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Research Progress on Artemisinin and Its Derivatives against Hematological Malignancies

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Abstract

Although current therapeutic methods against hematological malignancies are effective in the early stage, they usually lose their effectiveness because of the development of drug resistances. Seeking new drugs with significant therapeutic effects is one of the current research hotspots. Artemisinin, an extract from the plant Artemisia annua Linne, and its derivatives have excellent antimalarial effects in clinical applications as well as excellent safety. Recent studies have documented that artemisinin and its derivatives (ARTs) also have significant effects against multiple types of tumours, including hematological malignancies. This review focuses on the latest research achievements of ARTs in the treatment of hematological malignancies as well as its mechanisms and future applications. The mechanisms of ARTs against different types of hematological malignancies mainly include cell cycle arrest, induction autophagy and apoptosis, inhibition of angiogenesis, production of reactive oxygen species, and induction of differentiation. Additionally, the review also summarizes the anticancer effects of ARTs in many drug-resistant hematological malignancies and its synergistic effects with other drugs.

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References

  1. 1.

    Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375–2390.

  2. 2.

    Lu A, Chen K. Integrative medicine in clinical practice: from pattern differentiation in traditional Chinese medicine to disease treatment. Chin J Integr Med 2009;15:152–152.

  3. 3.

    Tshabalalamsimang M. Guidelines for the treatment of malaria. World Health Organization 2008;6:632–646. http://www.indiaenvironmentportal.org.in/files/WHO_Mar2010.pdf

  4. 4.

    Adam I, Ibrahim Y, Gasim GI. Efficacy and safety of artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria in Sudan: a systematic review and meta-analysis. Malar J 2018;17:110–117.

  5. 5.

    Wang W, Li HJ, Qu GL, Xing YT, Yang ZK, Dai JR, et al. Is there a reduced sensitivity of dihydroartemisinin against praziquantel-resistant Schistosoma japonicum? Parasitol Res 2014;113:223–228.

  6. 6.

    Wang W, Li TY, Ji Y, Qu GL, Qian YL, Li HJ, et al. Efficacy of artemether and artesunate in mice infected with praziquantel non-susceptible isolate of Schistosoma japonicum. Parasitol Res 2014;113:925–931.

  7. 7.

    Efferth T. Beyond malaria: the inhibition of viruses by artemisinin-type compounds. Biotechnol Adv 2018;36:1730–1737.

  8. 8.

    Efferth T, Marschall M, Wang X, Huong SM, Hauber I, Olbrich A, et al. Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses. J Mol Med (Berl) 2002;80:233–242.

  9. 9.

    Juteau F, Masotti V, Bessière JM, Dherbomez M, Viano J. Antibacterial and antioxidant activities of Artemisia annua essential oil. Fitoterapia 2002;73:532–535.

  10. 10.

    Ćavar S, Maksimović M, Vidic D, Parić A. Chemical composition and antioxidant and antimicrobial activity of essential oil of Artemisia annua L. from Bosnia. Ind Crops Prod 2012;37:479–485.

  11. 11.

    Algamal MA, Marei GIK, Saad MM, Abdelgaleil SA. Antimicrobial and phytotoxic properties of artemisinin and related derivatives. World Appl Sci J 2013;28:1382–1388.

  12. 12.

    Efferth T, Dunstan HA, Miyachi H, Chitambar C. The antimalarial artesunate is also active against cancer. Int J Oncol 2001;18:767–773.

  13. 13.

    Paiboon R, Samlee M. Modulation of multidrug resistance by artemisinin, artesunate and dihydroartemisinin in K562/ADR and GLC4/ADR resistant cell lines. Biol Pharm Bull 2002;25:1555–1561.

  14. 14.

    Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets 2006;7:407–421.

  15. 15.

    Junmei H, Disong W, Ruiwen Z, Hui W. Experimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res 2008;14:5519.

  16. 16.

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

  17. 17.

    Oranuch T, Pornthip W, Hiroaki S, Ikuo S. Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF- κ B and PI3K/Akt signaling pathways. Int J Oncol 2011;39:279–285.

