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http://dx.doi.org/10.4062/biomolther.2009.17.4.422

Anti-Invasive and Anti-Angiogenic Effects of Xanthohumol and Its Synthetic Derivatives  

Kim, Jung-Ae (College of Pharmacy, Yeungnam University)
Kang, You-Ra (College of Pharmacy, Yeungnam University)
Thapa, Dinesh (College of Pharmacy, Yeungnam University)
Lee, Jong-Suk (College of Pharmacy, Yeungnam University)
Park, Min-A (College of Pharmacy, Yeungnam University)
Lee, Kyung-Hee (Department of Food and Nutrition, Yeungnam University)
Lyoo, Won-Seok (School of Testiles, Yeungnam University)
Lee, Yong-Rok (School of Chemical Engineering and Technology, Yeungnam University)
Publication Information
Biomolecules & Therapeutics / v.17, no.4, 2009 , pp. 422-429 More about this Journal
Abstract
Invasion and metastasis is the main cause of cancer mortality. Angiogenesis is a prerequisite for the tumor growth and metastasis. Matrix metalloproteinases (MMPs) are the key enzymes playing in the invasive growth and metastasis of cancer as well as angiogenesis. Xanthohumol, a prenylated chalcone of the Hop plant (Humulus lupulus L), has been reported to suppress cancer invasion and angiogenesis. In the present study, we investigated the antiinvasive effects of xanthohumol (1) and its synthetic derivatives, 4'-O-methylxanthohumol SEM ether (2), xanthohumol C (3), and xanthohumol C MOM ether (4) in relation to MMP expression in HT-1080 human fibrosarcoma cells. The compound 1 and its derivative, 3 and 4, significantly inhibited serum-induced HT-1080 cell invasion, and 12-O-tetradecanoylphorbol-13-acetate (TPA)-enhanced activity and expression level of MMP-2 and MMP-9 in a concentration-dependant manner. In addition, they inhibited TPA-enhanced expression of MT1-MMP with relatively weak inhibition in tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 level. The compound 1 significantly decreased the cell viability, whereas the derivatives, 2 and 3 showed no cytotoxicity, and compound 4 showed slight cytotoxicity in the cells. Furthermore, in a chick chorioallantoic membrane (CAM) assay, the derivatives 3 and 4 dose-dependently suppressed vascular endothelial growth factor (VEGF)-induced angiogenesis, which is similar to that of compound 1. Taken together, the results indicate that compounds 3 and 4 may be valuable anti-angiogenic agents in the treatment of chronic diseases such as cancer and inflammation working through suppression of MMP-2 and MMP-9.
Keywords
Xanthohumol; Xanthohumol C; Cancer cell invasion; Angiogenesis; Matrix metalloproteinase;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
Times Cited By Web Of Science : 1  (Related Records In Web of Science)
Times Cited By SCOPUS : 3
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1 Plazar, J., Zegura, B., Lah, T. T. and Filipic, M. (2007). Protective effects of xanthohumol against the genotoxicity of benzo(a)pyrene (BaP), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and tert-butyl hydroperoxide (t-BOOH) in HepG2 human hepatoma cells. Mutat. Res. 632, 1-8.   DOI   ScienceOn
2 Thapa, D., Lee, J. S., Park, S. Y., Bae, Y. H., Bae, S. K., Kwon, J. B., Kim, K. J., Kwak, M. K., Park, Y. J., Choi, H. G. and Kim, J. A. (2008). Clotrimazole ameliorates intestinal inflammation and abnormal angiogenesis by inhibiting interleukin-8 expression through a nuclear factor-${\kappa}B$- dependent manner. J. Pharmacol. Exp. Ther. 327, 353-364.   DOI   ScienceOn
3 Miranda, C. L., Aponso, G. L. M., Stevens, J. F., Deinzer, M. L. and Buhler, D. R. (2000a). Prenylated chalcones and flavanones as inducers of quinone reductase in mouse Hepa 1x1C7 cells. Cancer Lett. 149, 21-29.   DOI   ScienceOn
