Skip to main content

Advertisement

SpringerLink
Log in

Dihydroartemisinin downregulates vascular endothelial growth factor expression and induces apoptosis in chronic myeloid leukemia K562 cells

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Dihydroartemisinin (DHA), a more water-soluble active metabolite of artemisinin derivatives, is safe and the most effective antimalarial analog of artemisinin. In the present investigation, we assessed the effect of DHA on vascular endothelial growth factor (VEGF) expression and apoptosis in chronic myeloid leukemia (CML) K562 cells. The results demonstrated that in addition to its antiproliferation effect on CML cells, DHA was also found to induce K562 cells apoptosis. The percentage of apoptotic cells was increased to 6.9 and 15.8% after being treated with 5 and 10 μmol/l DHA for 48 h, respectively (P<0.001). In order to analyze the effect of DHA on VEGF expression in K562 cells, we assessed the level of VEGF expression by western blot; detected the form of VEGF mRNA by RT-PCR and examined the level of VEGF secreted in conditioned media (CM) by ELISA assay. All these experiments suggested that DHA could inhibit the VEGF expression and secretion effectively in K562 cells, even at a lower concentration (2 μmol/l, P<0.05). Moreover, we further assessed the stimulating angiogenic activity of CM from K562 cells on CAM model. The angiogenic activity was decreased in response to the CM from K562 cells pretreated with DHA in a dose-dependent manner. Taken together, these results from our study together with its known low toxicity make it possible that DHA might present potential antileukemia effect as a treatment for CML therapy, or as an adjunct to standard chemotherapeutic regimens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D, Koller C, Estrov Z, O’Brien S, Keating M, Freireich E, Albitar M (2000) Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 96:2240–2245

    PubMed  CAS  Google Scholar 

  2. Aguayo A, Giles F, Albitar M (2003) Vascularity, angiogenesis and angiogenic factors in leukemias and myelodysplastic syndromes. Leuk Lymphoma 44:213–222

    Article  PubMed  CAS  Google Scholar 

  3. Bellamy WT, Richter L, Frutiger Y, Grogan TM (1999) Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res 59:728–733

    PubMed  CAS  Google Scholar 

  4. Benakis A, Paris M, Loutan L, Plessas CT, Plessas ST (1997) Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. Am J Trop Med Hyg 56:17–23

    PubMed  CAS  Google Scholar 

  5. Chen HH, Zhou HJ, Wu GD, Lou XE (2004) Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacology 71:1–9

    Article  PubMed  CAS  Google Scholar 

  6. Dias S, Hattori K, Heissig B, Zhu Z, Wu Y, Witte L, Hicklin DJ, Tateno M, Bohlen P, Moore MA, Rafii S (2001) Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci USA 98:10857–10862

    Article  PubMed  CAS  Google Scholar 

  7. Dias S, Shmelkov SV, Lam G, Rafii S (2002) VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood 99:2532–2540

    Article  PubMed  CAS  Google Scholar 

  8. Drake CJ, Little CD (1999) VEGF and vascular fusion: implications for normal and pathological vessels. J Histochem Cytochem 47:1351–1356

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  10. Efferth T, Olbrich A, Bauer R (2002) mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether. Biochem Pharmacol 64:617–623

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Ellis LM, Fidler IJ (1996) Angiogenesis and metastasis. Eur J Cancer 32A:2451–2460

    Article  Google Scholar 

  13. Folkman J (1992) The role of angiogenesis in tumor growth. Semin Cancer Biol 3:65–71

    PubMed  CAS  Google Scholar 

  14. Fusetti L, Pruneri G, Gobbi A, Rabascio C, Carboni N, Peccatori F, Martinelli G, Bertolini F (2000) Human myeloid and lymphoid malignancies in the non-obese diabetic/severe combined immunodeficiency mouse model: frequency of apoptotic cells in solid tumors and efficiency and speed of engraftment correlate with vascular endothelial growth factor production. Cancer Res 60:2527–2534

    PubMed  CAS  Google Scholar 

  15. He R, Liu B, Yang C, Yang RC, Tobelem G, Han ZC (2003) Inhibition of K562 leukemia angiogenesis and growth by expression of antisense vascular endothelial growth factor (VEGF) sequence. Cancer Gene Ther 10:879–886

