View at Google Scholar
  11. R. K. Haynes, H. W. Chan, M. K. Cheung et al., “C-10 ester and ether derivatives of dihydroartemisinin - 10-α artesunate, preparation of authentic 10-β artesunate, and of other ester and ether derivatives bearing potential aromatic intercalating groups at C-10,” European Journal of Organic Chemistry, vol. 2002, no. 1, pp. 113–132, 2002. View at Google Scholar · View at Scopus
  12. D. L. Klayman, “Qinghaosu (artemisinin): an antimalarial drug from China,” Science, vol. 228, no. 4703, pp. 1049–1055, 1985. View at Google Scholar · View at Scopus
  13. R. K. Haynes, “From artemisinin to new artemisinin antimalarials: biosynthesis, extraction, old and new derivatives, stereochemistry and medicinal chemistry requirements,” Current Topics in Medicinal Chemistry, vol. 6, no. 5, pp. 509–537, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. D. J. Creek, W. N. Charman, F. C. K. Chiu et al., “Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 4, pp. 1291–1296, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. C. W. Jefford, “New developments in synthetic peroxidic drugs as artemisinin mimics,” Drug Discovery Today, vol. 12, no. 11-12, pp. 487–495, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. A. P. Ramirez, A. M. Thomas, and K. A. Woerpel, “Preparation of bicyclic 1,2,4-trioxanes from γ,δ-unsaturated ketones,” Organic Letters, vol. 11, no. 3, pp. 507–510, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. D. K. Taylor, T. D. Avery, B. W. Greatrex et al., “Novel endoperoxide antimalarials: synthesis, heme binding, and antimalarial activity,” Journal of Medicinal Chemistry, vol. 47, no. 7, pp. 1833–1839, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. C. W. Jefford, J. Velarde, and G. Bernardinelli, “Synthesis of tricyclic arteannuin-like compounds,” Tetrahedron Letters, vol. 30, no. 34, pp. 4485–4488, 1989. View at Google Scholar · View at Scopus
  19. G. H. Posner, Chang Ho Oh, L. Gerena, and W. K. Milhous, “Extraordinarily potent antimalarial compounds: new, structurally simple, easily synthesized, tricyclic 1,2,4-trioxanes,” Journal of Medicinal Chemistry, vol. 35, no. 13, pp. 2459–2467, 1992. View at Publisher · View at Google Scholar · View at Scopus
  20. S. R. Meshnick, A. Thomas, A. Ranz, C. M. Xu, and H. Z. Pan, “Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial action,” Molecular and Biochemical Parasitology, vol. 49, no. 2, pp. 181–189, 1991. View at Publisher · View at Google Scholar · View at Scopus
  21. P. L. Olliaro, R. K. Haynes, B. Meunier, and Y. Yuthavong, “Possible modes of action of the artemisinin-type compounds,” Trends in Parasitology, vol. 17, no. 3, pp. 122–126, 2001. View at Publisher · View at Google Scholar · View at Scopus
  22. P. M. O'Neill, V. E. Barton, and S. A. Ward, “The molecular mechanism of action of artemisinin—the debate continues,” Molecules, vol. 15, no. 3, pp. 1705–1721, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. N. Klonis, M. P. Crespo-Ortiz, I. Bottova et al., “Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 28, pp. 11405–11410, 2011. View at Publisher · View at Google Scholar · View at PubMed
  24. X. Shuhua, S. Binggui, J. Utzinger, J. Chollet, and M. Tanner, “Ultrastructural alterations in adult Schistosoma mansoni caused by artemether,” Memorias do Instituto Oswaldo Cruz, vol. 97, no. 5, pp. 717–724, 2002. View at Google Scholar · View at Scopus
  25. A. M. Galal, S. A. Ross, M. A. ElSohly et al., “Deoxyartemisinin derivatives from photooxygenation of anhydrodeoxydihydroartemisinin and their cytotoxic evaluation,” Journal of Natural Products, vol. 65, no. 2, pp. 184–188, 2002. View at Publisher · View at Google Scholar · View at Scopus
  26. A. C. Beekman, P. K. Wierenga, H. J. Woerdenbag et al., “Artemisinin-derived sesquiterpene lactones as potential antitumour compounds: cytotoxic action against bone marrow and tumour cells,” Planta Medica, vol. 64, no. 7, pp. 615–619, 1998. View at Publisher · View at Google Scholar · View at PubMed
