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Development of artemisinin compounds for cancer treatment

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Summary

Artemisinin contains an endoperoxide moiety that can react with iron to form cytotoxic free radicals. Cancer cells contain significantly more intracellular free iron than normal cells and it has been shown that artemisinin and its analogs selectively cause apoptosis in many cancer cell lines. In addition, artemisinin compounds have been shown to have anti-angiogenic, anti-inflammatory, anti-metastasis, and growth inhibition effects. These properties make artemisinin compounds attractive cancer chemotherapeutic drug candidates. However, simple artemisinin analogs are less potent than traditional cancer chemotherapeutic agents and have short plasma half-lives, and would require high dosage and frequent administration to be effective for cancer treatment. More potent and target-selective artemisinin-compounds are being developed. These include artemisinin dimers and trimers, artemisinin hybrid compounds, and tagging of artemisinin compounds to molecules that are involved in the intracellular iron-delivery mechanism. These compounds are promising potent anticancer compounds that produce significantly less side effect than traditional chemotherapeutic agents.

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References

  1. Lai H, Singh NP (1995) Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin. Cancer Lett 91:41–46

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Woerdenbag HJ, Moskal TA, Pras N, Malingré TM, el-Feraly FS, Kampinga HH, Konings AW (1993) Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells. J Nat Prod 56:849–856

    Article  PubMed  CAS  Google Scholar 

  4. Alcậntara DD, Ribeiro HF, Cardoso PC, Araújo TM, Burbano RR, Guimarães AC, Khayat AS, Oliveira Bahia M (2011) In vitro evaluation of the cytotoxic and genotoxic effects of artemether, an antimalarial drug, in a gastric cancer cell line (PG100). J Appl Toxicol. doi:10.1002/jat.1734 [Epub ahead of print]

  5. Cabello CM, Lamore SD, Bair WB3th, Qiao S, Azimian S, Lesson JL, Wondrak GT (2011) The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis. Invest New Drugs May 6. [Epub ahead of print]

  6. Chen T, Li M, Zhang R, Wang H (2009) Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy. J Cell Mol Med 13:1358–1370

    Article  PubMed  CAS  Google Scholar 

  7. Hamacher-Brady A, Stein HA, Turschner S, Toegel I, Mora R, Jennewein N, Efferth T, Eils R, Brady NR (2011) Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem 286:6587–6601

    Article  PubMed  CAS  Google Scholar 

  8. Hou J, Wang D, Zhang R, Wang H (2008) Experimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res 14:5519–5530

    Article  PubMed  CAS  Google Scholar 

  9. Jiang Z, Chai J, Chuang HH, Li S, Wang T, Cheng Y, Chen W, Zhou D (2012) Artesunate induces G0/G1 cell cycle arrest and iron-mediated mitochondrial apoptosis in A431 human epidermoid carcinoma cells. Anticancer Drugs Mar 14. [Epub ahead of print]

  10. Jiao Y, Ge CM, Meng QH, Cao JP, Tong J, Fan SJ (2007) Dihydroartemisinin is an inhibitor of ovarian cancer cell growth. Acta Pharmacol Sinica 28:1045–1056

    Article  CAS  Google Scholar 

  11. Tin AS, Sundar SN, Tran KQ, Park AH, Poindexter KM, Firestone GL (2012) Antiproliferative effects of artemisinin on human breast cancer cells requires the downregulated expression of the E2F1 transcription factor and loss of E2F1-target cell cycle genes. Anticancer Drug 23:370–379

    Article  CAS  Google Scholar 

  12. Efferth T, Giaisi M, Merling A, Krammer Peter H, Li-Weber M (2007) Artesunate induces ROS-mediated apoptosis in doxorubicin-resistant T leukemia cells. PLoS One 2:e693

    Article  PubMed  CAS  Google Scholar 

  13. Gao X, Luo Z, Xiang T, Wang K, Li J, Wang P (2011) Dihydroartemisinin induces endoplasmic reticulum stress-mediated apoptosis in HepG2 human hepatoma cells. Tumori 97:771–780

    PubMed  CAS  Google Scholar 

  14. Handrick R, Ontikatze T, Bauer KD, Freier F, Rübel A, Dürig J, Belka C, Jendrossek V (2010) Dihydroartemisinin induces apoptosis by a Bak-dependent intrinsic pathway. Mol Cancer Ther 9:2497–2510

    Article  PubMed  CAS  Google Scholar 

  15. Huan-Huan C, Li-Li Y, Shang-Bin L (2004) Artesunate reduces chicken chorioallantoic membrane neovascularisation and exhibits antiangiogenic and apoptotic activity on human microvascular dermal endothelial cell. Cancer Lett 211:163–173

    Article  PubMed  CAS  Google Scholar 

  16. Lee J, Zhou HJ, Wu XH (2006) Dihydroartemisinin down-regulates vascular endothelial growth factor expression and induces apoptosis in chronic myeloid leukemia K562 cells. Cancer Chemother Pharmacol 57:213–220

    Article  PubMed  CAS  Google Scholar 

  17. Li S-H, Pan L, Xue F (2007) Strong suppression of SP2/0 myeloma cell proliferation and enhanced apoptosis by artesunate. Zhongchengyao 29:434–435

    CAS  Google Scholar 

  18. Lu JJ, Meng LH, Shankavaram UT, Zhu CH, Tong LJ, Chen G, Lin LP, Weinstein JN, Ding J (2010) Dihydroartemisinin accelerates c-MYC oncoprotein degradation and induces apoptosis in c-MYC-overexpressing tumor cells. Biochem Pharmacol 80:22–30

    Article  PubMed  CAS  Google Scholar 

  19. Lu YY, Chen TS, Qu JL, Pan WL, Sun L, Wei XB (2009) Dihydroartemisinin (DHA) induces caspase-3-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells. J Biomed Sci 16:16

    Article  PubMed  CAS  Google Scholar 

  20. Lu YY, Chen TS, Wang XP, Li L (2010) 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. J Biomed Opt 15:046028

    Article  PubMed  CAS  Google Scholar 

  21. Lu YY, Chen TS, Wang XP, Qu JL, Chen M (2010) The JNK inhibitor SP600125 enhances dihydroartemisinin-induced apoptosis by accelerating Bax translocation into mitochondria in human lung adenocarcinoma cells. FEBS Lett 584:4019–4026

    Article  PubMed  CAS  Google Scholar 

  22. Mercer AE, Copple IM, Maggs JL, O’Neill PM, Park BK (2011) The role of heme and the mitcohondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarials. J Biol Chem 286:987–996

    Article  PubMed  CAS  Google Scholar 

  23. Morrissey C, Gallis B, Solazzi JW, Kim BJ, Gulati R, Vakar-Lopez F, Goodlett DR, Vessella RL, Sasaki T (2010) Effect of artemisinin derivatives on apoptosis and cell cycle in prostate cancer cells. Anticancer Drugs 21:423–432

    Article  PubMed  CAS  Google Scholar 

  24. Mu D, Chen W, Yu B, Zhang C, Zhang Y, Qi H (2007) 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 29:33–38

    Article  PubMed  CAS  Google Scholar 

  25. Nam W, Tak J, Ryu JK, Jung M, Yook JI, Kim HJ, Cha IH (2007) Effects of artemisinin and its derivatives on growth inhibition and apoptosis of oral cancer cells. Head Neck 29:335–340

