Skip to main content
Log in

Anti-metastatic properties of the leaves of Eriobotrya japonica

  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The leaves of Eriobotrya japonica Lindl. have been widely used as a traditional medicine for the treatment of many diseases including gastroenteric disorders, diabetes mellitus, chronic bronchitis and asthma. In the present study, the anti-metastatic action of the EtOAc fraction of the leaves of E. japonica (LEJ) was investigated. LEJ showed potent inhibitory effects on MMP-2 and MMP-9 activities and expressions via down-regulation of NF-κB translocation to the nucleus in B16F10 cells. In addition, the cell migration and invasion were down-regulated by LEJ. LEJ also significantly suppressed lung metastasis in vivo. Moreover, we isolated the compounds ursolic acid and 2α-hydroxyursolic acid from LEJ and both compounds also significantly suppressed MMP-2 and MMP-9 activities, indicating that they are the active components of LEJ. The present results demonstrate that LEJ may be used as valuable antimetastatic agent for the treatment of cancer metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Arvelo, F. and Cotte, C., Metalloproteinases in tumor progression. Review. Invest. Clin., 47, 185–205 (2006).

    PubMed  Google Scholar 

  • Baek, W. K., Park, J. W., Lim, J. H., Suh, S. I., Suh, M. H., Gabrielson, E., and Kwon, T. K., Molecular cloning and characterization of the human budding uninhibited by benomyl (BUB3) promoter. Gene, 295, 117–123 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Bromm, B. and Lorenz, J., Neurophysiological evaluation of pain. Electroencephalogr. Clin. Neurophysiol., 107, 227–253 (1998).

    Article  CAS  Google Scholar 

  • Brooks, S. A., Lomax-Browne, H. J., Carter, T. M., Kinch, C. E., and Hall, D. M., Molecular interactions in cancer cell metastasis. Acta Histochem., 112, 3–25 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Dannenberg, A. J. and Subbaramaiah, K., Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell, 4, 431–436 (2003).

    Article  PubMed  CAS  Google Scholar 

  • De Tommasi, N., De Simone, F., Cirino, G., Cicala, C., and Pizza, C., Hypoglycemic effects of sesquiterpene glycosides and polyhydroxylated triterpenoids of Eriobotrya japonica. Planta Med., 57, 414–416 (1991).

    Article  PubMed  Google Scholar 

  • Eraso, A. J. and Albesa, I., Eriobotrya japonica counteracts reactive oxygen species and nitric oxide stimulated by chloramphenicol. Am. J. Chin. Med., 35, 875–885 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Gao, Z., Sasaoka, T., Fujimori, T., Oya, T., Ishii, Y., Sabit, H., Kawaguchi, M., Kurotaki, Y., Naito, M., Wada, T., Ishizawa, S., Kobayashi, M., Nabeshima, Y., and Sasahara, M., Deletion of the PDGFR-beta gene affects key fibroblast functions important for wound healing. J. Biol. Chem., 280, 9375–9389 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Hrabec, E., Strek, M., Nowak, D., Greger, J., Suwalski, M., and Hrabec, Z., Activity of type IV collagenases (MMP-2 and MMP-9) in primary pulmonary carcinomas: a quantitative analysis. J. Cancer Res. Clin. Oncol., 128, 197–204 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Huang, Y., Li, J., Cao, Q., Yu, S. C., Lv, X. W., Jin, Y., Zhang, L., Zou, Y. H., and Ge, J. F., Anti-oxidative effect of triterpene acids of Eriobotrya japonica (Thunb.) Lindl. leaf in chronic bronchitis rats. Life Sci., 78, 2749–2757 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Huang, Y., Li, J., Meng, X. M., Jiang, G. L., Li, H., Cao, Q., Yu, S. C., Lv, X. W., and Cheng, W. M., Effect of triterpene acids of Eriobotrya japonica (Thunb.) Lindl. leaf and MAPK signal transduction pathway on inducible nitric oxide synthase expression in alveolar macrophage of chronic bronchitis rats. Am. J. Chin. Med., 37, 1099–1111 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Ito, H., Kobayashi, E., Takamatsu, Y., Li, S. H., Hatano, T., Sakagami, H., Kusama, K., Satoh, K., Sugita, D., Shimura, S., Itoh, Y., and Yoshida, T., Polyphenols from Eriobotrya japonica and their cytotoxicity against human oral tumor cell lines. Chem. Pharm. Bull., 48, 687–693 (2000).

