Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases
Flavonoids have been proposed to act as chemopreventive agents in numerous epidemiological studies and have been shown to inhibit angiogenesis and proliferation of tumor cells and endothelial cells in vitro. Angiogenesis requires tightly controlled extracellular matrix degradation mediated by extrac...
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Veröffentlicht in: | Journal of cellular biochemistry 2003-06, Vol.89 (3), p.529-538 |
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description | Flavonoids have been proposed to act as chemopreventive agents in numerous epidemiological studies and have been shown to inhibit angiogenesis and proliferation of tumor cells and endothelial cells in vitro. Angiogenesis requires tightly controlled extracellular matrix degradation mediated by extracellular proteolytic enzymes including matrix metalloproteinases (MMPs) and serine proteases, in particular, the urokinase‐type plasminogen activator (uPA)‐plasmin system. In this study, we have investigated the antiangiogenic mechanism of the flavonoids, genistein, apigenin, and 3‐hydroxyflavone in a human umbilical vein endothelial cell (HUVEC) model. The stimulation of serum‐starved HUVECs with vascular endothelial growth factor/basic fibroblast growth factor (VEGF/bFGF) caused marked increase in MMP‐1 production and induced the pro‐MMP‐2 activation accompanied by the increase in MT1‐MMP expression. However, pretreatment with flavonoids before VEGF/bFGF stimulation completely abolished the VEGF/bFGF‐stimulated increase in MMP‐1 and MT1‐MMP expression and pro‐MMP‐2 activation. Genistein blocked VEGF/bFGF‐stimulated increase in TIMP‐1 expression and decrease in TIMP‐2 expression. Apigenin and 3‐hydroxyflavone further decreased TIMP‐1 expression below basal level and completely abolished TIMP‐2 expression. VEGF and bFGF stimulation also significantly induced uPA expression, most strikingly the level of 33 kDa uPA, and increased the expression of PA inhibitor (PAI)‐1. Genistein, apigenin, and 3‐hydroxyflavone effectively blocked the generation of 33 kDa uPA, and further decreased the activity of the 55 kDa uPA and the expression of PAI‐1 below the basal level. In conclusion, these data suggest that genistein, apigenin, and 3‐hydroxyflavone inhibit in vitro angiogenesis, in part via preventing VEGF/bFGF‐induced MMP‐1 and uPA expression and the activation of pro‐MMP‐2, and via modulating their inhibitors, TIMP‐1 and ‐2, and PAI‐1. © 2003 Wiley‐Liss, Inc. |
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Angiogenesis requires tightly controlled extracellular matrix degradation mediated by extracellular proteolytic enzymes including matrix metalloproteinases (MMPs) and serine proteases, in particular, the urokinase‐type plasminogen activator (uPA)‐plasmin system. In this study, we have investigated the antiangiogenic mechanism of the flavonoids, genistein, apigenin, and 3‐hydroxyflavone in a human umbilical vein endothelial cell (HUVEC) model. The stimulation of serum‐starved HUVECs with vascular endothelial growth factor/basic fibroblast growth factor (VEGF/bFGF) caused marked increase in MMP‐1 production and induced the pro‐MMP‐2 activation accompanied by the increase in MT1‐MMP expression. However, pretreatment with flavonoids before VEGF/bFGF stimulation completely abolished the VEGF/bFGF‐stimulated increase in MMP‐1 and MT1‐MMP expression and pro‐MMP‐2 activation. Genistein blocked VEGF/bFGF‐stimulated increase in TIMP‐1 expression and decrease in TIMP‐2 expression. Apigenin and 3‐hydroxyflavone further decreased TIMP‐1 expression below basal level and completely abolished TIMP‐2 expression. VEGF and bFGF stimulation also significantly induced uPA expression, most strikingly the level of 33 kDa uPA, and increased the expression of PA inhibitor (PAI)‐1. Genistein, apigenin, and 3‐hydroxyflavone effectively blocked the generation of 33 kDa uPA, and further decreased the activity of the 55 kDa uPA and the expression of PAI‐1 below the basal level. In conclusion, these data suggest that genistein, apigenin, and 3‐hydroxyflavone inhibit in vitro angiogenesis, in part via preventing VEGF/bFGF‐induced MMP‐1 and uPA expression and the activation of pro‐MMP‐2, and via modulating their inhibitors, TIMP‐1 and ‐2, and PAI‐1. © 2003 Wiley‐Liss, Inc.</description><identifier>ISSN: 0730-2312</identifier><identifier>EISSN: 1097-4644</identifier><identifier>DOI: 10.1002/jcb.10543</identifier><identifier>PMID: 12761886</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>3-hydroxyflavone ; antiangiogenesis ; apigenin ; Blotting, Western ; Cells, Cultured ; Culture Media, Conditioned ; Endothelial Growth Factors - physiology ; Enzyme-Linked Immunosorbent Assay ; Fibroblast Growth Factor 2 - physiology ; Flavonoids - pharmacology ; genistein ; Humans ; Hydrolysis ; In Vitro Techniques ; Intercellular Signaling Peptides and Proteins - physiology ; Lymphokines - physiology ; matrix metalloproteinase ; Matrix Metalloproteinases - metabolism ; Neovascularization, Pathologic - prevention & control ; Plasminogen Activator Inhibitor 1 - metabolism ; urokinase-type plasminogen activator ; Urokinase-Type Plasminogen Activator - antagonists & inhibitors ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors</subject><ispartof>Journal of cellular biochemistry, 2003-06, Vol.89 (3), p.529-538</ispartof><rights>Copyright © 2003 Wiley‐Liss, Inc.