    Article  PubMed  Google Scholar 

  26. Singh NP, Lai HC (2004) Artemisinin induces apoptosis in human cancer cells. Anticancer Res 24:2277–2280

    PubMed  CAS  Google Scholar 

  27. Thanaketpaisarn O, Waiwut P, Sakurai H, Saiki I (2011) Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF-κB and PI3K/Akt signaling pathways. Int J Oncol 39:279–285

    PubMed  CAS  Google Scholar 

  28. Wang SJ, Gao Y, Chen H, Kong R, Jiang HC, Pan SH, Xue DB, Bai XW, Sun B (2010) Dihydroartemisinin inactivates NF-kappaB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both in vitro and in vivo. Cancer Lett 293:99–108

    Article  PubMed  CAS  Google Scholar 

  29. Xu Q, Li ZX, Peng HQ, Sun ZW, Cheng RL, Ye ZM, Li WX (2011) Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo. J Zhejiang Univ Sci B 12:247–255

    Article  PubMed  CAS  Google Scholar 

  30. Xiao F, Gao W, Wang X, Chen T (2012) Amplification activation loop between caspase-8 and -9 dominates artemisinin-induced apoptosis of ASTC-a-1 cells. Apoptosis Mar 21. [Epub ahead of print]

  31. Zheng JS, Wang MH, Huang M, Luo YP, Mi C (2008) Artesunate suppresses human endometrial carcinoma RL95-2 cell proliferation by inducing cell apoptosis. Nanfang Yike Daxue Xuebao 28:2221–2223

    PubMed  CAS  Google Scholar 

  32. Chen H, Sun B, Wang S, Pan S, Gao Y, Bai X, Xue D (2010) Growth inhibitory effects of dihydroartemisinin on pancreatic cancer cells: involvement of cell cycle arrest and inactivation of nuclear factor-kappaB. J Cancer Res Clin Oncol 136:897–903

    Article  PubMed  CAS  Google Scholar 

  33. Huang XF, Yuan D, Zhang CC, Zhang XP (2008) Artesunate induces human prostate cancer cell line PC-3 differentiation and cell cycle arrest. Zhongxiyi Jiehe Xuebao 6:591–594

    PubMed  CAS  Google Scholar 

  34. Willoughby JA Sr, Sundar SN, Cheung M, Tin AS, Modiano J, Firestone GL (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. J Biol Chem 284:2203–2213

    Article  PubMed  CAS  Google Scholar 

  35. Wu J, Hu D, Yang G, Zhou J, Yang C, Gao Y, Zhu Z (2011) Down-regulation of BMI-1 cooperates with artemisinin on growth inhibition of nasopharyngeal carcinoma cells. J Cell Biochem 112:1938–1948

    Article  PubMed  CAS  Google Scholar 

  36. Zhao Y, Jiang W, Li B, Qi Yao Q, Dong J, Cen Y, Pan X, Li J, Zheng J, Pang X, Zhou H (2011) Artesunate enhances radiosensitivity of human non-small cell lung cancer A549 cells via increasing NO production to induce cell cycle arrest at G2/M phase. Int Immunopharmacol 11:2039–2046

    Article  PubMed  CAS  Google Scholar 

  37. Steinbrück L, Pereira G, Efferth T (2010) Effects of artesunate on cytokinesis and G2/M cell cycle progression of tumour cells and budding yeast. Cancer Genomics Proteomics 7:337–346

    PubMed  Google Scholar 

  38. Fafowora MV, Atanu F, Sanya O, Olorunsogo OO, Erukainure OL (2011) Effect of oral coadministration of artesunate with ferrous sulfate on rat liver mitochondrial membrane permeability transition. Drug Chem Toxicol 34:318–323

    Article  PubMed  CAS  Google Scholar 

  39. Li W, Mo W, Shen D, Sun L, Wang J, Lu S, Gitschier JM, Zhou B (2005) Yeast model uncovers dual roles of mitochondria in action of artemisinin. PLoS Genet 1:e36

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Zhang S, Chen H, Gerhard GS (2010) Heme synthesis increases artemisinin-induced radical formation and cytotoxicity that can be suppressed by superoxide scavengers. Chem Biol Interact 186:30–35

    Article  PubMed  CAS  Google Scholar 

  42. Lu JJ, Chen SM, Zhang XW, Ding J, Meng LH (2010) The anti-cancer activity of dihydroartemisinin is associated with induction of iron-dependent endoplasmic reticulum stress in colorectal carcinoma HCT116 cells. Invest New Drugs 29:1276–1283

    Article  PubMed  CAS  Google Scholar 

  43. Efferth T, Benakis A, Romero MR, Tomicic M, Rauh R, Steinbach D, Häfer R, Stamminger T, Oesch F, Kaina B, Marschall M (2004) Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron. Free Rad Biol Med 37:998–1009

    Article  PubMed  CAS  Google Scholar 

  44. Lu JJ, Meng LH, Cai YJ, Chen Q, Tong LJ, Lin LP, Ding J (2008) Dihydroartemisinin induces apoptosis in HL-60 leukemia cells dependent of iron and p38 mitogen-activated protein kinase activation but independent of reactive oxygen species. Cancer Biol Ther 7:1017–1023

    Article  PubMed  CAS  Google Scholar 

  45. Kelter G, Steinbach D, Konkimalla VB, Tahara T, Taketani S, Fiebig HH, Efferth T (2007) Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate. PLoS One 2:e798

    Article  PubMed  CAS  Google Scholar 

  46. Disbrow GL, Baege AC, Kierpiec KA, Yuan H, Centeno JA, Thibodeaux CA, Hartmann D, Schlegel R (2005) Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo. Cancer Res 65:10854–10861

    Article  PubMed  CAS  Google Scholar 

  47. Du JH, Ma ZJ, Li JX, Zhang HD (2008) An oncosis-like cell death of pancreatic cancer Panc-1 cells induced by artesunate is related to generation of reactive oxygen species. Zhongguo Aizheng Zazhi 18:410–414

    CAS  Google Scholar 

  48. Efferth T, Briehl MM, Tome ME (2003) Role of antioxidant genes for the activity of artesunate against tumor cells. Inter J Oncol 23:1231–1235

    CAS  Google Scholar 

  49. Kim SJ, Kim MS, Lee JW, Lee CH, Yoo H, Shin SH, Park MJ, Lee SH (2006) Dihydroartemisinin enhances radiosensitivity of human glioma cells in vitro. J Cancer Res Clin Oncol 132:129–135

    Article  PubMed  CAS  Google Scholar 

  50. Michaelis M, Kleinschmidt MC, Barth S, Rothweiler F, Geiler J, Breitling R, Mayer B, Deubzer H, Witt O, Kreuter J, Doerr HW, Cinatl J, Cinatl J Jr (2010) Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines. Biochem Pharmacol 79:130–136

    Article  PubMed  CAS  Google Scholar 

  51. Efferth T, Oesch F (2004) Oxidative stress response of tumor cells: microarray-based comparison between artemisinins and anthracyclines. Biochem Pharmacol 68:3–10

    Article  PubMed  CAS  Google Scholar 

  52. Aldieri E, Atragene D, Bergandi L, Riganti C, Costamagna C, Bosia A, Ghigo D (2003) Artemisinin inhibits inducible nitric oxide synthase and nuclear factor NF-kB activation. FEBS Lett 552:141–144