    PubMed  CAS  Google Scholar 

  • Jedinák, A., Mucková, M., Kost'álová, D., Maliar, T., and Masterova, I., Antiprotease and antimetastatic activity of ursolic acid isolated from Salvia officinalis. Z. Naturforsch C, 61, 777–782 (2006).

    PubMed  Google Scholar 

  • Jiang, J., Grieb, B., Thyagarajan, A., and Sliva, D., Ganoderic acids suppress growth and invasive behavior of breast cancer cells by modulating AP-1 and NF-kappaB signaling. Int. J. Mol. Med., 21, 577–584 (2008).

    PubMed  CAS  Google Scholar 

  • Johnsen, M., Lund, L. R., Romer, J., Almholt, K., and Dano, K., Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr. Opin. Cell Biol., 10, 667–671 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Jung, H. A., Park, J. C., Chung, H. Y., Kim, J., and Choi, J. S., Antioxidant flavonoids and chlorogenic acid from the leaves of Eriobotrya japonica. Arch. Pharm. Res., 22, 213–218 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Kim, M. M., Ta, Q. V., Mendis, E., Rajapakse, N., Jung, W. K., Byun, H. G., Jeon, Y. J., and Kim, S. K., Phlorotannins in Ecklonia cava extract inhibit matrix metalloproteinase activity. Life Sci., 79, 1436–1443 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Kim, M. S., You, M. K., Rhuy, D. Y., Kim Y. J., Baek, H. Y., and Kim, H. A., Loquat (Eriobotrya japonica) extracts suppress the adhesion, migration and invasion of human breast cancer cell line. Nutr. Res. Pract., 3, 259–264 (2009).

    Article  PubMed  Google Scholar 

  • Kim, S. H. and Shin, T. Y., Anti-inflammatory effect of leaves of Eriobotrya japonica correlating with attenuation of p38 MAPK, ERK, and NF-kappaB activation in mast cells. Toxicol. In Vitro, 23, 1215–1219 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Kitajima, J. and Tanaka, Y., Constituents of Prunus zippeliana leaves and branches. Chem. Pharm. Bull., 41, 2007–2009 (1993).

    CAS  Google Scholar 

  • Kohn, E. C. and Liotta, L. A., Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res., 55, 1856–1862 (1995).

    PubMed  CAS  Google Scholar 

  • Lee, C. H., Wu, S. L., Chen, J. C., Li, C. C., Lo, H. Y., Cheng, W. Y., Lin, J. G., Chang, Y. H., Hsiang, C. Y., and Ho, T. Y., Eriobotrya japonica leaf and its triterpenes inhibited lipopolysaccharide-induced cytokines and inducible enzyme production via the nuclear factor-kappaB signaling pathway in lung epithelial cells. Am. J. Chin. Med., 36, 1185–1198 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Liabakk, N. B., Talbot, I., Smith, R. A., Wilkinson, K., and Balkwill, F., Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res., 56, 190–196 (1996).

    PubMed  CAS  Google Scholar 

  • Lind, D. S., Hochwald, S. N., Malaty, J., Rekkas, S., Heby, P., and Mishra, G., Nuclear factor-κB is unregulated in colorectal cancer. Surgery, 130, 363–369 (2001).

