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Dihydroartemisinin inhibits angiogenesis in pancreatic cancer by targeting the NF-κB pathway

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Abstract

Purpose

Dihydroartemisinin (DHA) has recently shown antitumor activity in human pancreatic cancer cells. However, its effect on antiangiogenic activity in pancreatic cancer is unknown, and the mechanism is unclear. This study was aimed to investigate whether DHA would inhibit angiogenesis in human pancreatic cancer.

Methods

Cell viability and proliferation, tube formation of human umbilical vein endothelial cells (HUVECs), nuclear factor (NF)-κB DNA-binding activity, expressions of vascular endothelial growth factor (VEGF), interleukin (IL)-8, cyclooxygenase (COX)-2, and matrix metalloproteinase (MMP)-9 were examined in vitro. The effect of DHA on antiangiogenic activity in pancreatic cancer was also assessed using BxPC-3 xenografts subcutaneously established in BALB/c nude mice.

Results

DHA inhibited cell proliferation and tube formation of HUVECs in a time- and dose-dependent manner and also reduced cell viability in pancreatic cancer cells. DHA significantly inhibited NF-κB DNA-binding activity, so as to tremendously decrease the expression of NF-κB-targeted proangiogenic gene products: VEGF, IL-8, COX-2, and MMP-9 in vitro. In vivo studies, DHA remarkably reduced tumor volume, decreased microvessel density, and down-regulated the expression of NF-κB-related proangiogenic gene products.

Conclusions

Inhibition of NF-κB activation is one of the mechanisms that DHA inhibits angiogenesis in human pancreatic cancer. We also suggest that DHA could be developed as a novel agent against pancreatic cancer.

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References

  1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A (2005) Cancer statistics. CA Cancer J Clin 55:10–30

    Article  PubMed  Google Scholar 

  2. Liu MP, Ma JY, Pa BR, Ma LS (2001) The study of pancreatic cancer in China. World Chin J Digestol 9:1103–1109

    Google Scholar 

  3. Li D, Xie K, WolV R, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363:1049–1057

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. He Q, Shi J, Shen XL, An J, Sun H, Wang L (2010) Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cells. Cancer Biol Ther 9:819–824

    Article  PubMed  CAS  Google Scholar 

  6. 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 

  7. Chen H, Sun B, Wang S, Gao Y, Bai X (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 

  8. Wang SJ, Gao Y, Chen H, Kong R, Jiang HC, Pan SH (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 

  9. Chen H, Sun B, Pan SH, Jiang H, Sun X (2009) Dihydroartemisinin inhibits growth of pancreatic cancer cells in vitro and in vivo. Anticancer Drugs 20:131–140

    Article  PubMed  Google Scholar 

  10. 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 

  11. Chen HH, Zhou HJ, Wang WQ, Wu GD (2004) Antimalarial dihydroartemisinin also inhibits angiogenesis. Cancer Chemother Pharmacol 53:423–432

    Article  PubMed  CAS  Google Scholar 

  12. 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. Toxicology 241:66–74

    Article  PubMed  Google Scholar 

  13. Efferth T (2006) Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targ 407:407–421

    Article  Google Scholar 

  14. Wartenberg M, Wolf S, Budde P, Grünheck F, Acker H, Hescheler J (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 

  15. Huang XJ, Ma ZQ, Zhang WP (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 

  16. Zhou HJ, Wang WQ, Wu GD, Lu YB, Wei EQ (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 

  17. Dell’Eva R, Pfeffer U, Vené R, Anfosso L, Forlani A, Albini A (2004) Inhibition of angiogenesis in vivo and growth of Kaposi’s sarcoma xenograft tumors by the anti-malarial artesunate. Biochem Pharmaco 68:2359–2366

    Article  Google Scholar 

  18. Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ (1999) The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 5:119–127

    PubMed  CAS  Google Scholar 

  19. Liptay S, Weber CK, Ludwig L, Wagner M, Adler G, Schmid RM (2003) Mitogenic and antiapoptotic role of constitutive NF-κB/Relactivity in pancreatic cancer. Int J Cancer 105:735–746

    Article  PubMed  CAS  Google Scholar 

  20. Xiong HQ, Abbruzzese JL, Lin E, Wang L, Zheng L, Xie K (2004) NF-kappaB activity blockade impairs the angiogenic potential of human pancreatic cancer cells. Int J Cancer 108:181–188

    Article  PubMed  CAS  Google Scholar 

  21. Aggarwal BB (2004) Nuclear factor-κB: the enemy within. Cancer Cell 6:203–208

    Article  PubMed  CAS  Google Scholar 

  22. Folkman J (1986) How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res 46:467–473

    PubMed  CAS  Google Scholar 

  23. Gamble JR, Matthias LJ, Meyer G, Kaur P, Russ G, Faull R (1993) Regulation of in vitro capillary tube formation by anti-integrin antibodies. J Cell Biol 121:931–943