    Article  PubMed  CAS  Google Scholar 

  53. Hwang YP, Yun HJ, Kim HG, Han EH, Lee GW, Jeong HG (2010) Suppression of PMA-induced tumor cell invasion by dihydroartemisinin via inhibition of PKCalpha/Raf/MAPKs and NF-kappaB/AP-1-dependent mechanisms. Biochem Pharmacol 79:1714–1726

    Article  PubMed  CAS  Google Scholar 

  54. Wang SJ, Sun B, Cheng ZX, Zhou HX, Gao Y, Kong R, Chen H, Jiang HC, Pan SH, Xue DB, Bai XW (2011) Dihydroartemisinin inhibits angiogenesis in pancreatic cancer by targeting the NF-κB pathway. Cancer Chemother Pharmacol 68:1421–1430

    Article  PubMed  CAS  Google Scholar 

  55. Wang Y, Huang Z, Wang L, Meng S, Fan Y, Chen T, Cao J, Jiang R, Wang C (2011) The anti-malarial artemisinin inhibits pro-inflammatory cytokines via the NF-κB canonical signaling pathway in PMA-induced THP-1 monocytes. Int J Mol Med 27:233–241

    PubMed  Google Scholar 

  56. Xu H, He Y, Yang X, Liang L, Zhan Z, Ye Y, Yang X, Lian F, Sun L (2007) Anti-malarial agent artesunate inhibits TNF-{alpha}-induced production of proinflammatory cytokines via inhibition of NF-{kappa}B and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatol 46:920–926

    Article  CAS  Google Scholar 

  57. Anfosso L, Efferth T, Albini A, Pfeffer U (2006) Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics J 6:269–278

    PubMed  CAS  Google Scholar 

  58. Chen H-H, Zhou H-J, Wu G-D, Lou X-F (2004) Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacol 71:1–9

    Article  CAS  Google Scholar 

  59. He Y, Fan J, Lin H, Yang X, Ye Y, Liang L, Zhan Z, Dong X, Sun L, Xu H (2011) The anti-malaria agent artesunate inhibits expression of vascular endothelial growth factor and hypoxia-inducible factor-1alpha in human rheumatoid arthritis fibroblast-like synoviocyte. Rheumatol Int 31:53–60

    Article  PubMed  CAS  Google Scholar 

  60. Li J, Zhou HJ (2005) Dihydroartemisinin inhibits the expression of vascular endothelial growth factor in K562 cells. Yao Xue Xue Bao 240:1041–1045

    Google Scholar 

  61. Wang J, Zhang B, Guo Y, Li G, Xie Q, Zhu B, Gao J, Chen Z (2008) Artemisinin inhibits tumor lymphangiogenesis by suppression of vascular endothelial growth factor C. Pharmacol 82:148–155

    Article  CAS  Google Scholar 

  62. Wu XH, Zhou HJ, Lee J (2006) 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 17:839–848

    Article  PubMed  CAS  Google Scholar 

  63. Zhou HJ, Wang WQ, Wu GD, Lee J, Li A (2007) Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. Vascul Pharmacol 47:131–138

    Article  PubMed  CAS  Google Scholar 

  64. Tan X, Plouet J, Lang J, Wu M, Shen K (2008) Effects of dihydroartemisinin on proliferation and phosphorylation of mitogen-activated protein kinase in epithelial ovarian cancer cell lines. Zhonghua Fuchanke Zazhi 43:662–665

    CAS  Google Scholar 

  65. Huang XJ, Ma ZQ, Zhang WP, Lu YB, Wei EQ (2007) Dihydroartemisinin exerts cytotoxic effects and inhibits hypoxia inducible factor-1alpha activation in C6 glioma cells. J Pharm Pharmacol 59:849–856

    Article  PubMed  CAS  Google Scholar 

  66. Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX (2007) Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta -catenin pathway. Inter J Cancer 121:1360–1365

    Article  CAS  Google Scholar 

  67. Li LN, Zhang HD, Yuan SJ, Yang DX, Wang L, Sun ZX (2008) Differential sensitivity of colorectal cancer cell lines to artesunate is associated with expression of beta-catenin and E-cadherin. Eur J Pharmacol 588:1–8

    Article  PubMed  CAS  Google Scholar 

  68. Wang JX, Hou LF, Yang Y, Tang W, Li Y, Zuo JP (2009) SM905, an artemisinin derivative, inhibited NO and pro-inflammatory cytokine production by suppressing MAPK and NF-kappaB pathways in RAW 264.7 macrophages. Acta Pharmacol Sin 30:1428–1435

    Article  PubMed  CAS  Google Scholar 

  69. Sertel S, Eichhorn T, Simon CH, Plinkert PK, Johnson SW, Efferth T (2010) Pharmacogenomic identification of c-Myc/Max-regulated genes associated with cytotoxicity of artesunate towards human colon, ovarian and lung cancer cell lines. Molecules 15:2886–2910

    Article  PubMed  CAS  Google Scholar 

  70. Konkimalla VB, McCubrey JA, Efferth T (2009) The role of downstream signaling pathways of the epidermal growth factor receptor for artesunate’s activity in cancer cells. Cur Cancer Drug Targets 9:72–80

    Article  CAS  Google Scholar 

  71. Chen H, Zhou H (2004) Inhibitory effects of artesunate on angiogenesis. Yaoxue Xuebao 39:29–33

    CAS  Google Scholar 

  72. Chen HH, Zhou HJ, Fang X (2003) Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro. Pharmacol Res 48:231–236

    Article  PubMed  CAS  Google Scholar 

  73. Chen HH, Zhou HJ, Wang WQ, Wu GD (2004) Antimalarial dihydroartemisinin also inhibits angiogenesis. Cancer Chemther Pharmacol 53:423–431

    Article  CAS  Google Scholar 

  74. Chen H, Shi L, Yang X, Li S, Guo X, Pan L (2010) Artesunate inhibiting angiogenesis induced by human myeloma RPMI8226 cells. Int J Hematol 92:587–597

    Article  PubMed  CAS  Google Scholar 

  75. D’Alessandro S, Gelati M, Basilico N, Parati EA, Haynes RK, Taramelli D (2007) Differential effects on angiogenesis of two antimalarial compounds, dihydroartemisinin and artemisone: implications for embryotoxicity. Toxicol 241:66–74

    Article  CAS  Google Scholar 

  76. Dell’Eva R, Pfeffer U, Vené R, Anfosso L, Forlani A, Albini A, Efferth T (2004) Inhibition of angiogenesis in vivo and growth of Kaposi’s sarcoma xenograft tumors by the anti-malarial artesunate. Biochem Pharmacol 68:2359–2366

    Article  PubMed  CAS  Google Scholar 

  77. Jung M, Tak J, Chung WY, Park KK (2006) Antiangiogenic activity of deoxoartemisinin derivatives on chorioallantoic membrane. Bioorg Med Chem Lett 16:1227–1230

    Article  PubMed  CAS  Google Scholar 

  78. Oh S, Jeong IH, Shin WS, Lee S (2003) Growth inhibition activity of thioacetal artemisinin derivatives against human umbilical vein endothelial cells. Bioorg Med Chem Lett 13:3665–3668

    Article  PubMed  CAS  Google Scholar 

  79. Oh S, Jeong IH, Ahn CM, Shin WS, Lee S (2004) Synthesis and antiangiogenic activity of thioacetal artemisinin derivatives. Bioorg Med Chem 12:3783–3790