  18. 18.

    Liu L, Zuo LF, Zuo J, Wang J. Artesunate induces apoptosis and inhibits growth of Eca109 and Ec9706 human esophageal cancer cell lines in vitro and in vivo. Mol Med Rep 2015;12:1465–1472.

  19. 19.

    Zhou X, Sun WJ, Wang WM, Chen K, Zheng JH, Lu MD, et al. Artesunate inhibits the growth of gastric cancer cells through the mechanism of promoting oncosis both in vitro and in vivo. Anticancer Drugs 2013;24:920–927.

  20. 20.

    Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science 1985;228:1049–1055.

  21. 21.

    Agtmael MAV, Eggelte TA, Boxtel CJV. Artemisinin drugs in the treatment of malaria: from medicinal herb to registered medication. Trends Pharmacol Sci 1999;20:199.

  22. 22.

    Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med 2011;17:1217.

  23. 23.

    Tu Y. Artemisinin—a gift from traditional Chinese medicine to the world (Nobel Lecture). Angewandte Chemie 2016;47:10210–10226.

  24. 24.

    Kong LY, Tan RX. Artemisinin, a miracle of traditional Chinese medicine. Nat Prod Rep 2015;32:1617.

  25. 25.

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

  26. 26.

    Hou L, Block KE, Huang H. Artesunate abolishes germinal center B cells and inhibits autoimmune arthritis. PLoS One 2014;9:e104762.

  27. 27.

    Chen PQ, Li GQ, Guo XB, He KR, Fu YX, Fu LC, et al. The infectivity of gametocytes of Plasmodium falciparum from patients treated with artemisinin. Chin Med J (Engl) 1994;107:709–711.

  28. 28.

    De Vries PJ, Dien T K. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs 1996;52:818–836.

  29. 29.

    Wang Z, Hu W, Zhang JL, Wu XH, Zhou HJ. Dihydroartemisinin induces autophagy and inhibits the growth of iron-loaded human myeloid leukemia K562 cells via ROS toxicity. FEBS Open Bio 2012;2:103–112.

  30. 30.

    Kim C, Lee JH, Kim SH, Sethi G, Ahn KS. Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model. Oncotarget 2015;6:4020.

  31. 31.

    Sun YM, Zhao LZ, Qiang LI, Laboratory AO, University JM. The effects of cell proliferation and apoptosis induced by artesunate on leukemia cell. Chin J Gerontol (Chin) 2015;35:6647–6648.

  32. 32.

    Zhao X, Guo X, Yue W, Wang J, Yang J, Chen J. Artemether suppresses cell proliferation and induces apoptosis in diffuse large B cell lymphoma cells. Exp Ther Med 2017;14:4083–4090.

  33. 33.

    Toril H, Olsen OE, Kristine M, Hanne H, Anders W, Torstein BR, et al. Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate. Eur J Haematol 2013;91:339–346.

  34. 34.

    Li S, Xue F, Cheng Z, Yang X, Wang S, Geng F, et al. Effect of artesunate on inhibiting proliferation and inducing apoptosis of SP2/0 myeloma cells through affecting NFkappaB p65. Int J Hematol 2009;90:513–521.

  35. 35.

    Wang Y, Xu X, Wu X, Chen W, Huang F, Gui X. Dihydroartemisinin treatment of multiple myeloma cells causes activation of c-Jun leading to cell apoptosis. Oncol Lett 2018;15:2562–2566.

  36. 36.

    Gao N, Budhraja A, Cheng S, Liu EH, Huang C, Chen J, et al. Interruption of the MEK/ERK signaling cascade promotes dihydroartemisinin-induced apoptosis in vitro and in vivo. Apoptosis 2011;16:511–523.

  37. 37.

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

  38. 38.

    Lu JJ, Meng LH, Cai YJ, Chen Q, Tong LJ, Lin LP, et al. 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 2008;7:1017–1023.

  39. 39.