    Article  PubMed  CAS  Google Scholar 

  24. Kong R, Sun B, Jiang HC, Pan S, Chen H, Wang S (2010) Downregulation of nuclear factor-κB p65 subunit by small interfering RNA synergizes with gemcitabine to inhibit the growth of pancreatic cancer. Cancer Lett 291:90–98

    Article  PubMed  CAS  Google Scholar 

  25. Nakamura T, Kuwai T, Kim JS, Fan D, Kim SJ, Fidler IJ (2007) Stromal metalloproteinase-9 is essential to angiogenesis and progressive growth of orthotopic human pancreatic cancer in parabiont nude mice. Neoplasia 9:979–986

    Article  PubMed  CAS  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. Matsuo Y, Sawai H, Ochi N, Yasuda A, Sakamoto M, Takahashi H (2010) Proteasome inhibitor MG132 inhibits angiogenesis in pancreatic cancer by blocking NF-κB activity. Dig Dis Sci 55:1167–1176

    Article  PubMed  CAS  Google Scholar 

  28. Itakura J, Ishiwata T, Friess H, Fujii H, Matsumoto Y, Büchler MW (1997) Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res 3:1309–1316

    PubMed  CAS  Google Scholar 

  29. Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q, Xie K (1999) Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 5:7234–7243

    Google Scholar 

  30. Gupta MK, Qin RY (2003) Mechanism and its regulation of tumor-induced angiogenesis. World J Gastroenterol 9:1144–1155

    PubMed  CAS  Google Scholar 

  31. Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM (1992) Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258:1798–1801

    Article  PubMed  CAS  Google Scholar 

  32. Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ (2000) Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res 60:5334–5339

    PubMed  CAS  Google Scholar 

  33. Ko HM, Kang JH, Choi JH, Park SJ, Bai S, Im SY (2005) Platelet-activating factor induces matrix metalloproteinase-9 expression through Ca(2+)- or PI3K-dependent signaling pathway in a human vascular endothelial cell line. FEBS Lett 579:6451–6458

    Article  PubMed  CAS  Google Scholar 

  34. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744

    Article  PubMed  CAS  Google Scholar 

  35. Plummer SM, Holloway KA, Manson MM, Munks RJ, Kaptein A, Farrow S (1999) Inhibition of cyclooxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene 18:6013–6020

    Article  PubMed  CAS  Google Scholar 

  36. Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–1311

    PubMed  CAS  Google Scholar 

  37. Rozic JG, Chakraborty C, Lala PK (2001) Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration, invasiveness and angiogenesis. Int J Cancer 93:497–506

    Article  PubMed  CAS  Google Scholar 

  38. Chu JS, Lloyd FL, Trifan OC, Knapp B, Rizzo MT (2003) Potential involvement of the cyclooxygenase-2 pathway in the regulation of tumor-associated angiogenesis and growth in pancreatic cancer. Mol Cancer Ther 2:1–7

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by grants from the New Century Support Foundation for Elitist of Chinese Ministry of Education (NCET-07-0248), the Scientific Foundation for Prominent Youth of Heilongjiang Province, China (JC200717), the Scientific and Technological Project of Heilongjiang Province, China (GC09C407-2), and the National Natural Scientific Foundation of China (30571808, 30872987). The authors would like to extend their gratefulness to Ming Mu for her technical assistance.

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No conflict of interest.

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Authors and Affiliations

  1. Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 23 Youzheng Str, Nangang, Harbin, People’s Republic of China

    Shuang-Jia Wang, Bei Sun, Zhuo-Xin Cheng, Hao-Xin Zhou, Yue Gao, Rui Kong, Hua Chen, Hong-Chi Jiang, Shang-Ha Pan, Dong-Bo Xue & Xue-Wei Bai

  2. Department of Hepato-Biliary-Pancreatic and Vascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China

    Shuang-Jia Wang

  3. Department of Surgery, University Hospitals, Case Western Reserve University, Cleveland, OH, 44106, USA

    Yue Gao

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  1. Shuang-Jia Wang
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Correspondence to Bei Sun.

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Wang, SJ., Sun, B., Cheng, ZX. et al. Dihydroartemisinin inhibits angiogenesis in pancreatic cancer by targeting the NF-κB pathway. Cancer Chemother Pharmacol 68, 1421–1430 (2011). https://doi.org/10.1007/s00280-011-1643-7

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  • DOI: https://doi.org/10.1007/s00280-011-1643-7

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