    Article  PubMed  CAS  Google Scholar 

  80. Oh S, Jeong IH, Shin WS, Lee S (2004) Synthesis and antiangiogenic activity of exo-olefinated deoxoartemisinin derivatives. Bioorg Med Chem Lett 14:3683–3686

    Article  PubMed  CAS  Google Scholar 

  81. Ricci J, Park J, Chung WY, Park KK, Jung M (2010) Concise synthesis and antiangiogenic activity of artemisinin-glycolipid hybrids on chorioallantoic membranes. Bioorg Med Chem Lett 20:6858–6860

    Article  PubMed  CAS  Google Scholar 

  82. Soomro S, Konkimalla VB, Langenberg T, Mahringer A, Horwedel C, Holenya P, Brand A, Catin C, Fricker G, Dewerchin M, Carmeliet P, Conway EM, Jansen H, Efferth T (2011) Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties. J Cell Mol Med 15:1122–1135

    Article  PubMed  CAS  Google Scholar 

  83. Wang W, Zhou H, Wang M (2005) Inhibition of artesunate on angiogenesis of deciduoma and marrow in pseudopregnant rats. Zhongguo Linchuang Yaoxue Zazhi 14:375–377

    Google Scholar 

  84. Wartenberg W, Wolf S, Budde P, Grünheck F, Acker H, Hescheler J, Wartenberg G, Sauer H (2003) The antimalaria agent artemisinin exerts antiangiogenic effects in mouse embryonic stem cell-derived embryoid bodies. Lab Invest 83:1647–1655

    Article  PubMed  CAS  Google Scholar 

  85. Wu ZP, Gao CW, Wu YG, Zhu QS, Chen Y, Liu X, Liu C (2009) Inhibitive effect of artemether on tumor growth and angiogenesis in the rat C6 orthotopic brain gliomas model. Integr Cancer Ther 8:88–92

    Article  PubMed  Google Scholar 

  86. Zhang Z (2006) Progress in anti-angiogenesis drugs to lung cancer. Zhongguo Feiai Zazhi 9:96–99

    CAS  Google Scholar 

  87. Hou LF, He SJ, Li X, Wan CP, Yang Y, Zhang XH, He PL, Zhou Y, Zhu FH, Yang YF, Li Y, Tang W, Zuo JP (2012) SM934 Treated Lupus-Prone NZB × NZW F(1) Mice by Enhancing Macrophage Interleukin-10 Production and Suppressing Pathogenic T Cell Development. PLoS One 7:e32424

    Article  PubMed  CAS  Google Scholar 

  88. Lee IS, Ryu DK, Lim J, Cho S, Kang BY, Choi HJ (2012) Artesunate activates Nrf2 pathway-driven anti-inflammatory potential through ERK signaling in microglial BV2 cells. Neurosci Lett 509:17–21

    Article  PubMed  CAS  Google Scholar 

  89. Li T, Chen H, Wei N, Mei X, Zhang S, Liu DL, Gao Y, Bai SF, Liu XG, Zhou YX (2012) Anti-inflammatory and immunomodulatory mechanisms of artemisinin on contact hypersensitivity. Int Immunopharmacol 12:144–150

    Article  PubMed  CAS  Google Scholar 

  90. Wang JX, Tang W, Zhou R, Wan J, Shi LP, Zhang Y, Yang YF, Li Y, Zuo JP (2008) The new water-soluble artemisinin derivative SM905 ameliorates collagen-induced arthritis by suppression of inflammatory and Th17 responses. Br J Pharmacol 153:1303–1310

    Article  PubMed  CAS  Google Scholar 

  91. Buommino E, Baroni A, Canozo N, Petrazzuolo M, Nicoletti R, Vozza A, Tufano MA (2009) Artemisinin reduces human melanoma cell migration by down-regulating alphaVbeta3 integrin and reducing metalloproteinase 2 production. Invest New Drugs 27:412–418

    Article  PubMed  CAS  Google Scholar 

  92. Rasheed SA, Efferth T, Asangani IA, Allgayer H (2010) First evidence that the anti-malarial drug Artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases. Int J Cancer 127:1475–1485

    Article  PubMed  CAS  Google Scholar 

  93. Wang J, Guo Y, Zhang BC, Chen ZT, Gao JF (2007) Induction of apoptosis and inhibition of cell migration and tube-like formation by dihydroartemisinin in murine lymphatic endothelial cells. Pharmacol 80:207–218

    Article  CAS  Google Scholar 

  94. Weifeng T, Feng S, Xiangji L, Changqing S, Zhiquan Q, Huazhong Z, Peining Y, Yong Y, Mengchao W, Xiaoqing J, Wan-Yee L (2011) Artemisinin inhibits in vitro and in vivo invasion and metastasis of human hepatocellular carcinoma cells. Phytomedicine 18:158–162

    Article  PubMed  CAS  Google Scholar 

  95. Wu B, Hu K, Li S, Zhu J, Gu L, Shen H, Hambly BD, Bao S, Di W (2012) Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer. Oncol Rep 27:101–108

    PubMed  Google Scholar 

  96. Zhou HJ, Zhang JL, Li A, Wang Z, Lou XE (2010) Dihydroartemisinin improves the efficiency of chemotherapeutics in lung carcinomas in vivo and inhibits murine Lewis lung carcinoma cell line growth in vitro. Cancer Chemother Pharmacol 66:21–29

    Article  PubMed  CAS  Google Scholar 

  97. Wang SJ, Sun B, Pan SH, Chen H, Kong R, Li J, Xue DB, Bai XW, Jiang HC (2010) Experimental study of the function and mechanism combining dihydroartemisinin and gemcitabine in treating pancreatic cancer. Zhonghua Wai Ke Za Zhi 48:530–534

    PubMed  Google Scholar 

  98. Singh NP, Verma KB (2002) Case report of a laryngeal squamous cell carcinoma treated with artesunate. Arch Oncol 10:279–280

    Article  Google Scholar 

  99. Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, Schuler G (2005) Artesunate in the treatment of metastatic uveal melanoma - first experiences. Oncol Rep 14:1599–1603

    PubMed  CAS  Google Scholar 

  100. Singh NP, Panwar VK (2006) Case report of a pituitary macroadenoma treated with artemether. Integr Cancer Ther 5:391–394

    Article  PubMed  Google Scholar 

  101. Zhang ZY, Yu SQ, Miao LY, Huang XY, Zhang XP, Zhu YP, Xia XH, Li DQ (2008) Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: A randomized controlled trial. Zhongxiyi Jiehe Xuebao 6:134–138

    Article  PubMed  CAS  Google Scholar 

  102. Jansen FH, Adoubi I, J C KC, DE Cnodder T, Jansen N, Tschulakow A, Efferth T (2011) First study of oral Artenimol-R in advanced cervical cancer: clinical benefit, tolerability and tumor markers. Anticancer Res 31:4417-4422.

