Journal of Natural Medicines

, Volume 65, Issue 1, pp 149–156 | Cite as

Anti-angiogenic effect of triterpenoidal saponins from Polygala senega

  • Masayoshi Arai
  • Asami Hayashi
  • Mari Sobou
  • Shunsuke Ishida
  • Takashi Kawachi
  • Naoyuki Kotoku
  • Motomasa Kobayashi
Original Paper

Abstract

Senegasaponins [senegin II (1), senegin III (2), senegin IV (3), senegasaponin a (4), and senegasaponin b (5)] from Polygala senega were re-discovered as selective anti-proliferative substances against human umbilical vein endothelial cells (HUVECs). Senegasaponins (15) showed anti-proliferative activity against HUVECs with IC50 values in the range 0.6–6.2 μM, and the selective index was 7–100-fold in comparison with those for several cancer cell lines, while the desacyl mixture of senegasaponins (6) and tenuifolin (7) lost anti-proliferative activity, indicating that the 28-O-glycoside moiety and methoxycinnamoyl group were essential for the HUVEC-selective growth inhibition of senegasaponins. Senegin III (2) inhibited the vascular endothelial growth factor (VEGF)-induced in vitro tubular formation of HUVECs and basic fibroblast growth factor (bFGF)-induced in vivo neovascularization in the mouse Matrigel plug assay. Moreover, senegin III (2) suppressed tumor growth in the ddY mice s.c.-inoculated murine sarcoma S180 cells. The analysis of the action mechanism of senegin III (2) suggested that the induction of pigment epithelium-derived factor (PEDF) would contribute to the anti-angiogenic effects of senegasaponins.

Keywords

Senegasaponins Polygala senega Angiogenesis Cancer HUVECs Tubular formation 

References

  1. 1.
    Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31PubMedCrossRefGoogle Scholar
  2. 2.
    Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6PubMedCrossRefGoogle Scholar
  3. 3.
    Fan TP, Jaggar R, Bicknell R (1995) Controlling the vasculature: angiogenesis, anti-angiogenesis and vascular targeting of gene therapy. Trends Pharmacol Sci 16:57–66PubMedCrossRefGoogle Scholar
  4. 4.
    Aoki S, Cho SH, Ono M, Kuwano T, Nakao S, Kuwano M, Nakagawa S, Gao JQ, Mayumi T, Shibuya M, Kobayashi M (2006) Bastadin 6, a spongean brominated tyrosine derivative, inhibits tumor angiogenesis by inducing selective apoptosis to endothelial cells. Anticancer Drugs 17:269–278PubMedCrossRefGoogle Scholar
  5. 5.
    Aoki S, Sanagawa M, Watanabe Y, Setiawan A, Arai M, Kobayashi M (2007) Novel isomarabarican triterpenes, exhibiting selective anti-proliferative activity against vascular endothelial cells, from marine sponge Rhabdastrella globostellata. Bioorg Med Chem 15:4818–4828PubMedCrossRefGoogle Scholar
  6. 6.
    Aoki S, Watanabe Y, Sanagawa M, Setiawan A, Kotoku N, Kobayashi M (2006) Cortistatins A, B, C, and D, anti-angiogenic steroidal alkaloids, from the marine sponge Corticium simplex. J Am Chem Soc 128:3148–3149PubMedCrossRefGoogle Scholar
  7. 7.
    Yoshikawa M, Murakami T, Ueno T, Kadoya M, Matsuda H, Yamahara J, Murakami N (1995) E-senegasaponins A and B, Z-senegasaponins A and B, Z-senegins II and III, new type inhibitors of ethanol absorption in rats from senegae radix, the roots of Polygala senega L. var latifolia Torrey et Gray. Chem Pharm Bull 43:350–352PubMedGoogle Scholar
  8. 8.
    Yoshikawa M, Murakami T, Ueno T, Kadoya M, Matsuda H, Yamahara J, Murakami N (1995) Bioactive saponins and glycosides. I. Senegae radix. (1): E-senegasaponins a and b and Z-senegasaponins a and b, their inhibitory effect on alcohol absorption and hypoglycemic activity. Chem Pharm Bull 43:2115–2122PubMedGoogle Scholar
  9. 9.
    Yoshikawa M, Murakami T, Matsuda H, Ueno T, Kadoya M, Yamahara J, Murakami N (1996) Bioactive saponins and glycosides. II. Senegae Radix. (2): Chemical structures, hypoglycemic activity, and ethanol absorption-inhibitory effect of E-senegasaponin c, Z-senegasaponin c, and Z-senegins II, III, and IV. Chem Pharm Bull 44:1305–1313PubMedGoogle Scholar
  10. 10.
    Estrada A, Katselis GS, Laarveld B, Barl B (2000) Isolation and evaluation of immunological adjuvant activities of saponins from Polygala senega L. Comp Immunol Microbiol Infect Dis 23:27–43PubMedCrossRefGoogle Scholar
  11. 11.
    Sakuma S, Shoji J (1981) Studies on the constituents of the root of Polygala tenuifolia Willdenow. II. On the structures of onjisaponins A, B and E. Chem Pharm Bull 30:810–821Google Scholar
  12. 12.
    Desbène S, Hanquet B, Shoyama Y, Wagner H, Lacaille-Dubois MA (1999) Biologically active triterpene saponins from callus tissue of Polygala amarella. J Nat Prod 62:923–926PubMedCrossRefGoogle Scholar
  13. 13.
    Lin KT, Lien JC, Chung CH, Kuo SC, Huang TF (2010) A novel compound, NP-184, inhibits the vascular endothelial growth factor induced angiogenesis. Eur J Pharmacol 630:53–60PubMedCrossRefGoogle Scholar
  14. 14.
    Drabkin DL, Austin JH (1935) Spectrophotometric studies: II. Preparations from washed blood cells; nitric oxide hemoglobin and sulfhemoglobin. J Biol Chem 112:51–65Google Scholar
  15. 15.
    Hood JD, Frausto R, Kiosses WB, Schwartz MA, Cheresh DA (2003) Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis. J Cell Biol 162:933–943PubMedCrossRefGoogle Scholar
  16. 16.
    Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N (1998) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 273:30336–30343PubMedCrossRefGoogle Scholar
  17. 17.
    Ek ETH, Dass CR, Choong PFM (2006) PEDF: a potential molecular therapeutic target with multiple anti-cancer activities. Trends Mol Med 12:497–502PubMedCrossRefGoogle Scholar
  18. 18.
    Sengupta S, Toh SA, Sellers LA, Skepper JN, Koolwijk P, Leung HW, Yeung HW, Wong RN, Sasisekharan R, Fan TP (2004) Modulating angiogenesis: the yin and the yang in ginseng. Circulation 110:1219–1225PubMedCrossRefGoogle Scholar
  19. 19.
    Leung KW, Cheung LWT, Pon YL, Wong RNS, Mak NK, Fan TP, Au SCL, Tombran-Tink J, Wong AST (2007) Ginsenoside Rb1 inhibits tube-like structure formation of endothelial cells by regulating pigment epithelium-derived factor through the oestrogen beta receptor. Br J Pharmacol 152:207–215PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer 2010

Authors and Affiliations

  • Masayoshi Arai
    • 1
  • Asami Hayashi
    • 1
  • Mari Sobou
    • 1
  • Shunsuke Ishida
    • 1
  • Takashi Kawachi
    • 1
  • Naoyuki Kotoku
    • 1
  • Motomasa Kobayashi
    • 1
  1. 1.Graduate School of Pharmaceutical SciencesOsaka UniversitySuitaJapan

Personalised recommendations