  27. B. Meunier and A. Robert, “Heme as trigger and target for trioxane-containing antimalarial drugs,” Accounts of Chemical Research, vol. 43, no. 11, pp. 1444–1451, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. A. E. Mercer, J. L. Maggs, X. M. Sun et al., “Evidence for the involvement of carbon-centered radicals in the induction of apoptotic cell death by artemisinin compounds,” Journal of Biological Chemistry, vol. 282, no. 13, pp. 9372–9382, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. S. Zhang and G. S. Gerhard, “Heme mediates cytotoxicity from artemisinin and serves as a general anti-proliferation target,” PLoS ONE, vol. 4, no. 10, Article ID e7472, 2009. View at Publisher · View at Google Scholar · View at PubMed
  30. T. G. Berger, D. Dieckmann, T. Efferth et al., “Artesunate in the treatment of metastatic uveal melanoma–first experiences,” Oncology Reports, vol. 14, no. 6, pp. 1599–1603, 2005. View at Google Scholar · View at Scopus
  31. A. Hamacher-Brady, H. A. Stein, S. Turschner et al., “Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production,” Journal of Biological Chemistry, vol. 286, no. 8, pp. 6587–6601, 2011. View at Publisher · View at Google Scholar · View at PubMed
  32. N. P. Singh and H. C. Lai, “Artemisinin induces apoptosis in human cancer cells,” Anticancer Research, vol. 24, no. 4, pp. 2277–2280, 2004. View at Google Scholar · View at Scopus
  33. J. J. Lu, L. H. Meng, U. T. Shankavaram et al., “Dihydroartemisinin accelerates c-MYC oncoprotein degradation and induces apoptosis in c-MYC-overexpressing tumor cells,” Biochemical Pharmacology, vol. 80, no. 1, pp. 22–30, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. J. J. Lu, S. M. Chen, X. W. Zhang, J. Ding, and L. H. Meng, “The anti-cancer activity of dihydroartemisinin is associated with induction of iron-dependent endoplasmic reticulum stress in colorectal carcinoma HCT116 cells,” Investigational New Drugs, vol. 7, pp. 1–8, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. A. E. Mercer, I. M. Copple, J. L. Maggs, P. M. O'Neill, and B. K. Park, “The role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarials,” Journal of Biological Chemistry, vol. 283, no. 2, pp. 987–996, 2011. View at Publisher · View at Google Scholar · View at PubMed
  36. H. Lai and N. P. Singh, “Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin,” Cancer Letters, vol. 91, no. 1, pp. 41–46, 1995. View at Publisher · View at Google Scholar · View at Scopus
  37. H. Lai, I. Nakase, E. Lacoste, N. P. Singh, and T. Sasaki, “Artemisinin-transferrin conjugate retards growth of breast tumors in the rat,” Anticancer Research, vol. 29, no. 10, pp. 3807–3810, 2009. View at Google Scholar · View at Scopus
  38. I. Nakase, H. Lai, N. P. Singh, and T. Sasaki, “Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation,” International Journal of Pharmaceutics, vol. 354, no. 1-2, pp. 28–33, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. H. Lai, T. Sasaki, and N. P. Singh, “Targeted treatment of cancer with artemisinin and artemisinin-tagged iron-carrying compounds,” Expert Opinion on Therapeutic Targets, vol. 9, no. 5, pp. 995–1007, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. L. H. Stockwin, B. Han, S. X. Yu et al., “Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction,” International Journal of Cancer, vol. 125, no. 6, pp. 1266–1275, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. X. J. Huang, Z. Q. Ma, W. P. Zhang, Y. B. Lu, and E. Q. Wei, “Dihydroartemisinin exerts cytotoxic effects and inhibits hypoxia inducible factor-1α activation in C6 glioma cells,” Journal of Pharmacy and Pharmacology, vol. 59, no. 6, pp. 849–856, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. J. C. Kwok and D. R. Richardson, “The iron metabolism of neoplastic cells: alterations that facilitate proliferation?” Critical Reviews in Oncology/Hematology, vol. 42, no. 1, pp. 65–78, 2002. View at Publisher · View at Google Scholar · View at Scopus
  43. T. Efferth, A. Benakis, M. R. Romero et al., “Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron,” Free Radical Biology and Medicine, vol. 37, no. 7, pp. 998–1009, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. Q. Xu, Z. -X. Li, H. -Q. Peng et al., “Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line In vitro and In vivo,” Biomedicine and Biotechnology, vol. 12, no. 4, pp. 247–255, 2011. View at Publisher · View at Google Scholar · View at PubMed