4 Miranda, C. L., Stevens, J. F., Helmrich, A., Henderson, M. C., Rodriguez, R. J., Yang, Y. H., Deinzer, M. L., Barnes, D. W. and Buhler, D. R. (1999). Antiproliferative and cytotoxic effects of prenylated flavonoids from hops (Humulus lupulus) in human cancer cell lines. Food Chem. Toxicol. 37, 271-285.   DOI   ScienceOn
5 Park, B. C., Thapa, D., Lee, Y. S., Kwak, M. K., Lee, E. S., Choi, H. G., Yong, C. S. and Kim, J. A. (2007). 1-Furan-2-yl-3- pyridin-2-ylpropenone inhibits the invasion and migration of HT1080 human fibrosarcoma cells through the inhibition of proMMP-2 activation and down regulation of MMP-9 and MT1-MMP. Eur. J. Pharmacol. 567, 193-197.   DOI   ScienceOn
6 Johnson, L. L., Dyer, R. and Hupe, D. J. (1998). Matrix metalloproteinases. Curr. Opin. Chem. Biol. 2, 466-471.   DOI   ScienceOn
7 Lee, Y. R., Li, X., Lee, S. W., Yong, C. S., Hong, M. R. and Lyoo, W. S. (2008). ChemInform abstract: concise total synthesis of biologically interesting prenylated chalcone natural products: 4-O-Methylxanthohumol (VIII), xanthohumol E (XII), and sericone (XIII). Bull. Korean Chem. Soc. 29, 1205-1210.   DOI   ScienceOn
8 Halin, C. and Detmar, M. (2008). Chapter 1. Inflammation, angiogenesis, and lymphangiogenesis. Methods Enzymol. 445, 1-25.   DOI   ScienceOn
9 Henderson, M. C., Miranda, C. L., Stevens, J. F., Deinzer, M. L. and Buhler, D. R. (2000). In vitro inhibition of human P450 enzymes by prenylated flavonoids from hops, Humulus lupulus. Xenobiotica 30, 235-251.   DOI
10 John, A. and Tuszynski, G. (2001). The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol. Oncol. Res. 7, 14-23.   DOI   ScienceOn
11 Vanhoecke, B., Derycke, L., Van Marck, V., Depypere, H., De Keukeleire, D. and Bracke, M. (2005). Antiinvasive effect of xanthohumol, a prenylated chalcone present in hops (Humulus lupulus L.) and beer. Int. J. Cancer. 117, 889-895.   DOI   ScienceOn
12 Westermarck, J. and Kahari, V. M. (1999). Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 13, 781-792.   DOI
13 Wittekind, C. and Neid, M. (2005) Cancer invasion and metastasis. Oncology 69, 14-16.   DOI   ScienceOn
14 Woessner, Jr. J. F. (1991). Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 5, 2145-2154.
15 Mannello, F. and Gazzanelli, G. (2001). Tissue inhibitors of metalloproteinases and programmed cell death: conundrums, controversies and potential implications. Apoptosis 6, 479-482.   DOI   ScienceOn
16 Yang, S. F., Yang, W. E., Kuo, W. H., Chang, H. R., Chu, S. C. and Hsieh, Y. S. (2008). Antimetastatic potentials of flavones on oral cancer cell via an inhibition of matrix-degrading proteases. Arch. Oral. Biol. 53, 287-294.   DOI   ScienceOn
17 Park, B. C., Park, S. Y., Lee, J. S., Mousa, S. A., Kim, J. T., Kwak, M. K., Kang, K. W., Lee, E. S., Choi, H. G., Yong, C. S. and Kim, J. A. (2009). The anti-angiogenic effects of 1-furan-2-yl-3-pyridin-2-yl-propenone are mediated through the suppression of both VEGF production and VEGFinduced signaling. Vascul. Pharmacol. 50, 123-131.   DOI   ScienceOn
18 Stevens, J. F., Miranda, C. L., Frei, B. and Buhler, D. R. (2003). Inhibition of Peroxynitrite-Mediated LDL Oxidation by Prenylated Flavonoids: The $\alpha$,$\beta$-Unsaturated Keto Functionality of 2'-Hydroxychalcones as a Novel Antioxidant Pharmacophore. Chem. Res. Toxicol. 16, 1277-1286.   DOI   ScienceOn
19 Vogel, S., Ohmayer, S., Brunner, G. and Heilmann, J. (2008). Natural and non-natural prenylated chalcones: synthesis, cytotoxicity and anti-oxidative activity. Bioorg. Med. Chem. 16, 4286-4293.   DOI   ScienceOn
20 McCawley, L. J. and Matrisian, L. M. (2000). Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol. Med. Today 6, 149-156.   DOI   ScienceOn
