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Holotransferrin enhances selective anticancer activity of artemisinin against human hepatocellular carcinoma cells

  • Xiao-rong Deng (邓小荣)
  • Zhao-xia Liu (刘朝霞)
  • Feng Liu (刘 峰)
  • Lei Pan (潘 雷)
  • He-ping Yu (余和平)
  • Jin-ping Jiang (姜进平)
  • Jian-jun Zhang (张建军)
  • Li Liu (刘 立)
  • Jun Yu (喻 军)
Article

Summary

Artemisinin, also termed qinghaosu, is extracted from the traditional Chinese medicine artemesia annua L. (the blue-green herb) in the early 1970s, which has been confirmed for effectively treating malaria. Additionally, emerging data prove that artemisinin exhibits anti-cancer effects against many types of cancers such as leukemia, melanoma, etc. Artemisinin becomes cytotoxic in the presence of ferrous iron. Since iron influx is high in cancer cells, artemisinin and its analogs selectively kill cancer cells with increased intracellular iron concentrations. This study is aimed to investigate the selective inhibitory effects of artemisinin on SMMC-7721 cells in vitro and determine the effect of holotransferrin, which increases the concentration of ferrous iron in cancer cells, combined with artemisinin on the anticancer activity. MTT assay was used for assessing the proliferation of SMMC-7721 cells treated with artemisinin. The induction of apoptosis and inhibition of colony formation in SMMC-7721 cells treated with artemisinin were determined by TdT-mediated dUTP nick end labeling (TUNEL) and colony formation assay, respectively. The results showed that artemisinin at various concentrations significantly inhibited growth, colony formation and cell viability of SMMC-7721 cells (P<0.05), likely due to induction of apoptosis of SMMC-7721 cells. Of interest, it was found that incubation of artemisinin combined with holotransferrin sensitized the growth inhibitory effect of artemisinin on SMMC-7721 cells (P<0.01). Our data suggest that treatment with artemisinin leads to inhibition of viability and proliferation, and apoptosis of SMMC-7721 cells. Furthermore, we observed that holotransferrin significantly enhanced the anti-cancer activity of artemisinin. This study may provide a potential therapeutic choice for liver cancer.

Key words

human hepatocellular carcinoma SMMC-7721 cells artemisinin holotransferrin cell growth colony formation apoptosis 