  45. W. S. May and P. Cuatrecasas, “Transferrin receptor: its biological significance,” Journal of Membrane Biology, vol. 88, no. 3, pp. 205–215, 1985. View at Google Scholar · View at Scopus
  46. D. G. Bostwick, E. E. Alexander, R. Singh et al., “Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer,” Cancer, vol. 89, no. 1, pp. 123–134, 2000. View at Publisher · View at Google Scholar · View at Scopus
  47. U. N. Das, “A radical approach to cancer,” Medical Science Monitor, vol. 8, no. 4, pp. RA79–RA92, 2002. View at Google Scholar · View at Scopus
  48. J. B. Hansen, N. Fisker, M. Westergaard et al., “SPC3042: a proapoptotic survivin inhibitor,” Molecular Cancer Therapeutics, vol. 7, no. 9, pp. 2736–2745, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. M. D. P. Crespo, T. D. Avery, E. Hanssen et al., “Artemisinin and a series of novel endoperoxide antimalarials exert early effects on digestive vacuole morphology,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 1, pp. 98–109, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. I. D. Ferreira, D. Lopes, A. Martinelli, C. Ferreira, V. E. Do Rosário, and P. Cravo, “In vitro assessment of artesunate, artemether and amodiaquine susceptibility and molecular analysis of putative resistance-associated mutations of Plasmodium falciparum from São Tomé and Príncipe,” Tropical Medicine and International Health, vol. 12, no. 3, pp. 353–362, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. J. H. Du, H. D. Zhang, Z. J. Ma, and K. M. Ji, “Artesunate induces oncosis-like cell death In vitro and has antitumor activity against pancreatic cancer xenografts In vivo,” Cancer Chemotherapy and Pharmacology, vol. 65, no. 5, pp. 895–902, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. M. Michaelis, M. C. Kleinschmidt, S. Barth et al., “Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines,” Biochemical Pharmacology, vol. 79, no. 2, pp. 130–136, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. S. J. Kim, M. S. Kim, J. W. Lee et al., “Dihydroartemisinin enhances radiosensitivity of human glioma cells In vitro,” Journal of Cancer Research and Clinical Oncology., vol. 132, no. 2, pp. 129–135, 2006. View at Google Scholar · View at Scopus
  54. Y. Y. Lu, T. S. Chen, X. P. Wang, and L. Li, “Single-cell analysis of dihydroartemisinin-induced apoptosis through reactive oxygen species-mediated caspase-8 activation and mitochondrial pathway in ASTC-a-1 cells using fluorescence imaging techniques,” Journal of Biomedical Optics, vol. 15, no. 4, p. 046028, 2010. View at Google Scholar
  55. S. Noori, Z. M. Hassan, M. Taghikhani, B. Rezaei, and Z. Habibi, “Dihydroartemisinin can inhibit calmodulin, calmodulin-dependent phosphodiesterase activity and stimulate cellular immune responses,” International Immunopharmacology, vol. 10, no. 2, pp. 213–217, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. D. Mu, W. Chen, B. Yu, C. Zhang, Y. Zhang, and H. Qi, “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, vol. 29, no. 1, pp. 33–38, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. D. Mu, W. Zhang, D. Chu et al., “The role of calcium, P38 MAPK in dihydroartemisinin-induced apoptosis of lung cancer PC-14 cells,” Cancer Chemotherapy and Pharmacology, vol. 61, no. 4, pp. 639–645, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. T. Efferth, “Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin from bench to bedside,” Planta Medica, vol. 73, no. 4, pp. 299–309, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. C. Riganti, S. Doublier, D. Viarisio et al., “Artemisinin induces doxorubicin resistance in human colon cancer cells via calcium-dependent activation of HIF-1α and P-glycoprotein overexpression,” British Journal of Pharmacology, vol. 156, no. 7, pp. 1054–1066, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. Y. Liu, C. N. Lok, B. C. B. Ko, T. Y. T. Shum, M. K. Wong, and C. M. Che, “Subcellular localization of a fluorescent artemisinin derivative to endoplasmic reticulum,” Organic Letters, vol. 12, no. 7, pp. 1420–1423, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. C. Morrissey, B. Gallis, J. W. Solazzi et al., “Effect of artemisinin derivatives on apoptosis and cell cycle in prostate cancer cells,” Anti-Cancer Drugs, vol. 21, no. 4, pp. 423–432, 2010. View at Publisher · View at Google Scholar · View at PubMed