21 Barbara, V., Lara, D., Veerle Van, M., Herman, D., Denis De, K. and Marc, B. (2005). Antiinvasive effect of xanthohumol, a prenylated chalcone present in hops (Humulus lupulus L.) and beer. Int. J. Cancer. 117, 889-895.   DOI   ScienceOn
22 Monteghirfo, S., Tosetti, F., Ambrosini, C., Stigliani, S., Pozzi, S., Frassoni, F., Fassina, G., Soverini, S., Albini, A. and Ferrari, N. (2008). Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-$\kappa$B and p53 modulation. Mol. Cancer Ther. 7, 2692-2702.   DOI   ScienceOn
23 Mun-Bryce, S. and Rosenberg, G. A. (1998). Gelatinase B modulates selective opening of the blood-brain barrier during inflammation. J. Cerebral Blood Flow Metab. 18, 1163-1172.   DOI
24 Pan, L., Becker, H. and Gerhäuser, C. (2005). Xanthohumol induces apoptosis in cultured 40-16 human colon cancer cells by activation of the death receptor- and mitochondrial pathway. Mol. Nutr. Food Res. 49, 837-843.   DOI   ScienceOn
25 Lee, Y. R. and Xia, L. (2007). ChemInform abstract: concise total synthesis of biologically interesting pyranochalcone natural products: citrunobin (Ia), boesenbergin A (Ib), boesenbergin B (IIa), xanthohumol C (IIb), and glabrachromene (IIc). Synthesis 20, 3240-3246.   DOI   ScienceOn
26 Herron, G. S., Banda, M. J., Clark, E. J., Gavrilovic, J. and Werb, Z. (1986). Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors. The Journal of Biological Chemistry. 25, 2814-2818.
27 Miranda, C. L., Stevens, J. F., Ivanov, V., McCall, M., Frei, B., Deinzer, M. L. and Buhler, D. R. (2000b). Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro. J. Agric. Food Chem. 48, 3876-3884.   DOI   ScienceOn
28 Nikolic, D., Li, Y., Chadwick, L. R., Pauli, G. F. and van Breemen, R. B. (2005). Metabolism of xanthohumol and isoxanthohumol, prenylated flavonoids from hops (Humulus lupulus L.), by human liver microsomes. J. Mass Spectrom. 40, 289-299.   DOI   ScienceOn
29 Gerhauser, C., Alt, A., Heiss, E., Gamal-Eldeen, A., Klimo, K., Knauft, J., Neumann, I., Scherf, H. R., Frank, N., Bartsch, H. and Becker, H. (2002). Cancer chemopreventive activity of Xanthohumol, a natural product derived from hop. Mol. Cancer Ther. 1, 959-969.
30 Lee, K. S., Jin, S. M., Lee, H. and Lee, Y. C. (2004). Imbalance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in toluene diisocyanate-induced asthma. Clin. Exp. Allergy. 34, 276-284.   DOI
31 Liabakk, N. B., Talbot, I., Smith, R. A., Wilkinson, K. and Balkwill, F. (1996). Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res. 56, 190-196.
32 Galis, Z. S., Sukhova, G. K., Lark, M. W. and Libby, P. (1994). Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Invest. 94, 2493-2503.   DOI   ScienceOn
33 Albini, A., Dell'Eva, R., Vené, R., Ferrari, N., Buhler, D. R., Noonan, D. M. and Fassina, G. (2006). Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF-kappaB and Akt as targets. FASEB J. 20, 527-529.   DOI   ScienceOn
34 Bernardo, M. M. and Fridman, R. (2003). TIMP-2 (tissue inhibitor of metalloproteinase-2) regulates MMP-2 (matrix metalloproteinase- 2) activity in the extracellular environment after pro-MMP-2 activation by MT1 (membrane type 1)-MMP. Biochem. J. 374, 739-745.   DOI   ScienceOn
35 Delmulle, L., Bellahcéne, A., Dhooge, W., Comhaire, F., Roelens, F., Huvaere, K., Heyerick, A., Castronovo, V. and De Keukeleire, D. (2006). Anti-proliferative properties of prenylated flavonoids from hops (Humulus lupulus L.) in human prostate cancer cell lines. Phytomedicine 13, 732-734.   DOI   ScienceOn
36 Edwards, J. G., McLaren, J., Jones, J. L., Waller, D. A. and O'Byrne, K. J. (2003). Matrix metalloproteinases 2 and 9 (gelatinases A and B) expression in malignant mesothelioma and benign pleura. Brit. J. Cancer 88, 1553-1559.   DOI   ScienceOn