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Polyacetylenes Function as Anti-Angiogenic Agents

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Abstract

Purpose. To investigate the antiangiogenic effects of plant extracts and polyacetylenes isolated from Bidens pilosa Linn., which is a popular nutraceutical herbal tea and folk medicine in anti-inflammatory, antitumor, and other medications worldwide.

Methods. Anti-cell proliferation, anti-tube formation, and cell migration assays were used for the valuation of bioactivities of target plant extracts and phytocompounds against angiogenesis. Bioactivity-guided fractionation, HPLC, and various spectral analyses were used to identify active fraction and phytocompounds for anti-angiogenesis.

Results. We show that an ethyl acetate (EA) fraction of B. pilosa exhibited significant anti-cell proliferation and anti-tube formation activities against human umbilical vein endothelium cells (HUVEC). Bioassay-guided fractionation led to isolation of one new and one known polyacetylenes, 1,2-dihydroxytrideca-5,7,9,11-tetrayne (1) and 1,3-dihydroxy-6(E)- tetradecene-8,10,12-triyne (2), respectively, from the EA fraction. Compounds 1 and 2 manifested highly specific and significant activities against HUVEC proliferation with IC50 values of 2.5 and 0.375 μg/ml, respectively, however, compound 1 had a more potent effect on preventing tube formation of HUVEC than compound 2 at a dose of 2.5 μg/ml. Western blot analysis showed that both compounds upregulated p27(Kip) or p21(Cip1), cyclin-dependent kinase inhibitors, in HUVEC.

Conclusions. This is the first report to demonstrate that polyacetylenes possess significant anti-angiogenic activities and the ability to regulate the expression of cell cycle mediators, for example, p27(Kip1), p21(Cip1), or cyclin E.

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References

  1. J. Folkman and Y. Shing. Angiogenesis. J. Biol. Chem. 267: 10931–10934 (1992).

    PubMed  Google Scholar 

  2. J. Folkman. Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nat. Med. 1:27–31 (1995).

    PubMed  Google Scholar 

  3. F. Bussolino, A. Mantovani, and G. Persico. Molecular mecha-nisms of blood vessel formation. Trends Biochem. Sci. 22:251–256 (1997).

    PubMed  Google Scholar 

  4. D. Hanahan. and J. Folkman. Patterns and emerging mechanisms of the angiogenic switch during tumor angiogenesis. Cell 86:353–364 (1996).

    Article  PubMed  Google Scholar 

  5. M. S. O'Reilly, T. Boehm, Y. Shing, N. Fukai, G. Vasios, W. S. Lane, E. Flynn, J. R. Birkhead, B. R. Olsen, and J. Folkman. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285 (1997).

    PubMed  Google Scholar 

  6. M. S. O'Reilly. Angiostatin: an endogenous inhibitor of angio-genesis and of tumor growth. EXS 79:273–294 (1997).

    PubMed  Google Scholar 

  7. M. Yamaoka, T. Yamamoto, T. Masaki, S. Ikeyama, K. Sudo, and T. Fujita. Inhibition of tumor growth and metastasis of rodent tumors by the angiogenesis inhibitor O-(chloroacetyl-carbamoyl) fumagillol (TNP-470; AGM-1470). Cancer Res. 53:4262–4267 (1993).

    PubMed  Google Scholar 

  8. V. Brower. Tumor angiogenesis-new drugs on the block. Nat. Biotechnol. 17:963–968 (1999).

    PubMed  Google Scholar 

  9. P. Geissbergerand and U. Sequin. Constituents of Bidens pilosa L.: do the components found so far explain the use of this plant in traditional medicine? Acta Trop. 48:251–261 (1991).

    PubMed  Google Scholar 

  10. H. W. Chin, C. C. Lin, and K. S. Tang. The hepatoprotective effects of Taiwan folk medicine ham-hong-chho in rats. Am. J. Chin. Med. 24:231–240 (1996).