    Handrick R, Ontikatze T, Bauer KD, Freier F, Rubel A, Durig J, et al. Dihydroartemisinin induces apoptosis by a Bak-dependent intrinsic pathway. Mol Cancer Ther 2010;9:2497–2510.

  40. 40.

    Zeng Y, Ni X, Meng WT, Wen Q, Jia YQ. Inhibitive effect of artesunate on human lymphoblastic leukemia/lymphoma cells. J Sichuan Univ (Med Sci, Chin) 2009;40:1038–1043.

  41. 41.

    Vatsveen TK, Myhre MR, Steen CB, Walchli S, Lingjaerde OC, Bai B, et al. Artesunate shows potent anti-tumor activity in B-cell lymphoma. J Hematol Oncol 2018;11:23.

  42. 42.

    Cheng C, Wang T, Song Z, Peng L, Gao M, Hermine O, et al. Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044. Cancer Med 2018;7:380–396.

  43. 43.

    Holien T, Olsen OE, Misund K, Hella H, Waage A, Ro TB, et al. Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate. Eur J Haematol 2013;91:339–346.

  44. 44.

    Papanikolaou X, Johnson S, Garg T, Tian E, Tytarenko R, Zhang Q, et al. Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis. Oncotarget 2014;5:4118–4128.

  45. 45.

    Markovic O, Marisavljevic D, Cemerikic V, Vidovic A, Perunicic M, Todorovic M, et al. Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance. Med Oncol 2008;25:451–457.

  46. 46.

    Rajkumar SV, Fonseca R, Witzig TE, Gertz MA, Greipp PR. Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma. Leukemias 1999;13:469–472.

  47. 47.

    Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol 1997;150:815–821.

  48. 48.

    Rajkumar SV, Witzig TE. A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma. Cancer Treatment Rev 2000;26:351–362.

  49. 49.

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

  50. 50.

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

  51. 51.

    Wu XH, Zhou HJ, Lee J. Dihydroartemisinin inhibits angiogenesis induced by multiple myeloma RPMI8226 cells under hypoxic conditions via downregulation of vascular endothelial growth factor expression and suppression of vascular endothelial growth factor secretion. Anticancer Drugs 2006;17:839–848.

  52. 52.

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

  53. 53.

    Gopalakrishnan AM, Nirbhay K. Antimalarial action of artesunate involves DNA damage mediated by reactive oxygen species. Antimicrob Agents Chemother 2015;59:317–325.

  54. 54.

    Kumar B, Kalvala A, Chu S, Rosen S, Forman SJ, Marcucci G, et al. Antileukemic activity and cellular effects of the antimalarial agent artesunate in acute myeloid leukemia. Leuk Res 2017;59:124–135.

  55. 55.

    Wang Q, Wu S, Zhao X, Zhao C, Zhao H, Huo L. Mechanisms of dihydroartemisinin and dihydroartemisinin/holotransferrin cytotoxicity in T-cell lymphoma cells. PLoS One 2015;10:e0137331.

  56. 56.

    Xenofon P, Sarah J, Tarun G, Erming T, Ruslana T, Qing Z, et al. Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis. Oncotarget 2014;5:4118–4128.

  57. 57.

    Johnson SK, Garg TK, Tian E, Tytarenko R, Barlogie B, Epstein J, et al. The antimalarial agent artesunate exerts its antimyeloma activity by affecting the mitochondria and the reactive oxygen status of the myeloma cells and its efficacy depends on intracellular bivalent iron levels. Blood 2013;122:4444.

  58. 58.

    Bo J, Wang W, Wang Q, LI H, Zhao Y, Wu X, et al. Effects of artemisinin on apoptosis and differentiation of human leukemia U937 cells. J Fourth Milit Med Univ (Chin) 2008;29:634–637.

  59. 59.

    Kim SH, Kim HJ, Kim TS. Differential involvement of protein kinase C in human promyelocytic leukemia cell differentiation enhanced by artemisinin. Eur J Pharmacol 2003;482:67–76.

  60. 60.