    Article  PubMed  CAS  Google Scholar 

  • McCawley, L. J. and Matrisian, L. M., Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol. Med. Today, 6, 149–156 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Minn, A. J., Gupta, G. P., Siegel, P. M., Bos, P. D., Shu, W., Giri, D. D., Viale, A., Olshen, A. B., Gerald, W. L., and Massagué, J., Genes that mediate breast cancer metastasis to lung. Nature, 436, 518–524 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Nakshatri, H., Bhat-Nakshatri, P., Martin, D. A., Goulet, R. J., and Sledge, G. W., Constitutive activation of NF-κB during progression of breast cancer to hormone independent growth. Mol. Cell. Biol., 17, 3629–3639 (1997).

    PubMed  CAS  Google Scholar 

  • Numata, A., Yang, P., Takahashi, C., Fujiki, R., Nabae, M., and Fujita, E., Cytotoxic triterpenes from a chinese medicine, Goreishi. Chem. Pharm. Bull., 37, 648–651 (1989).

    PubMed  CAS  Google Scholar 

  • Oppenheimer, S. B., Cellular basis of cancer metastasis: A review of fundamentals and new advances. Acta Histochem., 108, 327–334 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Raphael, T. J. and Kuttan, G., Effect of naturally occurring triterpenoids ursolic acid and glycyrrhizic acid on the cell mediated immune responses of metastatic tumor-bearing animals. Immunopharmacol. Immunotoxicol., 30, 243–255 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Scorilas, A., Karameris, A., Arnogiannaki, N., Ardavanis, A., Bassilopoulos, P., Trangas, T., and Talieri, M., Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients. Br. J. Cancer, 84, 1488–1496 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Shimizu, M., Fukumura, H., Tsuji, H., Tanaami, S., Hayashi, T., and Morita, N., Antiinflammatory constituents of topically applied crude drugs. I. Constituents and anti-inflammatory effect of Eriobotrya japonica LINDL. Chem. Pharm. Bull., 34, 2614–2617 (1986).

    PubMed  CAS  Google Scholar 

  • Shishodia, S., Majumdar, S., Banerjee, S., and Aggarwal, B. B., Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res., 63 4375–4383 (2003).

    PubMed  CAS  Google Scholar 

  • Szatrowski, T. P. and Nathan, C. F., Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res., 51, 794–798 (1991).

    PubMed  CAS  Google Scholar 

  • Taniguchi, S., Imayoshi, Y., Kobayashi, E., Takamatsu, Y., Ito, H., Hatano, T., Sakagami, H., Tokuda, H., Nishino, H., Sugita, D., Shimura, S., and Yoshida, T., Production of bioactive triterpenes by Eriobotrya japonica calli. Phytochemistry, 59, 315–323 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Tryggvason, K., Hoyhtya, M., and Salo, T., Proteolytic degradation of extracellular matrix in tumor invasion. Biochim. Biophys. Acta, 907, 191–217 (1987).

    PubMed  CAS  Google Scholar 

  • Weiss, L., Metastatic inefficiency. Adv. Cancer Res., 54, 159–211 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Wyckoff, J. B., Wang, Y., Lin, E. Y., Li, J. F., Goswami, S., Stanley, E. R., Segall, J. E., Pollard, J. W., and Condeelis, J., Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res., 67, 2649–2656 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Yang, J. and Richmond, A., Constitutive IkappaB kinase activity correlates with nuclear factor-kappaB activation in human melanoma cells. Cancer Res., 61, 4901–4909 (2001).

    PubMed  CAS  Google Scholar 

  • Yoon, S. O., Park, S. J., Yoon, S. Y., Yun, C. H., and Chung, A. S., Sustained production of H2O2 activates pro-matrixmetalloproteinase-2 through receptor tyrosine kinases/phosphatidylinositol 3-kinase/NF-kappa B pathway. J. Biol. Chem., 277, 30271–30282 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Yoon, S. O., Park, S. J., Yun, C. H., and Chung, A. S., Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J. Biochem. Mol. Biol., 36, 128–137 (2003).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hoon Jeon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cha, D.S., Shin, T.Y., Eun, J.S. et al. Anti-metastatic properties of the leaves of Eriobotrya japonica . Arch. Pharm. Res. 34, 425–436 (2011). https://doi.org/10.1007/s12272-011-0310-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-011-0310-1

Key words

Navigation