  62. Y. Y. Lu, T. S. Chen, J. L. Qu, W. L. Pan, L. Sun, and X. B. Wei, “Dihydroartemisinin (DHA) induces caspase-3-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells,” Journal of Biomedical Science, vol. 16, no. 1, article 16, 2009. View at Publisher · View at Google Scholar · View at PubMed
  63. A. M. Gravett, W. M. Liu, S. Krishna et al., “In vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents,” Cancer Chemotherapy and Pharmacology, pp. 569–577, 2010. View at Publisher · View at Google Scholar · View at PubMed
  64. E. R. McDonald 3rd. E.R. and W. S. El-Deiry, “Cell cycle control as a basis for cancer drug development (Review),” International Journal of Oncology, vol. 16, no. 5, pp. 871–886, 2000. View at Google Scholar
  65. B. Vogelstein and K. W. Kinzler, “Cancer genes and the pathways they control,” Nature Medicine, vol. 10, no. 8, pp. 789–799, 2004. View at Publisher · View at Google Scholar · View at PubMed
  66. H. J. Woerdenbag, T. A. Moskal, N. Pras et al., “Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells,” Journal of Natural Products, vol. 56, no. 6, pp. 849–856, 1993. View at Google Scholar
  67. J. Hou, D. Wang, R. Zhang, and H. Wang, “Experimental therapy of hepatoma with artemisinin and Its derivatives: In vitro and In vivo activity, chemosensitization, and mechanisms of action,” Clinical Cancer Research, vol. 14, no. 17, pp. 5519–5530, 2008. View at Publisher · View at Google Scholar · View at PubMed
  68. L. Yao, H. Xie, Q.-Y. Jin, W.-L. Hu, and L.-J. Chen, “Analyzing anti-cancer action mechanisms of dihydroartemisinin using gene chip,” China Journal of Chinese Materia Medica, vol. 33, no. 13, pp. 1583–1586, 2008. View at Google Scholar
  69. Y. Jiao, C. M. Ge, Q. H. Meng, J. P. Cao, J. Tong, and S. J. Fan, “Dihydroartemisinin is an inhibitor of ovarian cancer cell growth,” Acta Pharmacologica Sinica, vol. 28, no. 7, pp. 1045–1056, 2007. View at Publisher · View at Google Scholar · View at PubMed
  70. M. Malumbres and M. Barbacid, “To cycle or not to cycle: a critical decision in cancer,” Nature Reviews Cancer, vol. 1, no. 3, pp. 222–231, 2001. View at Google Scholar
  71. D. G. Johnson and C. L. Walker, “Cyclins and cell cycle checkpoints,” Annual Review of Pharmacology and Toxicology, vol. 39, pp. 295–312, 1999. View at Publisher · View at Google Scholar · View at PubMed
  72. G. L. Firestone and S. N. Sundar, “Anticancer activities of artemisinin and its bioactive derivatives,” Expert Reviews in Molecular Medicine, vol. 11, p. e32, 2009. View at Google Scholar
  73. Y. Ji, Y. C. Zhang, L. B. Pei, L. L. Shi, J. L. Yan, and X. H. Ma, “Anti-tumor effects of dihydroartemisinin on human osteosarcoma,” Molecular and Cellular Biochemistry, vol. 351, no. 1-2, pp. 99–108, 2011. View at Publisher · View at Google Scholar · View at PubMed
  74. H. Chen, B. Sun, S. Pan, H. Jiang, and X. Sun, “Dihydroartemisinin inhibits growth of pancreatic cancer cells In vitro and In vivo,” Anti-Cancer Drugs, vol. 20, no. 2, pp. 131–140, 2009. View at Publisher · View at Google Scholar · View at PubMed
  75. W. Aung, C. Sogawa, T. Furukawa, and T. Saga, “Anticancer effect of dihydroartemisinin (DHA) in a pancreatic tumor model evaluated by conventional methods and optical imaging,” Anticancer Research, vol. 31, no. 5, pp. 1549–1558, 2011. View at Google Scholar
  76. S. -J. Wang, B. Sun, Z. -X. Cheng et al., “Dihydroartemisinin inhibits angiogenesis in pancreatic cancer by targeting the NF-κB pathway,” Cancer Chemotherapy and Pharmacology. In press. View at Publisher · View at Google Scholar · View at PubMed
  77. T. Chen, M. Li, R. Zhang, and H. Wang, “Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy,” Journal of Cellular and Molecular Medicine, vol. 13, no. 7, pp. 1358–1370, 2009. View at Publisher · View at Google Scholar · View at PubMed
  78. J. Wang, Y. Guo, B. C. Zhang, Z. T. Chen, and J. F. Gao, “Induction of apoptosis and inhibition of cell migration and tube-like formation by dihydroartemisinin in murine lymphatic endothelial cells,” Pharmacology, vol. 80, no. 4, pp. 207–218, 2007. View at Publisher · View at Google Scholar · View at PubMed
