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Norcantharidin Anti-Angiogenesis Activity Possibly through an Endothelial Cell Pathway in Human Colorectal Cancer

  • Yu, Tao (Department of Oncology, Shanghai Chinese Medical Hospital) ;
  • Hou, Fenggang (Department of Oncology, Shanghai Chinese Medical Hospital) ;
  • Liu, Manman (Department of Oncology, Shanghai Chinese Medical Hospital) ;
  • Zhou, Lihong (Department of Oncology & Cancer Institute, Putuo Hospital, Shanghai University of Traditional Chinese Medicine) ;
  • Li, Dan (Department of Pharmacy, the 6th People's Hospital, Shanghai Jiao Tong University) ;
  • Liu, Jianrong (Department of Oncology, Shanghai Chinese Medical Hospital) ;
  • Fan, Zhongze (Department of Oncology & Cancer Institute, Putuo Hospital, Shanghai University of Traditional Chinese Medicine) ;
  • Li, Qi (Department of Oncology & Cancer Institute, Putuo Hospital, Shanghai University of Traditional Chinese Medicine)
  • Published : 2012.02.29

Abstract

The present study was based on the unexpected discovery that norcantharidin exerted anti-angiogenesis activity when effects on growth of human colon cancer were studied. The aim was to further verify this finding and explore possible mechanisms using a tumor xenograft model in nude mice. We confirmed that norcantharidin (5 or 15 mg/kg) could inhibit angiogenesis of human colon cancer in vivo. In vitro, crossing river assay, cell adhesion assay and tube formation assay indicated that NCTD could reduce the migration, adhesion and vascular network tube formation ability of HUVECs. At the same time, the expression levels of VEGF and VEGFR-2 proteins which play important roles in angiogenesis were reduced as examined by western blotting analysis. Taken together, the results firstly showed NCTD could inhibit angiogenesis of human colon cancer in vivo, probably associated with effects on migration, adhesion and vascular network tube formation of HUVECs and expression levels of VEGF and VEGFR-2 proteins.

Keywords

References

  1. Cao Y (2009). Positive and negative modulation of angiogenesis by VEGFR1 ligands. Sci Signal, 2, e1. https://doi.org/10.1126/scisignal.262tr1
  2. Chen YJ, Kuo CD, Tsai YM, et al (2008). Norcantharidin induces anoikis through Jun-N-terminal kinase activation in CT26 colorectal cancer cells. Anticancer Drugs, 19, 55-64. https://doi.org/10.1097/CAD.0b013e3282f18826
  3. Chen YJ, Shieh CJ, Tsai TH, et al (2005). Inhibitory effect of norcantharidin, a derivative compound from blister beetles, on tumor invasion and metastasis in CT26 colorectal adenocarcinoma cells. Anticancer Drugs, 16, 293-9. https://doi.org/10.1097/00001813-200503000-00008
  4. Carmeliet P(2005). Angiogenesis in life, disease and medicine. Nature, 438, 932-6. https://doi.org/10.1038/nature04478
  5. Des Guetz G, Uzzan B, Nicolas P, et al (2006). Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br J Cancer, 94, 1823-32. https://doi.org/10.1038/sj.bjc.6603176
  6. De Vita F, Orditura M, Lieto E, et al (2004). Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma. Cancer, 100, 270-8. https://doi.org/10.1002/cncr.11911
  7. Ferrara N(2005). VEGF as a therapeutic target in cancer. Oncology, 69, 11-6. https://doi.org/10.1159/000088479
  8. Folkman J (1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med, 1, 27-31. https://doi.org/10.1038/nm0195-27
  9. Fang Y, Tian SL, Li KQ, et al (1993). Studies on antitumor agents II: synthesis and anticancer activity of dehydrogenated carboncyclic analogs of norcantharidin. Yao Xue Xue Bao, 28, 931-5 (in Chinese).
  10. Greenberg JI, Shields DJ, Barillas SG, et al (2008). A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature, 456, 809-13. https://doi.org/10.1038/nature07424
  11. Graziano F, Cascinu S (2003). Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes' B colorectal cancer patients: how much evidence is enough? Ann Oncol, 14, 1026-38. https://doi.org/10.1093/annonc/mdg284
  12. Gille H, Kowalski J, Li B, et al (2001). Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptorspecific vascular endothelial growth factor mutants. J Biol Chem, 276, 3222-30. https://doi.org/10.1074/jbc.M002016200
  13. Heath VL, Bicknell R (2009). Anticancer strategies involving the vasculature. Nat Rev Clin Oncol, 6, 395-404. https://doi.org/10.1038/nrclinonc.2009.52
  14. Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell, 100, 57-70. https://doi.org/10.1016/S0092-8674(00)81683-9
  15. Jain RK, Duda DG, Clark JW, et al (2006). Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol, 3, 24-40.
  16. Kitadai Y (2010). Angiogenesis and lymphangiogenesis of gastric cancer. J Oncol, 2010, 468725.
  17. Karamysheva AF (2008). Mechanisms of angiogenesis. Biochemistry (Mosc), 73, 751-62. https://doi.org/10.1134/S0006297908070031
  18. Kerbel RS (2008). Tumor angiogenesis. N Engl J Med, 358, 2039-49. https://doi.org/10.1056/NEJMra0706596
  19. Mohr B, Illmer T (2005). Structural chromosomal aberrations in the colon cancer cell line HCT 116--results of investigations based on spectral karyotyping. Cytogenet Genome Res, 108, 359-61. https://doi.org/10.1159/000081532
  20. Peng C, Liu X, Liu E, et al (2009). Norcantharidin induces HT-29 colon cancer cell apoptosis through the alphavbeta6- extracellular signal-related kinase signaling pathway. Cancer Sci, 100, 2302-8. https://doi.org/10.1111/j.1349-7006.2009.01320.x
  21. Pang RW, Poon RT (2006). Clinical implications of angiogenesis in cancers. Vasc Health Risk Manag, 2, 97-108. https://doi.org/10.2147/vhrm.2006.2.2.97
  22. Quesada AR, Munoz-Chapuli R, Medina MA (2006). Antiangiogenic drugs: from bench to clinical trials. Med Res Rev, 26, 483-530. https://doi.org/10.1002/med.20059
  23. Rodrigo JP, Cabanillas R, Chiara MD, et al (2009). Prognostic significance of angiogenesis in surgically treated supraglottic squamous cell carcinomas of the larynx. Acta Otorrinolaringol Esp, 60, 272-7 (in Spanish). https://doi.org/10.1016/j.otorri.2008.12.001
  24. Svagzdys S, Lesauskaite V, Pavalkis D, et al (2009). Microvessel density as new prognostic marker after radiotherapy in rectal cancer. Bmc Cancer, 9, 95. https://doi.org/10.1186/1471-2407-9-95
  25. Shibuya M, Claesson-Welsh L (2006). Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Experimental Cell Res, 312, 549-60. https://doi.org/10.1016/j.yexcr.2005.11.012
  26. Tanigawa N, Amaya H, Matsumura M, et al (1997). Tumor angiogenesis and mode of metastasis in patients with colorectal cancer. Cancer Res, 57, 1043-6.
  27. Veikkola T, Alitalo K (1999). VEGFs, receptors and angiogenesis. Semin Cancer Biol, 9, 211-20. https://doi.org/10.1006/scbi.1998.0091
  28. Wang GS (1989). Medical uses of mylabris in ancient China and recent studies. J Ethnopharmacol, 26, 147-62. https://doi.org/10.1016/0378-8741(89)90062-7

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