  103. Jung M, Li X, Bustos DA, elSohly HN, McChesney JD, Milhous WK (1990) Synthesis and antimalarial activity of (+)-deoxoartemisinin. J Med Chem 33:1516–1518

    Article  PubMed  CAS  Google Scholar 

  104. Lee CH, Hong H, Shin J, Jung M, Shin I, Yoon J, Lee W (2000) NMR studies on novel antitumor drug candidates, deoxoartemisinin and carboxypropyldeoxoartemisinin. Biochem Biophy Res Commun 274:359–369

    Article  CAS  Google Scholar 

  105. Jung M, Lee S, Ham J, Lee K, Kim H, Kim SK (2003) Antitumor activity of novel deoxoartemisinin monomers, dimers, and trimer. J Med Chem 46:987–994

    Article  PubMed  CAS  Google Scholar 

  106. Jeyadevan JP, Bray PG, Chadwick J, Mercer AE, Byrne A, Ward SA, Park BK, Williams DP, Cosstick R, Davies J, Higson AP, Irving E, Posner GH, O’Neill PM (2004) Antimalarial and Antitumor Evaluation of Novel C-10 Non-Acetal Dimers of beta -(2-Hydroxyethyl) deoxoartemisinin. J Med Chem 47:1290–1298

    Article  PubMed  CAS  Google Scholar 

  107. Posner GH, Northrop J, Paik IH, Borstnik K, Dolan P, Kensler TW, Xie S, Shapiro TA (2002) New chemical and biological aspects of artemisinin-derived trioxane dimmers. Bioorg Med Chem 10:227–232

    Article  PubMed  CAS  Google Scholar 

  108. Cho S, Oh S, Um Y, Jung JH, Ham J, Shin WS, Lee S (2009) Synthesis of 10-substituted triazolyl artemisinins possessing anticancer activity via Huisgen 1,3-dipolar cylcoaddition. Bioorg Med Chem Lett 19:382–385

    Article  PubMed  CAS  Google Scholar 

  109. Jung M, Park N, Moon HI, Lee Y, Chung WY, Park KK (2009) Synthesis and anticancer activity of novel amide derivatives of non-acetal deoxoartemisinin. Bioorg Med Chem Lett 19:6303–6306

    Article  PubMed  CAS  Google Scholar 

  110. Ricci J, Kim M, Chung WY, Park KK, Jung M (2011) Discovery of artemisinin-glycolipid hybrids as anti-oral cancer agents. Chem Pharm Bull (Tokyo) 59:1471–1475

    Article  CAS  Google Scholar 

  111. Enserink M (2010) If artemisinin drugs fail, what’s plan B? Science 328:846

    Article  PubMed  Google Scholar 

  112. Gravett AM, Liu WM, Krishna S, Chan WC, Haynes RK, Wilson NL, Dalgleish AG (2011) In vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents. Cancer Chemother Pharmacol 67:569–577

    Article  PubMed  CAS  Google Scholar 

  113. Schmuck G, Klaus AM, Krötlinger F, Langewische FW (2009) Developmental and reproductive toxicity studies on artemisone. Birth Defects Res B Dev Reprod Toxicol 86:131–143

    Article  PubMed  CAS  Google Scholar 

  114. Noori S, Taghikhani M, Hassan ZM, Allameh A, Mostafaei A (2009) Tehranolide could shift the immune response towards Th1 and modulate the intra-tumor infiltrated T regulatory cells. Iran J Immunol 6:216–224

    PubMed  CAS  Google Scholar 

  115. Noori S, Taghikhani M, Hassan ZM, Allameha A, Mostafaei A (2010) Tehranolide molecule modulates the immune response, reduce regulatory T cell and inhibits tumor growth in vivo. Mol Immunol 47:1579–1584

    Article  PubMed  CAS  Google Scholar 

  116. Noori S, Naderi GA, Hassan ZM, Habibi Z, Bathaie SZ, Hashemi SM (2004) Immunosuppressive activity of a molecule isolated from Artemisia annua on DTH responses compared with cyclosporin A. Int Immunopharmacol 4:1301–1306

    Article  PubMed  CAS  Google Scholar 

  117. Noori S, Hassan Z, Taghikhani M, Rezaei B, Habibi Z (2010) Dihydroartemisinin can inhibit calmodulin, calmodulin-dependent phosphodiesterase activity and stimulate cellular immune responses. Int Immunopharmacol 10:213–217

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  119. Langroudi L, Hassan ZM, Ebtekar M, Mahdavi M, Pakravan N, Noori S (2010) A comparison of low-dose cyclophosphamide treatment with artemisinin treatment in reducing the number of regulatory T cells in murine breast cancer model. Int Immunopharmacol 10:1055–1061

    Article  PubMed  CAS  Google Scholar 

  120. Noori S, Hassan ZM (2012) Tehranolide inhibits proliferation of MCF-7 human breast cancer cells by inducing G0/G1 arrest and apoptosis. Free Radic Biol Med 52:1987–1999

    Article  PubMed  CAS  Google Scholar 

  121. Yang X, Wang W, Tan J, Song D, Li M, Liu D, Jing Y, Zhao L (2009) Synthesis of a series of novel dihydroartemisinin derivatives containing a substituted chalcone with greater cytotoxic effects in leukemia cells. Bioorg Med Chem Lett 19:4385–4388

    Article  PubMed  CAS  Google Scholar 

  122. Xie L, Zhai X, Liu C, Li P, Li Y, Guo G, Gong P (2011) Anti-tumor activity of new artemisinin-chalcone hybrids. Arch Pharm (Weinheim) 344:639–647

    Article  CAS  Google Scholar 

  123. Xie L, Zhao Y, Zhai Y, Li P, Liu C, Li Y, Gong P (2011) The application of tandem aza-wittig reaction to synthesize artemisinin-guanidine hybrids and their anti-tumor activity. Arch Pharm (Weinheim) 344:631–638

    Article  CAS  Google Scholar 

  124. Liu Y, Wong VKW, Ko BCB, Wong MK, Che CM (2005) Synthesis and cytotoxicity studies of artemisinin derivatives containing lipophilic alkyl carbon chains. Organic Lett 7:1561–1564

    Article  CAS  Google Scholar 

  125. Beekman AC, Wierenga PK, Woerdenbag HJ, Van Uden W, Pras N, Konings AW, el-Feraly FS, Galal AM, Wikström HV (1998) Artemisinin-derived sesquiterpene lactones as potential antitumor compounds. Cytotoxic action against bone marrow and tumor cells. Planta Medica 64:615–619

    Article  PubMed  CAS  Google Scholar 

  126. Alagbala AA, McRiner AJ, Borstnik K, Labonte T, Chang W, D’Angelo JG, Posner GH, Foster BA (2006) Biological mechanisms of action of novel C-10 non-acetal trioxane dimers in prostate cancer cell lines. J Med Chem 49:7836–7842

    Article  PubMed  CAS  Google Scholar 

  127. Beekman AC, Woerdenbag HJ, Kampinga HH, Konings AWT (1996) Cytotoxicity of artemisinin, a dimer of dihydroartemisinin, artemisitene and eupatoriopicrin as evaluated by the MTT and clonogenic assay. Phytother Res 10:140–144

    Article  CAS  Google Scholar 

  128. Stockwin LH, Han B, Yu SX, Hollingshead MG, Elsohly MA, Gul W, Slade D, Galal AM, Newton DL (2009) Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction. Int J Cancer 125:1266–1275

    Article  PubMed  CAS  Google Scholar 

  129. Reiter C, Herrmann A, Capci A, Efferth T, Tsogoeva SB (2012) New artesunic acid homodimers: Potent reversal agents of multidrug resistance in leukemia cells. Bioorg Med Chem. 2012 Jul 22. [Epub ahead of print]

