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.
Similar content being viewed by others
References
Arvelo, F. and Cotte, C., Metalloproteinases in tumor progression. Review. Invest. Clin., 47, 185–205 (2006).
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).
Bromm, B. and Lorenz, J., Neurophysiological evaluation of pain. Electroencephalogr. Clin. Neurophysiol., 107, 227–253 (1998).
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).
Dannenberg, A. J. and Subbaramaiah, K., Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell, 4, 431–436 (2003).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Kitajima, J. and Tanaka, Y., Constituents of Prunus zippeliana leaves and branches. Chem. Pharm. Bull., 41, 2007–2009 (1993).
Kohn, E. C. and Liotta, L. A., Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res., 55, 1856–1862 (1995).
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).
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).
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).
McCawley, L. J. and Matrisian, L. M., Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol. Med. Today, 6, 149–156 (2000).
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).
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).
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).
Oppenheimer, S. B., Cellular basis of cancer metastasis: A review of fundamentals and new advances. Acta Histochem., 108, 327–334 (2006).
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).
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).
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).
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).
Szatrowski, T. P. and Nathan, C. F., Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res., 51, 794–798 (1991).
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).
Tryggvason, K., Hoyhtya, M., and Salo, T., Proteolytic degradation of extracellular matrix in tumor invasion. Biochim. Biophys. Acta, 907, 191–217 (1987).
Weiss, L., Metastatic inefficiency. Adv. Cancer Res., 54, 159–211 (1990).
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).
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).
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).
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).
Author information
Authors and Affiliations
Corresponding author
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-011-0310-1