The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Zerumbone, Sesquiterpene Photochemical from Ginger, Inhibits Angiogenesis

  • Park, Ju-Hyung (Department of Biomedical Science, Catholic University of Daegu) ;
  • Park, Geun Mook (Department of Biomedical Science, Catholic University of Daegu) ;
  • Kim, Jin-Kyung (Department of Biomedical Science, Catholic University of Daegu)
  • Received : 2015.02.04
  • Accepted : 2015.04.08
  • Published : 2015.07.01
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Abstract

Here, we investigated the role of zerumbone, a natural cyclic sesquiterpene of Zingiber zerumbet Smith, on angiogenesis using human umbilical vein endothelial cells (HUVECs). Zerumbone inhibited HUVECs proliferation, migration and tubule formation, as well as angiogenic activity by rat aorta explants. In particular, zerumbone inhibited phosphorylation of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1, which are key regulators of endothelial cell function and angiogenesis. In vivo matrigel plug assay in mice demonstrated significant decrease in vascularization and hemoglobin content in the plugs from zerumbone-treated mice, compared with control mice. Overall, these results suggest that zerumbone inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects.

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References

  1. Liu RH. Health-promoting components of fruits and vegetables in the diet. Adv Nutr. 2013;4:384S-392S. https://doi.org/10.3945/an.112.003517
  2. Key TJ, Appleby PN, Crowe FL, Bradbury KE, Schmidt JA, Travis RC. Cancer in British vegetarians: updated analyses of 4998 incident cancers in a cohort of 32,491 meat eaters, 8612 fish eaters, 18,298 vegetarians, and 2246 vegans. Am J Clin Nutr. 2014;100 Suppl 1:378S-385S. https://doi.org/10.3945/ajcn.113.071266
  3. Bhathena SJ, Velasquez MT. Beneficial role of dietary phytoestrogens in obesity and diabetes. Am J Clin Nutr. 2002;76:1191-1201. https://doi.org/10.1093/ajcn/76.6.1191
  4. Canter PH, Thomas H, Ernst E. Bringing medicinal plants into cultivation: opportunities and challenges for biotechnology. Trends Biotechnol. 2005;23:180-185. https://doi.org/10.1016/j.tibtech.2005.02.002
  5. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249-257. https://doi.org/10.1038/35025220
  6. Montesano R, Vassalli JD, Baird A, Guillemin R, Orci L. Basic fibroblast growth factor induces angiogenesis in vitro. Proc Natl Acad Sci U S A. 1986;83:7297-7301. https://doi.org/10.1073/pnas.83.19.7297
  7. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13:871-882. https://doi.org/10.1038/nrc3627
  8. Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9:653-660. https://doi.org/10.1038/nm0603-653
  9. Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Biochem J. 2011;437:169-183. https://doi.org/10.1042/BJ20110301
  10. Spano D, Zollo M. Tumor microenvironment: a main actor in the metastasis process. Clin Exp Metastasis. 2012;29:381-395. https://doi.org/10.1007/s10585-012-9457-5
  11. Gao F, Liang B, Reddy ST, Farias-Eisner R, Su X. Role of inflammation-associated microenvironment in tumorigenesis and metastasis. Curr Cancer Drug Targets. 2014;14:30-45. https://doi.org/10.2174/15680096113136660107
  12. Bellou S, Pentheroudakis G, Murphy C, Fotsis T. Anti-angiogenesis in cancer therapy: Hercules and hydra. Cancer Lett. 2013;338:219-228. https://doi.org/10.1016/j.canlet.2013.05.015
  13. Dev S. Studies in sesquiterpenes-XVI: zerumbone, a monocyclic sesquiterpene ketone. Tetrahedron. 1960;8:171-180. https://doi.org/10.1016/0040-4020(60)80027-0
  14. Murakami A, Takahashi M, Jiwajinda S, Koshimizu K, Ohigashi H. Identification of zerumbone in Zingiber zerumbet Smith as a potent inhibitor of 12-O-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus activation. Biosci Biotechnol Biochem. 1999;63:1811-1812. https://doi.org/10.1271/bbb.63.1811