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References

  1. 1.
    Badvie S. Hepatocellular carcinoma. Postgrad Med J, 2000,76(891):4–11PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    He SP, Tan GY, Li G, et al. Development of a sensitive monoclonal antibody-based enzyme-linked immunosorbent assay for the antimalaria active ingredient artemisinin in the Chinese herb Artemisia annua L. Anal Bioanal Chem, 2009,393(4):1297–1303PubMedCrossRefGoogle Scholar
  3. 3.
    Sriram D, Rao VS, Chandrasekhara KV, et al. Progress in the research of artemisinin and its analogues as antimalarials: an update. Nat Prod Res, 2004,18(6):503–527PubMedCrossRefGoogle Scholar
  4. 4.
    Li PC, Lam E, Roos WP, et al. Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Res, 2008,68(11):4347–4351PubMedCrossRefGoogle Scholar
  5. 5.
    Djimde AA, Fofana B, Sagara I, et al. Efficacy, safety, and selection of molecular markers of drug resistance by two ACTs in Mali. Am J Trop Med Hyg, 2008,78(3): 455–461PubMedGoogle Scholar
  6. 6.
    Mercer AE, Sarr Sallah M. The pharmacokinetic evaluation of artemisinin drugs for the treatment of malaria in paediatric populations. Expert Opin Drug Metab Toxicol, 2011,7(4):427–439PubMedCrossRefGoogle Scholar
  7. 7.
    Efferth T, Kaina B. Toxicity of the antimalarial artemisinin and its dervatives. Crit Rev Toxicol, 2010,40(5): 405–421PubMedCrossRefGoogle Scholar
  8. 8.
    Adam I, Elhassan EM, Omer EM, et al. Safety of artemisinins during early pregnancy, assessed in 62 Sudanese women. Ann Trop Med Parasitol, 2009,103(3): 205–210PubMedCrossRefGoogle Scholar
  9. 9.
    Smithuis F, Kyaw MK, Phe O, et al. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison. Lancet, 2006,367(9528):2075–2085PubMedCrossRefGoogle Scholar
  10. 10.
    Bousejra-El Garah F, Wong MH, Amewu RK, et al. Comparison of the reactivity of antimalarial 1,2,4,5-tetraoxanes with 1,2,4-trioxolanes in the presence of ferrous iron salts, heme, and ferrous iron salts/phosphatidylcholine. J Med Chem, 2011,54(19):6443–6455PubMedCrossRefGoogle Scholar
  11. 11.
    Anderson KM, Seed T, Ou D, et al. Free radicals and reactive oxygen species in programmed cell death. Med Hypotheses, 1999,52(5):451–463PubMedCrossRefGoogle Scholar
  12. 12.
    Deugnier Y, Turlin B. Iron and hepatocellular carcinoma. J Gastroenterol Hepatol, 2001,16(5):491–494PubMedCrossRefGoogle Scholar
  13. 13.
    Kim KS, Kim H, Kim NG, et al. Proteomic analysis and molecular characterization of tissue ferritin light chain in hepatocellular carcinoma. Hepatology, 2002,35(6):1459–1466PubMedGoogle Scholar
  14. 14.
    Lai H, Sasaki T, Singh NP, et al. Effects of artemisinin-tagged holotransferrin on cancer cells. Life Sci, 2005,76(11):1267–1279PubMedCrossRefGoogle Scholar
  15. 15.
    Tan WF, Shen F, Luo XJ, et al. Artemisinin inhibits in vitro and in vivo invasion and metastasis of human hepatocellular carcinoma cells. Phytomedicine, 2011,18(2–3): 158–162Google Scholar
  16. 16.
    Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology, 2004,127(5 Suppl 1):S79–S86PubMedCrossRefGoogle Scholar
  17. 17.
    Chen J, Chloupkova M. Abnormal iron uptake and liver cancer. Cancer Biol Ther, 2009,8(18):1699–1708PubMedCrossRefGoogle Scholar
  18. 18.
    Deng XR, Yu HP, Pan L, et al. Artemisinin and holotransferrin induces apoptosis in hepatoma cells. Chin J Exp Surg (Chinese), 2008,25(6):802Google Scholar
  19. 19.
    Reed JC. Mechanisms of apoptosis. Am J Pathol, 2000,157(5):1415–1430PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell, 2000,100(1):57–70PubMedCrossRefGoogle Scholar
  21. 21.
    Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature, 2001,411(6835):342–348PubMedCrossRefGoogle Scholar
  22. 22.
    Singh NP, Lai HC. Artemisinin induces apoptosis in human cancer cells. Anticancer Res, 2004,24(4):2277–2280PubMedGoogle Scholar

Copyright information

© Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Xiao-rong Deng (邓小荣)
    • 1
  • Zhao-xia Liu (刘朝霞)
    • 2
  • Feng Liu (刘 峰)
    • 3
  • Lei Pan (潘 雷)
    • 4
  • He-ping Yu (余和平)
    • 5
  • Jin-ping Jiang (姜进平)
    • 3
  • Jian-jun Zhang (张建军)
    • 1
  • Li Liu (刘 立)
    • 1
  • Jun Yu (喻 军)
    • 1
  1. 1.Department of General SurgeryNanshan Affiliated Hospital of Guangdong Medical CollegeShenzhenChina
  2. 2.Department of Obstetrics and GynecologyNanshan Affiliated Hospital of Guangdong Medical CollegeShenzhenChina
  3. 3.Department of General SurgeryFirst Affiliated Hospital of Nanchang UniversityNanchangChina
  4. 4.Department of General SurgeryQihe People’s HospitalQiheChina
  5. 5.Department of General SurgeryWuhan Pu’ai HospitalWuhanChina

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