  130. Paik IH, Xie S, Shapiro TA, Labonte T, Narducci Sarjeant AA, Baege AC, Posner GH (2006) Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity. J Med Chem 49:2731–2734

    Article  PubMed  CAS  Google Scholar 

  131. Horwedel C, Tsogoeva SB, Wei S, Efferth T (2010) Cytotoxicity of artesunic acid homo- and heterodimer molecules toward sensitive and multidrug-resistant CCRF-CEM leukemia cells. J Med Chem 53:4842–4848

    Article  PubMed  CAS  Google Scholar 

  132. He R, Mott BT, Rosenthal AS, Genna DT, Posner GH, Arav-Boger R (2011) An artemisinin-derived dimer has highly potent anti-cytomegalovirus (CMV) and anti-cancer activities. PLoS One 6(8):e24334

    Article  PubMed  CAS  Google Scholar 

  133. Slade D, Galal AM, Gul W, Radwan MM, Ahmed SA, Khan SI, Tekwani BL, Jacob MR, Ross SA, Elsohly MA (2009) Antiprotozoal, anticancer and antimicrobial activities of dihydroartemisinin acetal dimers and monomers. Bioorg Med Chem 17:7949–7957

    Article  PubMed  CAS  Google Scholar 

  134. Rosenthal AS, Chen X, Liu JO, West DC, Hergenrother PJ, Shapiro TA, Posner GH (2009) Malaria-infected mice are cured by a single oral dose of new dimeric trioxane sulfones which are also selectively and powerfully cytotoxic to cancer cells. J Med Chem 52:1198–1203

    Article  PubMed  CAS  Google Scholar 

  135. Posner GH, McRiner AJ, Paik IH, Sur S, Borstnik K, Xie S, Shapiro TA, Alagbala A, Foster B (2004) Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents. J Med Chem 47:1299–1301

    Article  PubMed  CAS  Google Scholar 

  136. Galal AM, Gul W, Slade D, Ross SA, Feng S, Hollingshead MG, Alley MC, Kaur G, ElSohly MA (2009) Synthesis and evaluation of dihydroartemisinin and dihydroartemisitene acetal dimers showing anticancer and antiprotozoal activity. Bioorg Med Chem 17:741–751

    Article  PubMed  CAS  Google Scholar 

  137. Singh NP, Lai HC, Park JS, Gerhardt TE, Kim BJ, Wang S, Sasaki T (2011) Effects of artemisinin dimers on rat breast cancer cells in vitro and in vivo. Anticancer Res 31:4111–4114

    PubMed  CAS  Google Scholar 

  138. Beekman AC, Barentsen AR, Woerdenbag HJ, Van Uden W, Pras N, Konings AW, el-Feraly FS, Galal AM, Wikström HV (1997) Stereochemistry-dependent cytotoxicity of some artemisinin derivatives. J Nat Prod 60:325–330

    Article  PubMed  CAS  Google Scholar 

  139. Chadwick J, Mercer AE, Park BK, Cosstick R, O’Neill PM (2009) Synthesis and biological evaluation of extraordinarily potent C-10 carba artemisinin dimers against P. falciparum malaria parasites and HL-60 cancer cells. Bioorg Med Chem 17:1325–1338

    Article  PubMed  CAS  Google Scholar 

  140. Vennerstrom JL, Fu HN, Ellis WY, Ager AL Jr, Wood JK, Andersen SL, Gerena L, Milhous WK (1992) Dispiro-1,2,4,5-tetraoxanes: a new class of antimalarial peroxides. J Med Chem 35:3023–3027

    Article  PubMed  CAS  Google Scholar 

  141. Vennerstrom JL, Dong Y, Andersen SL, Ager AL Jr, Fu H, Miller RE, Wesche DL, Kyle DE, Gerena L, Walters SM, Wood JK, Edwards G, Holme AD, McLean WG, Milhous WK (2000) Synthesis and antimalarial activity of sixteen dispiro-1,2,4, 5-tetraoxanes: alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadecanes. J Med Chem 43:2753–2758

    Article  PubMed  CAS  Google Scholar 

  142. Opsenica D, Kyle DE, Milhous WK, Solaja BA (2003) Antimalarial, antimycobacterial and antiproliferative activity of phenyl substituted mixed tetraoxanes. J Serbian Chem Soc 68:291–302

    Article  CAS  Google Scholar 

  143. Terzić N, Opsenica D, Milić D, Tinant B, Smith KS, Milhous WK, Solaja BA (2007) Deoxycholic acid-derived tetraoxane antimalarials and antiproliferatives(1). J Med Chem 50:5118–5127

    Article  PubMed  CAS  Google Scholar 

  144. Opsenica I, Opsenica D, Smith KS, Milhous WK, Solaja BA (2008) Chemical stability of the peroxide bond enables diversified synthesis of potent tetraoxane antimalarials. J Med Chem 51:2261–2266

    Article  PubMed  CAS  Google Scholar 

  145. Cvijetić IN, Zizak ZP, Stanojković TP, Juranić ZD, Terzić N, Opsenica IM, Opsenica DM, Juranić IO, Drakulić BJ (2010) An alignment independent 3D QSAR study of the antiproliferative activity of 1,2,4,5-tetraoxanes. Eur J Med Chem 45:4570–4577

    Article  PubMed  CAS  Google Scholar 

  146. Kumura N, Furukawa H, Onyango AN, Izumi M, Nakajima S, Ito H, Hatano T, Kim HS, Wataya Y, Baba N (2009) Different behavior of artemisinin and tetraoxane in the oxidative degradation of phospholipid. Chem Phys Lipids 160:114–120

    Article  PubMed  CAS  Google Scholar 

  147. Kumar N, Khan SI, Atheaya H, Mamgain R, Rawat DS (2011) Synthesis and in vitro antimalarial activity of tetraoxane-amine/amide conjugates. Eur J Med Chem 46:2816–2827

    Article  PubMed  CAS  Google Scholar 

  148. Kumar N, Sharma M, Rawat DS (2011) Medicinal chemistry perspectives of trioxanes and tetraoxanes. Curr Med Chem 18:3889–3928

    Article  PubMed  CAS  Google Scholar 

  149. Andrews NC (2000) Iron homeostasis: insights from genetics and animal models. Nature Rev: Genet 1:208–217

    Article  CAS  Google Scholar 

  150. Reizenstein P (1991) Iron, free radicals and cancer. Med Oncol Tumor Pharmacother 8:229–233

    PubMed  CAS  Google Scholar 

  151. Shterman N, Kupfer B, Moroz C (1991) Comparison of transferrin receptors, iron content and isoferritin profile in normal and malignant human breast cell lines. Pathobiol 59:19–25

    Article  CAS  Google Scholar 

  152. Mason AB, Miller MK, Funk WD, Banfield DK, Savage KJ, Oliver RWA, Green BN, MacGillivray RTA, Woodworth RC (1993) Expression of glycosylated and nonglycosylated human transferrin in mammalian cells. Characterization of the recombinant proteins with comparison to three commercially available transferrins. Biochem 32:5472–5479

    Article  CAS  Google Scholar 

  153. Van Halbeek H, Dorland L, Vliegenthart JFG, Spik G, Cheron A, Montreuil J (1981) Structure determination of two oligomannoside-type glycopeptides obtained from bovine lactotransferrin, by 500 MHz proton NMR spectroscopy. Biochim Biophy Acta 675:293–296