  15. Kirana C, McIntosh GH, Record IR, Jones GP. Antitumor activity of extract of Zingiber aromaticum and its bioactive sesquiterpenoid zerumbone. Nutr Cancer. 2003;45:218-225. https://doi.org/10.1207/S15327914NC4502_12
  16. Huang GC, Chien TY, Chen LG, Wang CC. Antitumor effects of zerumbone from Zingiber zerumbet in P-388D1 cells in vitro and in vivo. Planta Med. 2005;71:219-224. https://doi.org/10.1055/s-2005-837820
  17. Szabolcs A, Tiszlavicz L, Kaszaki J, Posa A, Berko A, Varga IS, Boros I, Szuts V, Lonovics J, Takacs T. Zerumbone exerts a beneficial effect on inflammatory parameters of cholecystokinin octapeptide-induced experimental pancreatitis but fails to improve histology. Pancreas. 2007;35:249-255. https://doi.org/10.1097/mpa.0b013e318070d791
  18. Kitayama T. Attractive reactivity of a natural product, zerumbone. Biosci Biotechnol Biochem. 2011;75:199-207. https://doi.org/10.1271/bbb.100532
  19. Shamoto T, Matsuo Y, Shibata T, Tsuboi K, Nagasaki T, Takahashi H, Funahashi H, Okada Y, Takeyama H. Zerumbone inhibits angiogenesis by blocking NF-${\kappa}B$ activity in pancreatic cancer. Pancreas. 2014;43:396-404. https://doi.org/10.1097/MPA.0000000000000039
  20. Tsuboi K, Matsuo Y, Shamoto T, Shibata T, Koide S, Morimoto M, Guha S, Sung B, Aggarwal BB, Takahashi H, Takeyama H. Zerumbone inhibits tumor angiogenesis via NF-${\kappa}$B in gastric cancer. Oncol Rep. 2014;31:57-64. https://doi.org/10.3892/or.2013.2842
  21. Arnaoutova I, George J, Kleinman HK, Benton G. The endothelial cell tube formation assay on basement membrane turns 20: state of the science and the art. Angiogenesis. 2009;12:267-274. https://doi.org/10.1007/s10456-009-9146-4
  22. Go RS, Owen WG. The rat aortic ring assay for in vitro study of angiogenesis. Methods Mol Med. 2003;85:59-64.
  23. Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res. 2006;312:549-560. https://doi.org/10.1016/j.yexcr.2005.11.012
  24. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8:235-253. https://doi.org/10.1038/nrd2792
  25. Woad KJ, Hunter MG, Mann GE, Laird M, Hammond AJ, Robinson RS. Fibroblast growth factor 2 is a key determinant of vascular sprouting during bovine luteal angiogenesis. Reproduction. 2012;143:35-43. https://doi.org/10.1530/REP-11-0277
  26. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438:932-936. https://doi.org/10.1038/nature04478
  27. Mittal K, Ebos J, Rini B. Angiogenesis and the tumor microenvironment: vascular endothelial growth factor and beyond. Semin Oncol. 2014;41:235-251. https://doi.org/10.1053/j.seminoncol.2014.02.007
  28. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146:873-887. https://doi.org/10.1016/j.cell.2011.08.039
  29. Ayers M, Fargnoli J, Lewin A, Wu Q, Platero JS. Discovery and validation of biomarkers that respond to treatment with brivanib alaninate, a small-molecule VEGFR-2/FGFR-1 antagonist. Cancer Res. 2007;67:6899-6906. https://doi.org/10.1158/0008-5472.CAN-06-4555
  30. Renhowe PA, Pecchi S, Shafer CM, Machajewski TD, Jazan EM, Taylor C, Antonios-McCrea W, McBride CM, Frazier K, Wiesmann M, Lapointe GR, Feucht PH, Warne RL, Heise CC, Menezes D, Aardalen K, Ye H, He M, Le V, Vora J, Jansen JM, Wernette-Hammond ME, Harris AL. Design, structureactivity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors. J Med Chem. 2009;52:278-292. https://doi.org/10.1021/jm800790t
  31. Bello E, Colella G, Scarlato V, Oliva P, Berndt A, Valbusa G, Serra SC, D'Incalci M, Cavalletti E, Giavazzi R, Damia G, Camboni G. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011;71:1396-1405. https://doi.org/10.1158/0008-5472.CAN-10-2700

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