  79. C. M. Cabello, S. D. Lamore, W. B. Bair III et al., “The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis,” Investigational New Drugs. In press. View at Publisher · View at Google Scholar · View at PubMed
  80. R. Handrick, T. Ontikatze, K. D. Bauer et al., “Dihydroartemisinin induces apoptosis by a bak-dependent intrinsic pathway,” Molecular Cancer Therapeutics, vol. 9, no. 9, pp. 2497–2510, 2010. View at Publisher · View at Google Scholar · View at PubMed
  81. Y. P. Hwang, H. J. Yun, H. G. Kim, E. H. Han, G. W. Lee, and H. G. Jeong, “Suppression of PMA-induced tumor cell invasion by dihydroartemisinin via inhibition of PKCα/Raf/MAPKs and NF-κB/AP-1-dependent mechanisms,” Biochemical Pharmacology, vol. 79, no. 12, pp. 1714–1726, 2010. View at Publisher · View at Google Scholar · View at PubMed
  82. H. J. Zhou, W. Q. Wang, G. D. Wu, J. Lee, and A. Li, “Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells,” Vascular Pharmacology, vol. 47, no. 2-3, pp. 131–138, 2007. View at Publisher · View at Google Scholar · View at PubMed
  83. J. Wang, B. Zhang, Y. Guo et al., “Artemisinin inhibits tumor lymphangiogenesis by suppression of vascular endothelial growth factor C,” Pharmacology, vol. 82, no. 2, pp. 148–155, 2008. View at Publisher · View at Google Scholar · View at PubMed
  84. H. J. Zhou, J. L. Zhang, A. Li, Z. Wang, and X. E. Lou, “Dihydroartemisinin improves the efficiency of chemotherapeutics in lung carcinomas In vivo and inhibits murine Lewis lung carcinoma cell line growth In vitro,” Cancer Chemotherapy and Pharmacology, vol. 66, no. 1, pp. 21–29, 2010. View at Publisher · View at Google Scholar · View at PubMed
  85. G. L. Disbrow, A. C. Baege, K. A. Kierpiec et al., “Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells In vitro and In vivo,” Cancer Research, vol. 65, no. 23, pp. 10854–10861, 2005. View at Publisher · View at Google Scholar · View at PubMed
  86. W. Lijuan, “Effect of artesunate on human endometrial carcinoma,” Journal of Medical Colleges of PLA, vol. 25, no. 3, pp. 143–151, 2010. View at Publisher · View at Google Scholar
  87. M. Youns, T. Efferth, J. Reichling, K. Fellenberg, A. Bauer, and J. D. Hoheisel, “Gene expression profiling identifies novel key players involved in the cytotoxic effect of Artesunate on pancreatic cancer cells,” Biochemical Pharmacology, vol. 78, no. 3, pp. 273–283, 2009. View at Publisher · View at Google Scholar · View at PubMed
  88. S. A. K. Rasheed, T. Efferth, I. A. Asangani, and H. Allgayer, “First evidence that the antimalarial drug artesunate inhibits invasion and In vivo metastasis in lung cancer by targeting essential extracellular proteases,” International Journal of Cancer, vol. 127, no. 6, pp. 1475–1485, 2010. View at Publisher · View at Google Scholar · View at PubMed
  89. L. N. Li, H. D. Zhang, S. J. Yuan, D. X. Yang, L. Wang, and Z. X. Sun, “Differential sensitivity of colorectal cancer cell lines to artesunate is associated with expression of beta-catenin and E-cadherin,” European Journal of Pharmacology, vol. 588, no. 1, pp. 1–8, 2008. View at Publisher · View at Google Scholar · View at PubMed
  90. S. Li, F. Xue, Z. Cheng et al., “Effect of artesunate on inhibiting proliferation and inducing apoptosis of SP2/0 myeloma cells through affecting NFκB p65,” International Journal of Hematology, vol. 90, no. 4, pp. 513–521, 2009. View at Publisher · View at Google Scholar · View at PubMed
  91. T. Weifeng, S. Feng, L. Xiangji et al., “Artemisinin inhibits In vitro and In vivo invasion and metastasis of human hepatocellular carcinoma cells,” Phytomedicine, vol. 18, no. 2-3, pp. 158–162, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  92. J. Wu, D. Hu, G. Yang et al., “Down-regulation of BMI-1 cooperates with artemisinin on growth inhibition of nasopharyngeal carcinoma cells,” Journal of Cellular Biochemistry, vol. 112, no. 7, pp. 1938–1948, 2011. View at Publisher · View at Google Scholar · View at PubMed