</rights><rights>Copyright 2003 Wiley-Liss, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3403-8fda33bae0e7b7aa7f44227f851e18eedde689a3215a12c54c98a93d0bab8ae13</citedby><cites>FETCH-LOGICAL-c3403-8fda33bae0e7b7aa7f44227f851e18eedde689a3215a12c54c98a93d0bab8ae13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcb.10543$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcb.10543$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12761886$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Myoung H.</creatorcontrib><title>Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases</title><title>Journal of cellular biochemistry</title><addtitle>J. Cell. Biochem</addtitle><description>Flavonoids have been proposed to act as chemopreventive agents in numerous epidemiological studies and have been shown to inhibit angiogenesis and proliferation of tumor cells and endothelial cells in vitro. Angiogenesis requires tightly controlled extracellular matrix degradation mediated by extracellular proteolytic enzymes including matrix metalloproteinases (MMPs) and serine proteases, in particular, the urokinase‐type plasminogen activator (uPA)‐plasmin system. In this study, we have investigated the antiangiogenic mechanism of the flavonoids, genistein, apigenin, and 3‐hydroxyflavone in a human umbilical vein endothelial cell (HUVEC) model. The stimulation of serum‐starved HUVECs with vascular endothelial growth factor/basic fibroblast growth factor (VEGF/bFGF) caused marked increase in MMP‐1 production and induced the pro‐MMP‐2 activation accompanied by the increase in MT1‐MMP expression. However, pretreatment with flavonoids before VEGF/bFGF stimulation completely abolished the VEGF/bFGF‐stimulated increase in MMP‐1 and MT1‐MMP expression and pro‐MMP‐2 activation. Genistein blocked VEGF/bFGF‐stimulated increase in TIMP‐1 expression and decrease in TIMP‐2 expression. Apigenin and 3‐hydroxyflavone further decreased TIMP‐1 expression below basal level and completely abolished TIMP‐2 expression. VEGF and bFGF stimulation also significantly induced uPA expression, most strikingly the level of 33 kDa uPA, and increased the expression of PA inhibitor (PAI)‐1. Genistein, apigenin, and 3‐hydroxyflavone effectively blocked the generation of 33 kDa uPA, and further decreased the activity of the 55 kDa uPA and the expression of PAI‐1 below the basal level. In conclusion, these data suggest that genistein, apigenin, and 3‐hydroxyflavone inhibit in vitro angiogenesis, in part via preventing VEGF/bFGF‐induced MMP‐1 and uPA expression and the activation of pro‐MMP‐2, and via modulating their inhibitors, TIMP‐1 and ‐2, and PAI‐1. © 2003 Wiley‐Liss, Inc.</description><subject>3-hydroxyflavone</subject><subject>antiangiogenesis</subject><subject>apigenin</subject><subject>Blotting, Western</subject><subject>Cells, Cultured</subject><subject>Culture Media, Conditioned</subject><subject>Endothelial Growth Factors - physiology</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Fibroblast Growth Factor 2 - physiology</subject><subject>Flavonoids - pharmacology</subject><subject>genistein</subject><subject>Humans</subject><subject>Hydrolysis</subject><subject>In Vitro Techniques</subject><subject>Intercellular Signaling Peptides and Proteins - physiology</subject><subject>Lymphokines - physiology</subject><subject>matrix metalloproteinase</subject><subject>Matrix Metalloproteinases - metabolism</subject><subject>Neovascularization, Pathologic - prevention & control</subject><subject>Plasminogen Activator Inhibitor 1 - metabolism</subject><subject>urokinase-type plasminogen activator</subject><subject>Urokinase-Type Plasminogen Activator - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor A</subject><subject>Vascular Endothelial Growth Factors</subject><issn>0730-2312</issn><issn>1097-4644</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMtOwzAQRS0EgvJY8AMoKyQWoX4kcbKEQspLsOG1s8bxJBjSBOwU6N-T0gIrVjManXtHOoTsMnrIKOXD50L3SxyJFTJgNJNhlETRKhlQKWjIBeMbZNP7Z0pplgm-TjYYlwlL02RAqryG97ZprfGBbZ6stl1wfzrOhzof56FtzLRAE0BT2bbCBr2dY8G77Vwb6NlPxDZV0D1hMIHO2c_QYOXAzI-vru0QPPptslZC7XFnObfIXX56OzoLr27G56Ojq7AQERVhWhoQQgNSlFoCyDKKOJdlGjNkKaIxmKQZCM5iYLyIoyJLIROGatApIBNbZH_R239-m6Lv1MT6AusaGmynXknBMxHHtAcPFmDhWu8dlurV2Qm4mWJUza2q3qr6ttqze8vSqZ6g-SOXGntguAA-bI2z_5vUxej4pzJcJKzv8PM3Ae5FJVLIWD1cj9VjTi_zy5OROhNf-7ORjg</recordid><startdate>20030601</startdate><enddate>20030601</enddate><creator>Kim, Myoung H.