    PubMed  Google Scholar 

  11. R. L. Pereira, T. Ibrahim, L. Lucchetti, A. J. da Silva, and V. L. Goncalves de Moraes. Immunosuppressive and anti-inflamma-tory effects of methanolic extract and the polyacetylene isolated from Bidens pilosa L. Immunopharmacology 43:31–37 (1999).

    PubMed  Google Scholar 

  12. T. Dimo, S. V. Rakotonirina, P. V. Tan, J. Azay, E. Dongo, and G. Cros. Leaf methanol extract of Bidens pilosa prevents and attenuates the hypertension induced by high-fructose diet in Wistar rats. J. Ethnopharmacol. 83:183–191 (2002).

    PubMed  Google Scholar 

  13. R. P. Ubillas, C. D. Mendez, S. D. Jolad, J. Luo, S. R. King, T. J. Carlson, and D. M. Fort. Antihyperglycemic acetylenic gluco-sides from Bidens pilosa. Planta Med. 66:82–83 (2000).

    PubMed  Google Scholar 

  14. M. M. Levin, V. S. Iasnetsov, A. I. Sul'zhenko, and N. F. Farash-chuk. Experience in treating alopecia areata with galenicals of Bidens triparta. Sov. Med. 10:135–136 (1974).

    PubMed  Google Scholar 

  15. S. S. Mirvish, E. F. Rose, and D. M. Sutherland. Studies on the esophagus. II. Enhancement of [ 3 H]thymidine incorporation in the rat esophagus by Bidens pilosa (a plant eaten in South Africa) and by croton oil. Cancer Lett. 6:159–165 (1979).

    PubMed  Google Scholar 

  16. S. S. Mirvish, S. Salmasi, T. A. Lawson, P. Pour, and D. Suther-land. Test of catechol, tannic acid, Bidens pilosa, croton oil, and phorbol for cocarcinogenesis of esophageal tumors induced in rats by methyl-n-amylnitrosamine. J. Natl. Cancer Inst. 74:1283–1290 (1985).

    PubMed  Google Scholar 

  17. J. S. Chang, L. C. Chiang, C. C. Chen, L. T. Liu, K. C. Wang, and C. C. Lin. Antileukemic activity of Bidens pilosa L. var. minor (Blume) Sherff and Houttuynia cordata Thunb. Am. J. Chin. Med. 29:303–312 (2001).

    PubMed  Google Scholar 

  18. Y. Sashida, K. Ogawa, M. Kitada, H. Karikome, Y. Mimaki, and H. Shimomura. New aurone glucosides and new phenylpropa-noid glucosides from Bidens pilosa. Chem. Pharm. Bull. 39:709–711 (1991).

    Google Scholar 

  19. L. Alvarez, S. Marquina, M. L. Villarreal, D. Alonso, E. Aranda, and G. Delgado. Bioactive polyacetylenes from Bidens pilosa. Planta Med. 62:355–357 (1996).

    PubMed  Google Scholar 

  20. M. G. Brandao, A. U. Krettli, L. S. Soares, C. G. Nery, and H. C. Marinuzzi. Antimalarial activity of extracts and fractions from Bidens pilosa and other Bidens species (Asteraceae) correlated with the presence of acetylene and flavonoid compounds. J. Eth-nopharmacol. 57:131–138 (1997).

    Google Scholar 

  21. C. A. Zulueta, A. Zulueta, M. Tada, and C. Y. Ragasa. A diter-pene from Bidens pilosa. Phytochemistry 38:1449–1450 (1995).

    Google Scholar 

  22. M. G. Brandao, C. G. Nery, M. A. Mamao, and A. U. Krettli. Two methoxylated flavone glycosides from Bidens pilosa. Phyto-chemistry 48:397–399 (1998).

    Google Scholar 

  23. J. Wang, H. Yang, Z. W. Lin, and H. D. Sun. Flavonoids from Bidens pilosa var. radiata. Phytochemistry 46:1275–1278 (1997).