  93. E. Buommino, A. Baroni, N. Canozo et al., “Artemisinin reduces human melanoma cell migration by down-regulating αvβ3 integrin and reducing metalloproteinase 2 production,” Investigational New Drugs, vol. 27, no. 5, pp. 412–418, 2008. View at Publisher · View at Google Scholar · View at PubMed
  94. S. J. Wang, Y. Gao, H. Chen et al., “Dihydroartemisinin inactivates NF-κB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both In vitro and In vivo,” Cancer Letters, vol. 293, no. 1, pp. 99–108, 2010. View at Publisher · View at Google Scholar · View at PubMed
  95. A. G. Uren, L. Wong, M. Pakusch et al., “Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype,” Current Biology, vol. 10, no. 21, pp. 1319–1328, 2000. View at Publisher · View at Google Scholar
  96. J. A. Willoughby, S. N. Sundar, M. Cheung, A. S. Tin, J. Modiano, and G. L. Firestone, “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, vol. 284, no. 4, pp. 2203–2213, 2009. View at Publisher · View at Google Scholar · View at PubMed
  97. D. Karnak and L. Xu, “Chemosensitization of prostate cancer by modulating Bcl-2 family proteins,” Current Drug Targets, vol. 11, no. 6, pp. 699–707, 2010. View at Publisher · View at Google Scholar
  98. S. Elmore, “Apoptosis: a review of programmed cell death,” Toxicologic Pathology, vol. 35, no. 4, pp. 495–516, 2007. View at Publisher · View at Google Scholar · View at PubMed
  99. T. Efferth, M. Glaisi, A. Merling, P. H. Krammer, and M. Li-Weber, “Artesunate induces ROS-mediated apoptosis in Doxorubicin-resistant T leukemia cells,” PLoS ONE, vol. 2, no. 8, article e693, 2007. View at Publisher · View at Google Scholar · View at PubMed
  100. Q. He, J. Shi, X. L. Shen et al., “Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cells,” Cancer Biology and Therapy, vol. 9, no. 10, pp. 817–823, 2010. View at Google Scholar
  101. P. S. Steeg, “Tumor metastasis: mechanistic insights and clinical challenges,” Nature Medicine, vol. 12, no. 8, pp. 895–904, 2006. View at Publisher · View at Google Scholar · View at PubMed
  102. M. J. Duffy, P. M. McGowan, and W. M. Gallagher, “Cancer invasion and metastasis: changing views,” Journal of Pathology, vol. 214, no. 3, pp. 283–293, 2008. View at Publisher · View at Google Scholar · View at PubMed
  103. W. C. Hung and H. C. Chang, “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, vol. 57, no. 1, pp. 76–82, 2009. View at Publisher · View at Google Scholar · View at PubMed
  104. E. Hur, H. H. Kim, S. M. Choi et al., “Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1α/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol,” Molecular Pharmacology, vol. 62, no. 5, pp. 975–982, 2002. View at Publisher · View at Google Scholar
  105. L. Anfosso, T. Efferth, A. Albini, and U. Pfeffer, “Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins,” Pharmacogenomics Journal, vol. 6, no. 4, pp. 269–278, 2006. View at Publisher · View at Google Scholar · View at PubMed
  106. H. H. Chen, H. J. Zhou, W. Q. Wang, and G. D. Wu, “Antimalarial dihydroartemisinin also inhibits angiogenesis,” Cancer Chemotherapy and Pharmacology, vol. 53, no. 5, pp. 423–432, 2004. View at Publisher · View at Google Scholar · View at PubMed
  107. X. J. Huang, C. T. Li, W. P. Zhang, Y. B. Lu, S. H. Fang, and E. Q. Wei, “Dihydroartemisinin potentiates the cytotoxic effect of temozolomide in rat C6 glioma cells,” Pharmacology, vol. 82, no. 1, pp. 1–9, 2008. View at Publisher · View at Google Scholar · View at PubMed
  108. R. O'Connor, “The pharmacology of cancer resistance,” Anticancer Research, vol. 27, no. 3 A, pp. 1267–1272, 2007. View at Google Scholar
  109. W. Chaijaroenkul, V. Viyanant, W. Mahavorasirikul, and K. Na-Bangchang, “Cytotoxic activity of artemisinin derivatives against cholangiocarcinoma (CL-6) and hepatocarcinoma (Hep-G2) cell lines,” Asian Pacific Journal of Cancer Prevention, vol. 12, no. 1, pp. 55–59, 2011. View at Google Scholar
  110. N. P. Singh and H. C. Lai, “Synergistic cytotoxicity of artemisinin and sodium butyrate on human cancer cells,” Anticancer Research, vol. 25, no. 6 B, pp. 4325–4331, 2005. View at Google Scholar
  111. W. M. Liu, A. M. Gravett, and A. G. Dalgleish, “The antimalarial agent artesunate possesses anticancer properties that can be enhanced by combination strategies,” International Journal of Cancer, vol. 128, no. 6, pp. 1471–1480, 2011. View at Publisher · View at Google Scholar · View at PubMed