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20030601</creationdate><title>Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases</title><author>Kim, Myoung H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3403-8fda33bae0e7b7aa7f44227f851e18eedde689a3215a12c54c98a93d0bab8ae13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>3-hydroxyflavone</topic><topic>antiangiogenesis</topic><topic>apigenin</topic><topic>Blotting, Western</topic><topic>Cells, Cultured</topic><topic>Culture Media, Conditioned</topic><topic>Endothelial Growth Factors - physiology</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Fibroblast Growth Factor 2 - physiology</topic><topic>Flavonoids - pharmacology</topic><topic>genistein</topic><topic>Humans</topic><topic>Hydrolysis</topic><topic>In Vitro Techniques</topic><topic>Intercellular Signaling Peptides and Proteins - physiology</topic><topic>Lymphokines - physiology</topic><topic>matrix metalloproteinase</topic><topic>Matrix Metalloproteinases - metabolism</topic><topic>Neovascularization, Pathologic - prevention & control</topic><topic>Plasminogen Activator Inhibitor 1 - metabolism</topic><topic>urokinase-type plasminogen activator</topic><topic>Urokinase-Type Plasminogen Activator - antagonists & inhibitors</topic><topic>Vascular Endothelial Growth Factor A</topic><topic>Vascular Endothelial Growth Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Myoung H.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of cellular biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Myoung H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases</atitle><jtitle>Journal of cellular biochemistry</jtitle><addtitle>J. Cell. Biochem</addtitle><date>2003-06-01</date><risdate>2003</risdate><volume>89</volume><issue>3</issue><spage>529</spage><epage>538</epage><pages>529-538</pages><issn>0730-2312</issn><eissn>1097-4644</eissn><abstract>Flavonoids have been proposed to act as chemopreventive agents in numerous epidemiological studies and have been shown to inhibit angiogenesis and proliferation of tumor cells and endothelial cells in vitro. Angiogenesis requires tightly controlled extracellular matrix degradation mediated by extracellular proteolytic enzymes including matrix metalloproteinases (MMPs) and serine proteases, in particular, the urokinase‐type plasminogen activator (uPA)‐plasmin system. In this study, we have investigated the antiangiogenic mechanism of the flavonoids, genistein, apigenin, and 3‐hydroxyflavone in a human umbilical vein endothelial cell (HUVEC) model. The stimulation of serum‐starved HUVECs with vascular endothelial growth factor/basic fibroblast growth factor (VEGF/bFGF) caused marked increase in MMP‐1 production and induced the pro‐MMP‐2 activation accompanied by the increase in MT1‐MMP expression. However, pretreatment with flavonoids before VEGF/bFGF stimulation completely abolished the VEGF/bFGF‐stimulated increase in MMP‐1 and MT1‐MMP expression and pro‐MMP‐2 activation. Genistein blocked VEGF/bFGF‐stimulated increase in TIMP‐1 expression and decrease in TIMP‐2 expression. Apigenin and 3‐hydroxyflavone further decreased TIMP‐1 expression below basal level and completely abolished TIMP‐2 expression. VEGF and bFGF stimulation also significantly induced uPA expression, most strikingly the level of 33 kDa uPA, and increased the expression of PA inhibitor (PAI)‐1. Genistein, apigenin, and 3‐hydroxyflavone effectively blocked the generation of 33 kDa uPA, and further decreased the activity of the 55 kDa uPA and the expression of PAI‐1 below the basal level. In conclusion, these data suggest that genistein, apigenin, and 3‐hydroxyflavone inhibit in vitro angiogenesis, in part via preventing VEGF/bFGF‐induced MMP‐1 and uPA expression and the activation of pro‐MMP‐2, and via modulating their inhibitors, TIMP‐1 and ‐2, and PAI‐1. © 2003 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>12761886</pmid><doi>10.1002/jcb.10543</doi><tpages>10</tpages></addata></record> |
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subjects | 3-hydroxyflavone antiangiogenesis apigenin Blotting, Western Cells, Cultured Culture Media, Conditioned Endothelial Growth Factors - physiology Enzyme-Linked Immunosorbent Assay Fibroblast Growth Factor 2 - physiology Flavonoids - pharmacology genistein Humans Hydrolysis In Vitro Techniques Intercellular Signaling Peptides and Proteins - physiology Lymphokines - physiology matrix metalloproteinase Matrix Metalloproteinases - metabolism Neovascularization, Pathologic - prevention & control Plasminogen Activator Inhibitor 1 - metabolism urokinase-type plasminogen activator Urokinase-Type Plasminogen Activator - antagonists & inhibitors Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors |
title | Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases |
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