    Google Scholar 

  24. G. Rucker, S. Kehrbaum, H. Sakulas, B. Lawong, and F. Goelten-both. Acetylenic glucosides from Microglossa pyrifolia. Planta Med. 58:266–269 (1992).

    PubMed  Google Scholar 

  25. E. A. Jaffe, R. L. Nachman, C. G. Becker, and C. R. Minick. Culture of human endothelial cells derived from umbilical veins. J. Clin. Invest. 52:2745–2756 (1973).

    PubMed  Google Scholar 

  26. P. Boukamp, R. T. Petrussevska, D. Breitkreutz, J. Hornung, A. Markham, and N. E. Fusenig. Normal keratinization in a spon-taneously immortalized aneuploid human keratinocyte cell line. J. Cell Biol. 106:761–771 (1988).

    PubMed  Google Scholar 

  27. R. Montesano, L. Orci, and P. Vassalli. In vitro rapid organiza-tion of endothelial cells into capillary-like networks is promoted by collagen matrices. J. Cell Biol. 97:1648–1652 (1983).

    PubMed  Google Scholar 

  28. M. Jang, L. Cai, G. O. Udeani, K. V. Slowing, C. F. Thomas, C. W. Beecher, H. H. Fong, N. R. Farnsworth, A. D. Kinghorn, R. G. Mehta, R. C. Moon, and J. M. Pezzuto. Cancer chemopreven-tive activity of resveratrol, a natural product derived from grapes. Science 275:218–220 (1997).

    Article  PubMed  Google Scholar 

  29. J. A. Rose and C. M. Kasum. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu. Rev. Nutr. 22:19–34 (2002).

    PubMed  Google Scholar 

  30. K. Igura, T. Ohta, Y. Kuroda, and K. Kaji. Resveratrol and quer-cetin inhibit angiogenesis in vitro. Cancer Lett. 171:11–16 (2001).

    Google Scholar 

  31. C. J. Sherr. G1 phase progression: cycling on cue. Cell 79:551–555 (1994).

    Article  PubMed  Google Scholar 

  32. K. H. Vousden. Switching from life to death: the Miz-ing link between Myc and p53. Cancer Cell 2:351–352 (2002).

    PubMed  Google Scholar 

  33. L. Hengstand and S. I. Reed. Inhibitors of the Cip/Kip family. Curr. Top. Microbiol. Immunol. 227:25–41 (1998).

    PubMed  Google Scholar 

  34. D. Goukassian, A. Diez-Juan, T. Asahara, P. Schratzberger, M. Silver, T. Murayama, J. M. Isner, and V. Andres. Overexpression of p27(Kip1) by doxycycline-regulated adenoviral vectors inhibits endothelial cell proliferation and migration and impairs angio-genesis. FASEB J. 15:1877–1885 (2001).

    PubMed  Google Scholar 

  35. S. B. Parker, G. Eichele, P. Zhang, A. Rawls, A. T. Sands, A. Bradley, E. N. Olson, J. W. Harper, and S. J. Elledege. p53-independent expression of p21 Cip1 in muscle and other terminally differentiating cells. Science 267:1024–1027 (1995).

    PubMed  Google Scholar 

  36. W. S. El-Deiry. WAF1/CIP1 is induced in p53-mediated G1 ar-rest and apoptosis. Cancer Res. 54:1169–1174 (1994).

    PubMed  Google Scholar 

Download references

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Authors and Affiliations

  1. Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, Republic of China

    Li-Wha Wu, Hsiao-Ching Chuang, Ga-Wen Yang & Ling-Ya Lai

  2. Institute of BioAgricultural Sciences, Academia Sinica, Taipei, Taiwan, Republic of China

    Yi-Ming Chiang, Sheng-Yang Wang & Lie-Fen Shyur

  3. Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan, Republic of China

    Ya-Huey Chen

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Wu, LW., Chiang, YM., Chuang, HC. et al. Polyacetylenes Function as Anti-Angiogenic Agents. Pharm Res 21, 2112–2119 (2004). https://doi.org/10.1023/B:PHAM.0000048204.08865.41

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