    Kim SH, Chun SY, Kim TS. Interferon-α enhances artemisinin-induced differentiation of HL-60 leukemia cells via a PKCα/ERK pathway. Eur J Pharmacol 2008;587:65–72.

  61. 61.

    Efferth T, Davey M, Olbrich A, Rucker G, Gebhart E, Davey R. 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 2002;28:160–168.

  62. 62.

    Rubini G, Altini C, Notaristefano A, Merenda N, Rubini D, Ianora AAS, et al. Role of 18F-FDG PET/CT in diagnosing peritoneal carcinomatosis in the restaging of patient with ovarian cancer as compared to contrast enhanced CT and tumor marker CA-125. Rev Esp Med Nucl Imag Mol 2014;33:22–27.

  63. 63.

    Budhraja A, Turnis ME, Churchman ML, Kothari A, Yang X, Xu H, et al. Modulation of navitoclax sensitivity by dihydroartemisinin-mediated MCL-1 repression in BCR-ABL(+) B-lineage acute lymphoblastic leukemia. Clin Cancer Res 2017;23:7558–7568.

  64. 64.

    Kim SH, Chun SY, Kim TS. Interferon-alpha enhances artemisinin-induced differentiation of HL-60 leukemia cells via a PKC alpha/ERK pathway. Eur J Pharmacol 2008;587:65–72.

  65. 65.

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

  66. 66.

    Kim C, Lee JH, Kim SH, Sethi G, Ahn KS. Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model. Oncotarget 2015;6:4020–4035.

  67. 67.

    Zhao X, Zhong H, Wang R, Liu D, Waxman S, Zhao L, et al. Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety. Oncotarget 2015;6:5582–5596.

  68. 68.

    Kumar B, Kalvala A, Chu S, Rosen S, Forman SJ, Marcucci G, et al. Antileukemic activity and cellular effects of the antimalarial agent artesunate in acute myeloid leukemia. Leuk Res 2017;59:124–135.

  69. 69.

    Tan M, Rong Y, Su Q, Chen Y. Artesunate induces apoptosis via inhibition of STAT3 in THP-1 cells. Leuk Res 2017;62:98–103.

  70. 70.

    Cao JT, Mo HM, Wang Y, Zhao K, Zhang TT, Wang CQ, et al. Dihydroartemisinin-induced apoptosis in human acute monocytic leukemia cells. Oncol Lett 2018;15:3178–3184.

  71. 71.

    Gao JL, Ding XP, Li QJ, Xia ZL, Xia QJ. Effect of dihydroartemisinin on the expression of BCR/ABL fusion gene in leukemia K562 cells. Chin J Med Genet (Chin) 2012;29:19–22.

  72. 72.

    Lee J, Zhang G, Wu X, Xu F, Zhou J, Zhang X. Growth inhibitory effect of dihydroartemisinin on Bcr/Abl+ chronic myeloid leukemia K562 cells involve AKT, ERK and NF-kappaB modulation. J Cancer Res Clin Oncol 2012;138:2095–2102.

  73. 73.

    Wang ZC, Liu Y, Wang H, Han QK, Lu C. Research on the relationship between artesunate and Raji cell autophagy and apoptosis of Burkitt’s lymphoma and its mechanism. Eur Rev Med Pharmacol Sci 2017;21:2238–2243.

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Author information

Li Y was responsible for reviewing the literature, summarizing data and was a major contributor in writing the manuscript. Shan NN and Sui XH conceptualized and developed an outline for the manuscript. All authors read and approved the final manuscript for publication.

Correspondence to Ying Li.

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The authors declare that they have no competing interests.

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Supported by the National Natural Science Foundation of China (No. 81570104), Key Research and Development Project of Shandong Province (No. 2015GSF118025, 2015GSF118058, 2016GSF201026)

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Li, Y., Shan, N. & Sui, X. Research Progress on Artemisinin and Its Derivatives against Hematological Malignancies. Chin. J. Integr. Med. (2020). https://doi.org/10.1007/s11655-019-3207-3

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Keywords

  • artemisinin
  • artesunate
  • dihydroartemisinin
  • hematological malignancies
  • review