    Article  Google Scholar 

  154. Lai H, Sasaki T, Singh NP, Messay A (2005) Effects of artemisinin-tagged holotransferrin on cancer cells. Life Sci 76:1267–1279

    Article  PubMed  CAS  Google Scholar 

  155. Xie WL, Yang PH, Zeng X, Cai JY (2009) Effect of 4-(12-dihydroartemisininoxy) benzoic acid hydrazide transferrin tagged drug on human breast cancer cells. Chin J Anal Chem 37:671–675

    Article  CAS  Google Scholar 

  156. Xie WL, Yang PH, Zeng X, Wang H, Cai HH, Cai JY (2010) Visual characterization of targeted effect of holo-transferrin-tagged dihydroartemisinin on human breast cancer cells. Chin Biol Bull 55:2390–2395

    Article  CAS  Google Scholar 

  157. Nakase I, Gallis B, Takatani-Nakase T, Oh S, Lacoste E, Singh NP, Goodlet DR, Tanaka S, Futaki S, Lai H, Sasaki T (2009) Transferrin receptor-dependent cytotoxicity of artemisinin-transferrin conjugates on prostate cancer cells and induction of apoptosis. Cancer Lett 274:290–298

    Article  PubMed  CAS  Google Scholar 

  158. Lai H, Nakase I, Lacoste E, Singh NP, Sasaki T (2009) Artemisinin-transferrin conjugate retards growth of breast tumors in the rat. Anticancer Res 29:3807–3810

    PubMed  CAS  Google Scholar 

  159. Oh S, Kim BJ, Singh NP, Lai H, Sasaki T (2009) Synthesis and anti-cancer activity of covalent conjugates of artemisinin and a transferrin-receptor targeting peptide. Cancer Lett 274:33–39

    Article  PubMed  CAS  Google Scholar 

  160. Lai H, Sasaki T, Singh NP (2005) (2005) Targeted treatment of cancer with artemisinin and artemisinin-tagged iron-carrying compounds. Exp Opin Therapeut Targets 9:995–1007

    Article  CAS  Google Scholar 

  161. Miller MJ, Walz AJ, Zhu H, Wu C, Moraski G, Möllmann U, Tristani EM, Crumbliss AL, Ferdig MT, Checkley L, Edwards RL, Boshoff HI (2011) Design, synthesis, and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria. J Am Chem Soc 133:2076–2079

    Article  PubMed  CAS  Google Scholar 

  162. Efferth T, Ramirez T, Gebhart E, Halatsch ME (2004) Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774. Biochem Pharmacol 67:1689–1700

    Article  PubMed  CAS  Google Scholar 

  163. Huang XJ, Li CT, Zhang WP, Lu YB, Fang SH, Wei EQ (2008) Dihydroartemisinin potentiates the cytotoxic effect of Temozolomide in Rat C6 glioma cells. Pharmac 82:1–9

    CAS  Google Scholar 

  164. Sieber S, Gdynia G, Roth W, Bonavida B, Efferth T (2009) Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate. Int J Oncol 35:149–158

    PubMed  CAS  Google Scholar 

  165. Riganti C, Doublier S, Viarisio D, Miraglia E, Pescarmona G, Ghigo D, Bosia A (2009) Artemisinin induces doxorubicin resistance in human colon cancer cells via calcium-dependent activation of HIF-1alpha and P-glycoprotein overexpression. Brit J Pharmac 156:1054–1066

    Article  CAS  Google Scholar 

  166. Mukanganyama S, Widersten M, Naik YS, Mannervik B, Hasler JA (2002) Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer 97:700–705

    Article  PubMed  CAS  Google Scholar 

  167. Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber HO, Hengstler JG, Halatsch ME, Volm M, Tew KD, Ross DD, Funk JO (2003) Molecular Modes of Action of Artesunate in Tumor Cell Lines. Mol Pharmacol 64:382–394

    Article  PubMed  CAS  Google Scholar 

  168. Efferth T, Volm M (2005) Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate. In Vivo 19:225–232

    PubMed  CAS  Google Scholar 

  169. Reungpatthanaphong P, Mankhetkorn S (2002) Modulation of multidrug resistance by artemisinin, artesunate and dihydroartemisinin in K562/adr and GLC4/adr resistant cell lines. Biol Pharmaceut Bull 25:1555–1561

    Article  CAS  Google Scholar 

  170. Lai H, Singh NP (2006) Oral artemisinin prevents and delays the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in the rat. Cancer Lett 231:43–48

    Article  PubMed  CAS  Google Scholar 

  171. Bachmeier B, Fichtner I, Killian PH, Kronski E, Pfeffer U, Efferth T (2011) Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells. PLoS One 6:e20550

    Article  PubMed  CAS  Google Scholar 

  172. Beekman AC, Woerdenbag HJ, Van Uden W, Pras N, Konings AW, Wikström HV (1997) Stability of artemisinin in aqueous environments: impact on its cytotoxic action to Ehrlich ascites tumour cells. J Pharm Pharmacol 49:1254–1258

    Article  PubMed  CAS  Google Scholar 

  173. Lin F, Qian Z, Xue H, Ding J, Lin L (2003) Comparison of inhibitory effects between artemisinin and artemisunate on proliferation of MCF-7 cells in vitro. Zhongcaoyao 34:347–349

    CAS  Google Scholar 

  174. Sundar SN, Marconett CN, Doan VB, Willoughby JA Sr, Firestone GL (2008) Artemisinin selectively decreases functional levels of estrogen receptor-alpha and ablates estrogen-induced proliferation in human breast cancer cells. Carcinogenesis 29:2252–2258

    Article  PubMed  CAS  Google Scholar 

  175. Zhao XB, Liu MX, Wu KN, Xing TY (2006) Effects of artesunate and its mechanism on MCF-7 cells. Zhongliu Fangzhi Yanjiu 33:745–747

    CAS  Google Scholar 

  176. Cui C, Wang RT, Tong H, Wang ZH, Ding JY, Zhang ZZ (2006) Influence of artesunate and oxymatrine on immunosuppressive effect of mouse colon-rectal carcinoma cell line. Xiandai Mianyixue 26:152–156

    CAS  Google Scholar 

  177. Lu JJ, Chen SM, Ding J, Meng LH (2012) Characterization of dihydroartemisinin-resistant colon carcinoma HCT116/R cell line. Mol Cell Biochem 360:329–337

    Article  PubMed  CAS  Google Scholar 

  178. Deng XR, Yu HP, Wang KQ, Li XM (2007) Inhibitory effect of artemisinin on hepatoma H22 cells. Shiyong Linchuang Yixue 8(1–3):7

    Google Scholar 

  179. Zhang X, Yang X, Pan Q (1998) Antitumor effect and apoptosis induction in human liver cancer cell line (BEL-7402) by sodium artesunate. Zhongcaoyao 29:467–469

    CAS  Google Scholar 

  180. Lu JJ, Yang Z, Lu DZ, Wo XD, Shi JJ, Lin TQ, Wang MM, Li Y, Tang LH (2012) Dihydroartemisinin-induced inhibition of proliferation in BEL-7402 cells: An analysis of the mitochondrial proteome. Mol Med Rep. doi:10.3892/mmr.2012.906 [Epub ahead of print]

  181. Efferth T, Davey M, Olbrich A, Rücker G, Gebhart E, Davey R (2002) 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 28:160–168