  112. Y. Ohgami, C. A. Elstad, E. Chung, D. Y. Shirachi, R. M. Quock, and H. C. Lai, “Effect of hyperbaric oxygen on the anticancer effect of artemisinin on molt-4 human leukemia cells,” Anticancer Research, vol. 30, no. 11, pp. 4467–4470, 2010. View at Google Scholar
  113. B. Witkowski, J. Lelièvre, M. J.L. Barragán et al., “Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 5, pp. 1872–1877, 2010. View at Publisher · View at Google Scholar · View at PubMed
  114. J. F. Head, F. Wang, and R. L. Elliott, “Antineoplastic drugs that interfere with iron metabolism in cancer cells,” Advances in Enzyme Regulation, vol. 37, pp. 147–169, 1997. View at Publisher · View at Google Scholar
  115. S. Sertel, T. Eichhorn, S. Sieber et al., “Factors determining sensitivity or resistance of tumor cell lines towards artesunate,” Chemico-Biological Interactions, vol. 185, no. 1, pp. 42–52, 2010. View at Publisher · View at Google Scholar · View at PubMed
  116. B. Bachmeier, I. Fichtner, P. H. Killian, E. Kronski, U. Pfeffer, and T. Efferth, “Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells,” PLoS ONE, vol. 6, no. 5, article e20550, 2011. View at Publisher · View at Google Scholar · View at PubMed
  117. W. McLean and S. A. Ward, “In vitro neurotoxicity of artemisinin derivatives,” Médecine Tropicale, vol. 58, no. 3, pp. 28–31, 1998. View at Google Scholar
  118. G. Schmuck, E. Roehrdanz, R. K. Haynes, and R. Kahl, “Neurotoxic mode of action of artemisinin,” Antimicrobial Agents and Chemotherapy, vol. 46, no. 3, pp. 821–827, 2002. View at Publisher · View at Google Scholar
  119. E. Kissinger, T. T. Hien, N. T. Hung et al., “Clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain-stem function in vietnamese patients,” American Journal of Tropical Medicine and Hygiene, vol. 63, no. 1-2, pp. 48–55, 2000. View at Google Scholar
  120. Y. Si, Q. Li, L. Xie et al., “Neurotoxicity and toxicokinetics of artelinic acid following repeated oral administration in rats,” International Journal of Toxicology, vol. 26, no. 5, pp. 401–410, 2007. View at Publisher · View at Google Scholar · View at PubMed
  121. T. Efferth and B. Kaina, “Toxicity of the antimalarial artemisinin and its dervatives,” Critical Reviews in Toxicology, vol. 40, no. 5, pp. 405–421, 2010. View at Publisher · View at Google Scholar · View at PubMed
  122. N. P. Singh and K. B. Verma, “Case report of a laryngeal squamous cell carcinoma treated with artesunate,” Archive of Oncology, vol. 10, no. 4, pp. 279–280, 2002. View at Publisher · View at Google Scholar
  123. N. P. Singh and V. K. Panwar, “Case report of a pituitary macroadenoma treated with artemether,” Integrative Cancer Therapies, vol. 5, no. 4, pp. 391–394, 2006. View at Publisher · View at Google Scholar · View at PubMed
  124. L. A. Panossian, N. I. Garga, and D. Pelletier, “Toxic brainstem encephalopathy after artemisinin treatment for breast cancer,” Annals of Neurology, vol. 58, no. 5, pp. 812–813, 2005. View at Publisher · View at Google Scholar · View at PubMed
  125. S. Campos, P. de la Cerda, and A. Rivera, “Fatal artesunate toxicity in a child,” Journal of Pediatric Infectious Diseases, vol. 3, no. 1, pp. 69–75, 2008. View at Google Scholar
  126. Z. Y. Zhang, S. Q. Yu, L. Y. Miao et al., “Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial,” Journal of Chinese Integrative Medicine, vol. 6, no. 2, pp. 134–138, 2008. View at Publisher · View at Google Scholar
  127. S. Lee, “Synthesis of 10B-Substituited triazolyl artemisinins and their growth inhibitory activity against various cancer cells,” Bulletin of the Korean Chemical Society, vol. 32, no. 2, pp. 737–740, 2011. View at Google Scholar
  128. F. S. Feng, E. M. Guantai, M. J. Nell, C. E. J. van Rensburg, H. Hoppe, and K. Chibale, “Antiplasmodial and antitumor activity of dDHA analogs derived via the aza-Michael addition reaction,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 10, pp. 2882–2886, 2000. View at Google Scholar
  129. C. H. Lee, H. Hong, J. Shin et al., “NMR studies on novel antitumor drug candidates, deoxoartemisinin and carboxypropyldeoxoartemisinin,” Biochemical and Biophysical Research Communications, vol. 274, no. 2, pp. 359–369, 2000. View at Publisher · View at Google Scholar · View at PubMed
