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Anti-angiogenic activity of sesterterpenes; natural product inhibitors of FGF-2-induced angiogenesis

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Abstract

Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is of physiological and pathological importance. We have investigated the anti-angiogenic potential of two naturally occurring sesterterpenes, leucosesterterpenone (compound 1) and leucosterlactone (compound 2) isolated from the Himalayan plant Leucosceptrum canum and identified as having biological activity in preliminary screening. Compound 1 inhibited fibroblast growth factor-2-induced proliferation, migration in a wounding assay, chemotaxis and tube formation with small vessel (human dermal) and large vessel (bovine aortic) endothelial cells while compound 2 was largely inactive. Both compounds were also active in an in vivo angiogenic model using the chick chorioallantoic membrane. Neither compounds showed inhibitory activity in the absence of fibroblast growth factor-2. We were able to demonstrate in a binding assay that compounds 1 and 2 bound to the fibroblast growth factor-2 receptor-1 with IC50 values of 1.4 ± 0.956 and 132.47 ± 7.90 μM, respectively, with a concomitant down regulation of phosphorylated ERK1/2 but did not bind to receptor-2. Compound 1 was less hydrophobic than compound 2 and this may contribute to its increased activity. Compound 1 is a new addition to the small number of inhibitors of fibroblast growth factor-2-induced angiogenesis. The compound was a specific inhibitor in that it had no effect on vascular endothelial growth factor or epithelial growth factor-induced angiogenesis. Since angiogenesis is essential for tumour development we conclude that these compounds may have potential as anti-tumour agents.

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References

  1. Bobick BE, Kulyk WM (2006) The MEK-ERK signalling pathway plays diverse roles in the regulation of facial chondrogenesis. Exp Cell Res 312:1079–1092

    Article  PubMed  CAS  Google Scholar 

  2. Carolyn AS, Stephen M, Stribbling A, Simon T, Russell H, Nicola JB, Claire EL (2004) Current methods for assaying angiogenesis in vitro and in vivo. Int J Exp Path 85:233–248

    Article  Google Scholar 

  3. Choi K, Hong J, Lee CO, Kim DK, Sim CJ, Im KS, Jung JH (2004) Cytotoxic furanosesterterpenes from a marine sponge Psammocinia sp. J Nat Prod 67:1186–189

    Article  PubMed  CAS  Google Scholar 

  4. Choudhary MI, Ranjit R, A-ur-Rahman, Hussain S, Devkota KP, Shreshta TM, Parvez M (2004) Novel sesterterpenes from Leucosceptrum canum of Nepalese origin. Organic Lett 6:4139–4142

    Article  CAS  Google Scholar 

  5. Crews P, Naylor S (1985) Sesterterpenes: an emerging group of metabolites from marine and terrestrial organisms. Fortschr Chem Org Naturst 48:203–269

    PubMed  CAS  Google Scholar 

  6. Duraisamy Y, Slevin M, Smith N, Bailey J, Zweit J, Smith C, Ahmed N, Gaffney J (2001) Effect of glycation on basic fibroblast growth factor induced angiogenesis and activation of associated signal transduction pathways in vascular endothelial cells: possible relevance to wound healing. Angiogenesis 4:277–288

    Article  PubMed  CAS  Google Scholar 

  7. Folkman J (2003) Fundamental concepts of the angiogenic process. Curr Mol Med 3:643–651

    Article  PubMed  CAS  Google Scholar 

  8. Hamano Y, Kalluri R (2005) Tumstatin, the NC1 domain of alpha 3 chain of type IV collagen is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth. Biochem Biophys Res Commun 333:292–298

    Article  PubMed  CAS  Google Scholar 

  9. Ifat S, Tamer L, Lubinsky-Mink S, Kuhn J, Adir N, Chaterjee S, Schomburg D, Ron D, Mink S, Noam A, Shivani C, Dietmar S, Dina R (2000) Identification of residues important both for primary receptor binding and specificity in fibroblast growth factor-7. J Biol Chem 275:34881–34886

    Article  Google Scholar 

  10. Kirsch G, Kong GM, Wright AD, Kaminsky R (2000) A new bioactive sesterterpene and antiplasmodial alkaloid from the marine sponge hyrtios cf. erecta. J Nat Prod 63:825–829

    Article  PubMed  CAS  Google Scholar 

  11. Kok TW, Yue PW, Mak NK, Fan TP, Liu L, Wong RN (2005) The anti-angiogenic effects of simonenine. Angiogenesis 8:3–12

    Article  PubMed  CAS  Google Scholar 

  12. Krupindki J, Stroemer P, Slevin M, Marti E, Kumar P, Rubio F (2003) Three-dimensional structure and survival of newly formed blood vessels after focal global ischaemia. Neuroreport 14:1171–1176

    Article  Google Scholar 

  13. Lawler J (2002) Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med 6:1–12

    Article  PubMed  CAS  Google Scholar 

  14. Li XJ, Yue PY, Ha WY, Wong DY, Tin MM, Wang PX, Wong RN, Liu L (2006) Effect of sinomenine on gene expression of the Il-1 beta-activated human synovial sarcoma. Life Sci 79:665–673