    Article  PubMed  Google Scholar 

  182. Zhou HJ, Wang Z, Li A (2008) Dihydroartemisinin induces apoptosis in human leukemia cells HL60 via downregulation of transferrin receptor expression. Anticancer Drugs 19:247–255

    Article  PubMed  Google Scholar 

  183. Wang Z, Zhou HJ (2008) Dihydroartemisinin down-regulates the expression of transferrin receptor in myeloid leukemia cells. Yao Xue Xue Bao 43:576–583

    Article  PubMed  CAS  Google Scholar 

  184. Mu D, Zhang W, Chu D, Liu T, Xie Y, Fu E, Jin F (2008) The role of calcium, P38 MAPK in dihydroartemisinin-induced apoptosis of lung cancer PC-14 cells. Cancer Chemother Pharmacol 61:639–645

    Article  PubMed  CAS  Google Scholar 

  185. Sadava D, Phillips T, Lin C, Kane SE (2002) Transferrin overcomes drug resistance to artemisinin in human small-cell lung carcinoma cells. Cancer Lett 179:151–156

    Article  PubMed  CAS  Google Scholar 

  186. Wang Y, Zhu K, Cui X, Huang J, Song X (2007) Induction of apoptosis of human lung adenocarcinoma A549 cells by artesunate. Zhonghua Shiyan Waike Zazhi 24:121–122

    Google Scholar 

  187. Li S, Pan L, Xue F (2008) Effects of artesunate on myeloma cell line SP2/0 and its mechanism. Zhonghua Zhongliu Zazhi 30:16–20

    Google Scholar 

  188. Yamachika E, Habte T, Oda D (2004) Artemisinin: an alternative treatment for oral squamous cell carcinoma. Anticancer Res 24:2153–2160

    PubMed  CAS  Google Scholar 

  189. Hosoya K, Murahari S, Laio A, London CA, Couto CG, Kisseberth WC (2008) Biological activity of dihydroartemisinin in canine osteosarcoma cells lines. Am J Vet Res 69:519–526

    Article  PubMed  CAS  Google Scholar 

  190. Tan XJ, Lang JH, Plouet J, Wu M, Shen K (2008) Effects of dihydroartiminisin on the adhesion, migration, and invasion of epithelial ovarian cancer cells. Zhonghua Yi Xue Za Zhi 88:2642–2646

    PubMed  CAS  Google Scholar 

  191. Chen H, Sun B, Pan SH, Li J, Xue DB, Meng QH, Jiang HC (2009) Study on anticancer effect of dihydroartemisinin on pancreatic cancer. Zhonghua Wai Ke Za Zhi 47:1002–1005

    PubMed  Google Scholar 

  192. Yuan D, Zhang C (2007) Effect of artesunate on prostate cancer cell line PC-3. Zhongguo Yiyuan Yaoxue Zazhi 27:1049–1051

    CAS  Google Scholar 

  193. Rinner B, Siegl V, Pürstner P, Efferth T, Brem B, Greger H, Pfragner R (2004) Activity of novel plant extracts against medullary thyroid carcinoma cells. Anticancer Res 24:495–500

    PubMed  Google Scholar 

  194. Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR (2001) The anti-malarial artesunate is also active against cancer. Inter J Oncol 18:767–773

    CAS  Google Scholar 

  195. Chen H, Sun B, Pan S, Jiang H, Sun X (2009) Dihydroartemisinin inhibits growth of pancreatic cancer cells in vitro and in vivo. Anti-Cancer Drugs 20:131–140

    Article  PubMed  CAS  Google Scholar 

  196. Du JH, Zhang HD, Ma ZJ, Ji KM (2010) Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo. Cancer Chemother Pharmacol 65:895–902

    Article  PubMed  CAS  Google Scholar 

  197. Farsam V, Hassan ZM, Hosseini AZ, Noori S, Mahdavi M, Ranjbar M (2011) Antitumor and immunomodulatory properties of artemether and its ability to reduce CD4(+) CD25(+) FoxP3(+) T reg cells in vivo. Int Immunopharmacol 11:1802–1808

    Article  PubMed  CAS  Google Scholar 

  198. Gao N, Budhraja A, Cheng S, Liu EH, Huang C, Chen J, Yang Z, Chen D, Zhang Z, Shi X (2011) Interruption of the MEK/ERK signaling cascade promotes dihydroartemisinin-induced apoptosis in vitro and in vivo. Apoptosis 16:511–523

    Article  PubMed  CAS  Google Scholar 

  199. Ma H, Yao Q, Zhang AM, Lin S, Wang XX, Wu L, Sun JG, Chen ZT (2011) The effects of artesunate on the expression of EGFR and ABCG2 in A549 human lung cancer cells and a xenograft model. Molecules 16:10556–10569

    Article  PubMed  Google Scholar 

  200. Moore JC, Lai H, Li JR, Ren RL, McDougall JA, Singh NP, Chou CK (1995) Oral administration of dihydroartemisinin and ferrous sulfate retarded implanted fibrosarcoma growth in the rat. Cancer Lett 98:83–87

    PubMed  CAS  Google Scholar 

  201. Noori S, Hassan ZM, Rezaei B, Rustaiyan A, Habibi Z, Fallahian F (2008) Artemisinin can inhibit the calmodulin-mediated activation of phosphodiesterase in comparison with Cyclosporin A. Int Immunopharmacol 8:1744–1747

    Article  PubMed  CAS  Google Scholar 

  202. Wang J, Liu L, Li JM, Liu JH, Guo JW, Zuo LF (2007) Inhibitory effect of artesunate on human esophageal carcinoma associated with CDC25A modulation. Di-San Junyi Daxue Xuebao 29:428–431

    CAS  Google Scholar 

  203. Zhang CZ, Zhang H, Yun J, Chen GG, Lai PB (2012) Dihydroartemisinin exhibits antitumor activity toward hepatocellular carcinoma in vitro and in vivo. Biochem Pharmacol Feb 9. [Epub ahead of print]

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Acknowledgments

The authors’ research on artemisinin was supported by the Breast Cancer Funding of California, the Akibene Foundation, Holley Holdings, Susan Komen for the Cure, the Meryl and Charles Witmer Foundation, the Washington Technology Center, and the Life Sciences Discovery Fund of the State of Washington.

Conflict of interest statement

The authors are co-inventors of technologies, of which the patents are owned by the University of Washington, related to artemisinin-tagged transferrin, artemisinin-tagged transferrin receptor binding peptides, and artemisinin-dimer hydrazone. These technologies are licensed to Holley Pharmaceuticals (China) and Artemisia Biomedical (USA) for commercial development.

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Authors and Affiliations

  1. Departments of Bioengineering, University of Washington, Box 355061, Seattle, WA, 98195, USA

    Henry C. Lai & Narendra P. Singh

  2. Departments of Chemistry, University of Washington, Seattle, WA, 98195, USA

    Tomikazu Sasaki

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  1. Henry C. Lai
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  3. Tomikazu Sasaki
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Correspondence to Henry C. Lai.

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Lai, H.C., Singh, N.P. & Sasaki, T. Development of artemisinin compounds for cancer treatment. Invest New Drugs 31, 230–246 (2013). https://doi.org/10.1007/s10637-012-9873-z

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  • DOI: https://doi.org/10.1007/s10637-012-9873-z

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