    Article  PubMed  CAS  Google Scholar 

  16. Holmes DI, Zachary I (2004) Placental growth factor induces FosB and c-Fos gene expression via Flt-1 receptors. FEBS Lett 557:93–98

    Article  PubMed  CAS  Google Scholar 

  17. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW (1991) The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5:1806–1814

    Article  PubMed  CAS  Google Scholar 

  18. Keyhani A, Jendiroba DB, Freireich EJ (2001) Angiogenesis and leukemia. Leuk Res 25:639–645

    Article  PubMed  CAS  Google Scholar 

  19. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844

    Article  PubMed  CAS  Google Scholar 

  20. Kini AR, Peterson LA, Tallman MS, Lingen MW (2001) Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid. Blood 97:3919–3924

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. 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 

  23. Mordenti J, Thomsen K, Licko V, Chen H, Meng YG, Ferrara N (1999) Efficacy and concentration-response of murine anti-VEGF monoclonal antibody in tumor-bearing mice and extrapolation to humans. Toxicol Pathol 27:14–21

    PubMed  CAS  Google Scholar 

  24. Nikiforidis G, Papazafiropoulos D, Siablis D, Karnabatidis D, Hatjikondi O, Dimopoulos J (1999) Quantitative assessment of angiogenesis in the chick embryo and its chorioallantoic membrane by computerised analysis of angiographic images. Eur J Radiol 29:168–179

    Article  PubMed  CAS  Google Scholar 

  25. Ruan GR, Liu YR, Chen SS, Li JL, Qin YZ, Fu JY, Bai RK (2001) Expression of Vascular Endothelial Growth Factor in the Bone Marrow Cells from Adult Chronic Myelogenous Leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 9:5–9

    PubMed  Google Scholar 

  26. Ruan GR, Liu YR, Chen SS, Fu JY, Chang Y, Qin YZ, Li JL, Yu H, Wang H (2004) Effect of antisense VEGF cDNA transfection on the growth of chronic myeloid leukemia K562 cells in vitro and in nude mice. Leuk Res 28:763–769

    Article  PubMed  CAS  Google Scholar 

  27. 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 

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

    PubMed  CAS  Google Scholar 

  29. Sun WC, Han JX, Yang WY, Deng DA, Yue XF (1992) Antitumor activities of 4 derivatives of artemisic acid and artemisinin B in vitro. Zhongguo Yao Li Xue Bao 13:541–543

    PubMed  CAS  Google Scholar 

  30. Tu Y (1999) The development of new antimalarial drugs: qinghaosu and dihydro-qinghaosu. Chin Med J (Engl) 112:976–977

    CAS  Google Scholar 

  31. Vacca A, Ribatti D, Iurlaro M, Albini A, Minischetti M, Bussolino F, Pellegrino A, Ria R, Rusnati M, Presta M, Vincenti V, Persico MG, Dammacco F (1998) Human lymphoblastoid cells produce extracellular matrix-degrading enzymes and induce endothelial cell proliferation, migration, morphogenesis, and angiogenesis. Int J Clin Lab Res 28:55–68

    Article  PubMed  CAS  Google Scholar 

  32. Verstovsek S, Lunin S, Kantarjian H, Manshouri T, Faderl S, Cortes J, Giles F, Albitar M (2003) Clinical relevance of VEGF receptors 1 and 2 in patients with chronic myelogenous leukemia. Leuk Res 27:661–669

    Article  PubMed  CAS  Google Scholar 

  33. Weindel K, Marme D, Weich HA (1992) AIDS-associated Kaposi’s sarcoma cells in culture express vascular endothelial growth factor. Biochem Biophys Res Commun 183:1167–1174

    Article  PubMed  CAS  Google Scholar 

  34. Woerdenbag HJ, Pras N, van Uden W, Wallaart TE, Beekman AC, Lugt CB (1994) Progress in the research of artemisinin-related antimalarials: an update. Pharm World Sci 16:169–180

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the grants from the Zhejiang Provincal foundation of Natural Science (No. M303842).

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310031, PR China

    Jun Lee, Hui-Jun Zhou & Xiu-Hua Wu

Authors
  1. Jun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui-Jun Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiu-Hua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hui-Jun Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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 57, 213–220 (2006). https://doi.org/10.1007/s00280-005-0002-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-005-0002-y

Keywords

Search

Navigation