    Article  PubMed  CAS  Google Scholar 

  15. Liu L, Resch K, Kasever V (1994) Inhibition of lymphocyte proliferation by the anti-arthritic drug sinomenine. Int J Immunopharmacol 16:685–691

    Article  PubMed  CAS  Google Scholar 

  16. Powers CJ, Mcleskey SW, Wellstein A (2000) Fibroblast growth factors, their receptors and signalling. Endocr Relat Cancer 7:165–197

    Article  PubMed  CAS  Google Scholar 

  17. Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon A, Linhardt RJ, Mohammadi M (2000) Crystal structure of aternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell 6:743–750

    Article  PubMed  CAS  Google Scholar 

  18. Sher I, Lang T, Lubinsky-Mink S, Kuhn J, Adir N, Chaterjee S, Schomburg D, Ron D (2000) Identification of residues important for primary receptor binding and specificity in fibroblast growth factor-7. J Biol Chem 45:34861–34866

    Google Scholar 

  19. Simons S (2004) Integrative signaling in angiogenesis. Mol Cell Biochem 264:99–102

    Article  PubMed  CAS  Google Scholar 

  20. Slevin M, Krupinski J, Kumar S, Gaffney J (1998) Angiogenic oligosaccharides of hyaluronan induce protein tyrosine kinase activity in endothelial cells and activate a cytoplasmic signal transduction pathway resulting in proliferation. Lab Invest 78:987–1003

    PubMed  CAS  Google Scholar 

  21. Slevin M, Kumar S, Gaffney J (2002) Angiogenic oligosaccharides of hyaluronan induce multiple signalling pathways affecting vascular endothelial cell mitogenic and wound healing responses. J Biol Chem 277:41046–410459

    Article  PubMed  CAS  Google Scholar 

  22. Slevin M, Krupinski J, Kumar P, Gaffney J, Kumar S (2005) Gene activation and protein expression following ischaemic stroke: strategies towards neuroprotection. J Cell Mol Med 9:85–102

    Article  PubMed  CAS  Google Scholar 

  23. Slevin M, Kumar P, Gaffney J, Kumar S, Krupinski J (2006) Can angiogenesis be exploited to improve stroke outcomes? Mechanisms and therapeutic potential. Clin Sci (Lond) 111:171–183

    Article  CAS  Google Scholar 

  24. Tabruyn SP, Griffioen AW (2007) Molecular pathways of angiogenesis inhibition. Biochem Biophys Res Commun 355:1–5

    Article  PubMed  CAS  Google Scholar 

  25. Tsukamato S, Miura S, van Soest RW, Ohta T (2003) Three new cytotoxic sesterterpenes from a marine sponge Spongia sp. J Nat Prod 66:438–440

    Article  CAS  Google Scholar 

  26. West DC, Thompson WD, Sellls PG, Burbridge MF (2001) Angiogenesis assays using the chick chorioallantoic membrane. In: Murray JC (ed) Methods in molecular medicine-angiogenesis: reviews and protocols. Humana Press, pp 107–130

  27. West DC, Rees CG, Duchesne L, Patey SJ, Terry CJ, Turnbull JE, Delehedde M, Heegard CW, Allain F, Vanpouille C, Ron D, Fernig DG (2005) Interactions of multiple heparin binding growth factors with neuropilin-1 and potentiation of the activity of fibroblast growth factor-2. J Biol Chem 280:13457–13464

    Article  PubMed  CAS  Google Scholar 

  28. Wonganuchitmeta SN, Yuenyongsawad S, Keawpradub N, Plubrukarn A (2004) Antitubercular sesterterpenes from the Thai sponge Brachiaster sp. J Nat Prod 67:1767–1770

    Article  PubMed  CAS  Google Scholar 

  29. Youssef DT, Shaala LA, Emara S (2006) antimycobacterial scalarane-based sesterterpenes from the Red Sea sponge Hyrtios erecta. J Nat Prod 68:1782–1784

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. School of Biology, Chemistry and Health Science, Manchester Metropolitan University, Chester St., Manchester, M1 5GD, UK

    S. Hussain, M. Slevin, S. Matou, N. Ahmed & J. Gaffney

  2. H.E.J. Research Institute of Chemistry, International Centre for Biological and Chemical Sciences, University of Karachi, Karachi, 75720, Pakistan

    M. Iqbal Choudhary & R. Ranjit

  3. School of Biological Sciences, University of Liverpool, Liverpool, L69 7ZB, UK

    D. West

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  1. S. Hussain
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  2. M. Slevin
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Correspondence to M. Slevin.

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Hussain, S., Slevin, M., Matou, S. et al. Anti-angiogenic activity of sesterterpenes; natural product inhibitors of FGF-2-induced angiogenesis. Angiogenesis 11, 245–256 (2008). https://doi.org/10.1007/s10456-008-9108-2

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  • DOI: https://doi.org/10.1007/s10456-008-9108-2

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