  130. A. A. Alagbala, A. J. McRiner, K. Borstnik et al., “Biological mechanisms of action of novel C-10 non-acetal trioxane dimers in prostate cancer cell lines,” Journal of Medicinal Chemistry, vol. 49, no. 26, pp. 7836–7842, 2006. View at Publisher · View at Google Scholar · View at PubMed
  131. C. Horwedel, S. B. Tsogoeva, S. Wei, and T. Efferth, “Cytotoxicity of artesunic acid homo- and heterodimer molecules toward sensitive and multidrug-resistant CCRF-CEM leukemia cells,” Journal of Medicinal Chemistry, vol. 53, no. 13, pp. 4842–4848, 2010. View at Publisher · View at Google Scholar · View at PubMed
  132. J. P. Jeyadevan, P. G. Bray, J. Chadwick et al., “Antimalarial and Antitumor Evaluation of Novel C-10 Non-Acetal Dimers of 10β-(2-Hydroxyethyl)deoxoartemisinin,” Journal of Medicinal Chemistry, vol. 47, no. 5, pp. 1290–1298, 2004. View at Publisher · View at Google Scholar · View at PubMed
  133. M. Jung, S. Lee, J. Ham, K. Lee, H. Kim, and S. Kie Kim, “Antitumor activity of novel deoxoartemisinin monomers, dimers, and trimer,” Journal of Medicinal Chemistry, vol. 46, no. 6, pp. 987–994, 2003. View at Publisher · View at Google Scholar · View at PubMed
  134. D. Opsenica, G. Pocsfalvi, Z. Juranic et al., “Cholic acid derivatives as 1,2,4,5-tetraoxane carriers: structure and antimalarial and antiproliferative activity,” Journal of Medicinal Chemistry, vol. 43, no. 17, pp. 3274–3282, 2000. View at Publisher · View at Google Scholar
  135. S. Soomro, T. Langenberg, A. Mahringer et al., “Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties,” Journal of Cellular and Molecular Medicine, vol. 15, no. 5, pp. 1122–1135, 2011. View at Publisher · View at Google Scholar · View at PubMed
  136. P. J. de Vries and T. K. Dien, “Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria,” Drugs, vol. 52, no. 6, pp. 818–836, 1996. View at Google Scholar
  137. S. Krishna, A. C. Uhlemann, and R. K. Haynes, “Artemisinins: mechanisms of action and potential for resistance,” Drug Resistance Updates, vol. 7, no. 4-5, pp. 233–244, 2004. View at Publisher · View at Google Scholar · View at PubMed
  138. S. A. Charman, S. Arbe-Barnes, I. C. Bathurst et al., “Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 11, pp. 4400–4405, 2011. View at Publisher · View at Google Scholar · View at PubMed
  139. S. -H. Xiao, J. Keiser, J. Chollet et al., “In vitro and In vivo activities of synthetic trioxolanes against major human schistosome species,” Antimicrobial Agents and Chemotherapy, vol. 51, no. 4, pp. 1440–1445, 2007. View at Publisher · View at Google Scholar · View at PubMed
  140. I. Opsenica, D. Opsenica, K. S. Smith, W. K. Milhous, and B. A. Šolaja, “Chemical stability of the peroxide bond enables diversified synthesis of potent tetraoxane antimalarials,” Journal of Medicinal Chemistry, vol. 51, no. 7, pp. 2261–2266, 2008. View at Publisher · View at Google Scholar · View at PubMed
  141. N. Terzić, D. Opsenica, D. Milić et al., “Deoxycholic acid-derived tetraoxane antimalarials and antiproliferatives,” Journal of Medicinal Chemistry, vol. 50, no. 21, pp. 5118–5127, 2007. View at Publisher · View at Google Scholar · View at PubMed
  142. World Health Organization, Guidelines for the Treatment of Malaria, WHO press, Geneva, Switzerland, 2006.
  143. A. R. Yuen, G. Zou, A. T. Turrisi et al., “Reproductive functions in female patients treated with adjuvant and neoadjuvant chemotherapy for localized osteosarcoma of the extremity,” Cancer, vol. 89, no. 9, pp. 1961–1965, 2000. View at Publisher · View at Google Scholar
  144. Z. P. Wu, C. W. Gao, Y. G. Wu et al., “Inhibitive effect of artemether on tumor growth and angiogenesis in the rat C6 orthotopic brain gliomas model,” Integrative Cancer Therapies, vol. 8, no. 1, pp. 88–92, 2009. View at Publisher · View at Google Scholar · View at PubMed
  145. F. Cavallo, C. de Giovanni, P. Nanni, G. Forni, and P. -L. Lollini, “2011: the immune hallmarks of cancer,” Cancer Immunology, Immunotherapy, vol. 60, no. 3, pp. 319–326, 2011. View at Publisher · View at Google Scholar · View at PubMed