Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells
Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular end...
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| Veröffentlicht in: | Toxicology and applied pharmacology 2014-12, Vol.281 (3), p.310-316 |
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| description | Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression.
Possible mechanisms of α-TEA on inhibited angiogenesis of human umbilical vein endothelial cells.
Brief summary
In the present study, we have demonstrated that VEGF-mediated angiogenesis is significantly inhibited by α-TEA, and that this effect involves inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways related to invasion and migration. [Display omitted]
•The anti-angiogenic effect and the mechanistic action of α-TEA were investigated.•α-TEA significantly inhibited VEGF-mediated angiogenesis both in vitro and ex vivo.•α-TEA down-regulated MMP-2 via VEGFR-2-mediated FAK and p38 signaling pathways.•α-TEA up-regulated TIMP-2 and nm23-H1 expression in relation to invasion and migration.•Further studies are warranted on the anti-angiogenesis potential of α-TEA. |
| doi_str_mv | 10.1016/j.taap.2014.10.018 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_osti_</sourceid><recordid>TN_cdi_osti_scitechconnect_22439935</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0041008X14003871</els_id><sourcerecordid>1647014769</sourcerecordid><originalsourceid>FETCH-LOGICAL-c513t-deeb8ef07cf7b8bbbb2bbce70a8aad554bec86945ed289b0522101b3cf6719323</originalsourceid><addsrcrecordid>eNqNks9u1DAQxiNERZfCC3BAlhASl2zHifNP4oKqtiBV6qGAuFm2M-l6cexgJ5V4Fl6WCbvADeHLyOPffJqZz1n2gsOWA6_P99tZqWlbABeU2AJvH2UbDl2dQ1mWj7MNgOA5QPvlNHua0h4AOiH4k-y0qIRoBDSb7MfdMk0RU7LBszAw5aadyudgwrTDGBzDmWLurP-KPVMGZ2so2J5Zzz5fXl_l1veLWd_8vQ336DHZRJeeUSGbAilrh2xEs1PepjGthbtlVJ4to7bOGuXYA1ISfR-oxllKGHQuPctOBuUSPj_Gs-zT1eXHi_f5ze31h4t3N7mpeDnnPaJucYDGDI1uNZ1Ca4MNqFapvqqERtPWnaiwL9pOQ1UUtD5dmqFueFcW5Vn26qAb0mxlMnamZk3wHs0si0KUXVdWRL05UFMM3xZMsxxtWvtUHsOSJK8rQsuKt_-BioZMa-qO0OKAmkirijjIKdpRxe-Sg1xdlnu5uixXl9cc_NJ_edRf9Ij9n5LfthLw-gioRPsdovLGpr9cBw19C0Hc2wOHtN4Hi3GdHj3ZaeM6fB_sv_r4CVvVyDk</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1647014769</pqid></control><display><type>article</type><title>Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Chuang, Cheng-Hung ; Liu, Chia-Hua ; Lu, Ta-Jung ; Hu, Miao-Lin</creator><creatorcontrib>Chuang, Cheng-Hung ; Liu, Chia-Hua ; Lu, Ta-Jung ; Hu, Miao-Lin</creatorcontrib><description>Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression.
Possible mechanisms of α-TEA on inhibited angiogenesis of human umbilical vein endothelial cells.
Brief summary
In the present study, we have demonstrated that VEGF-mediated angiogenesis is significantly inhibited by α-TEA, and that this effect involves inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways related to invasion and migration. [Display omitted]
•The anti-angiogenic effect and the mechanistic action of α-TEA were investigated.•α-TEA significantly inhibited VEGF-mediated angiogenesis both in vitro and ex vivo.•α-TEA down-regulated MMP-2 via VEGFR-2-mediated FAK and p38 signaling pathways.•α-TEA up-regulated TIMP-2 and nm23-H1 expression in relation to invasion and migration.•Further studies are warranted on the anti-angiogenesis potential of α-TEA.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/j.taap.2014.10.018</identifier><identifier>PMID: 25447407</identifier><identifier>CODEN: TXAPA9</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>60 APPLIED LIFE SCIENCES ; ACETIC ACID ; ANGIOGENESIS ; Angiogenesis Inhibitors - pharmacology ; Animals ; Antimetabolites, Antineoplastic - pharmacology ; Biological and medical sciences ; Cell Adhesion - drug effects ; CELL CULTURES ; Cell invasion ; Cell migration ; Cell Movement - drug effects ; Cells, Cultured ; Chick Embryo ; CHICKENS ; Chorioallantoic Membrane - blood supply ; Chorioallantoic Membrane - drug effects ; Chorioallantoic Membrane - metabolism ; Dose-Response Relationship, Drug ; Endothelium, Vascular - cytology ; Endothelium, Vascular - drug effects ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - pathology ; ENZYME IMMUNOASSAY ; ENZYMES ; ETHERS ; FETAL MEMBRANES ; Focal Adhesion Kinase 1 - antagonists & inhibitors ; Focal Adhesion Kinase 1 - metabolism ; GROWTH FACTORS ; Human umbilical vein endothelial cells ; Human Umbilical Vein Endothelial Cells - cytology ; Humans ; IN VITRO ; INHIBITION ; MAP Kinase Signaling System - drug effects ; Matrix Metalloproteinase 2 - chemistry ; Matrix Metalloproteinase 2 - metabolism ; Matrix metalloproteinase-2 ; Medical sciences ; METASTASES ; MIGRATION ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; NEOPLASMS ; Neovascularization, Pathologic - metabolism ; Neovascularization, Pathologic - pathology ; Neovascularization, Pathologic - prevention & control ; NM23 Nucleoside Diphosphate Kinases - chemistry ; NM23 Nucleoside Diphosphate Kinases - metabolism ; PLANT GROWTH ; RECEPTORS ; Tocopherols - pharmacology ; Toxicology ; Tumors ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - antagonists & inhibitors ; Vascular Endothelial Growth Factor A - metabolism ; Vascular Endothelial Growth Factor Receptor-2 - agonists ; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors ; Vascular Endothelial Growth Factor Receptor-2 - metabolism ; VEINS ; VITAMIN E ; α-Tocopherol ether-linked acetic acid</subject><ispartof>Toxicology and applied pharmacology, 2014-12, Vol.281 (3), p.310-316</ispartof><rights>2013</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2013. Published by Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-deeb8ef07cf7b8bbbb2bbce70a8aad554bec86945ed289b0522101b3cf6719323</citedby><cites>FETCH-LOGICAL-c513t-deeb8ef07cf7b8bbbb2bbce70a8aad554bec86945ed289b0522101b3cf6719323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0041008X14003871$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=29070084$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25447407$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/22439935$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Chuang, Cheng-Hung</creatorcontrib><creatorcontrib>Liu, Chia-Hua</creatorcontrib><creatorcontrib>Lu, Ta-Jung</creatorcontrib><creatorcontrib>Hu, Miao-Lin</creatorcontrib><title>Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells</title><title>Toxicology and applied pharmacology</title><addtitle>Toxicol Appl Pharmacol</addtitle><description>Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression.
Possible mechanisms of α-TEA on inhibited angiogenesis of human umbilical vein endothelial cells.
Brief summary
In the present study, we have demonstrated that VEGF-mediated angiogenesis is significantly inhibited by α-TEA, and that this effect involves inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways related to invasion and migration. [Display omitted]
•The anti-angiogenic effect and the mechanistic action of α-TEA were investigated.•α-TEA significantly inhibited VEGF-mediated angiogenesis both in vitro and ex vivo.•α-TEA down-regulated MMP-2 via VEGFR-2-mediated FAK and p38 signaling pathways.•α-TEA up-regulated TIMP-2 and nm23-H1 expression in relation to invasion and migration.•Further studies are warranted on the anti-angiogenesis potential of α-TEA.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>ACETIC ACID</subject><subject>ANGIOGENESIS</subject><subject>Angiogenesis Inhibitors - pharmacology</subject><subject>Animals</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Adhesion - drug effects</subject><subject>CELL CULTURES</subject><subject>Cell invasion</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Cells, Cultured</subject><subject>Chick Embryo</subject><subject>CHICKENS</subject><subject>Chorioallantoic Membrane - blood supply</subject><subject>Chorioallantoic Membrane - drug effects</subject><subject>Chorioallantoic Membrane - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Endothelium, Vascular - cytology</subject><subject>Endothelium, Vascular - drug effects</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Endothelium, Vascular - pathology</subject><subject>ENZYME IMMUNOASSAY</subject><subject>ENZYMES</subject><subject>ETHERS</subject><subject>FETAL MEMBRANES</subject><subject>Focal Adhesion Kinase 1 - antagonists & inhibitors</subject><subject>Focal Adhesion Kinase 1 - metabolism</subject><subject>GROWTH FACTORS</subject><subject>Human umbilical vein endothelial cells</subject><subject>Human Umbilical Vein Endothelial Cells - cytology</subject><subject>Humans</subject><subject>IN VITRO</subject><subject>INHIBITION</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Matrix Metalloproteinase 2 - chemistry</subject><subject>Matrix Metalloproteinase 2 - metabolism</subject><subject>Matrix metalloproteinase-2</subject><subject>Medical sciences</subject><subject>METASTASES</subject><subject>MIGRATION</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>NEOPLASMS</subject><subject>Neovascularization, Pathologic - metabolism</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>Neovascularization, Pathologic - prevention & control</subject><subject>NM23 Nucleoside Diphosphate Kinases - chemistry</subject><subject>NM23 Nucleoside Diphosphate Kinases - metabolism</subject><subject>PLANT GROWTH</subject><subject>RECEPTORS</subject><subject>Tocopherols - pharmacology</subject><subject>Toxicology</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - agonists</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - metabolism</subject><subject>VEINS</subject><subject>VITAMIN E</subject><subject>α-Tocopherol ether-linked acetic acid</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNks9u1DAQxiNERZfCC3BAlhASl2zHifNP4oKqtiBV6qGAuFm2M-l6cexgJ5V4Fl6WCbvADeHLyOPffJqZz1n2gsOWA6_P99tZqWlbABeU2AJvH2UbDl2dQ1mWj7MNgOA5QPvlNHua0h4AOiH4k-y0qIRoBDSb7MfdMk0RU7LBszAw5aadyudgwrTDGBzDmWLurP-KPVMGZ2so2J5Zzz5fXl_l1veLWd_8vQ336DHZRJeeUSGbAilrh2xEs1PepjGthbtlVJ4to7bOGuXYA1ISfR-oxllKGHQuPctOBuUSPj_Gs-zT1eXHi_f5ze31h4t3N7mpeDnnPaJucYDGDI1uNZ1Ca4MNqFapvqqERtPWnaiwL9pOQ1UUtD5dmqFueFcW5Vn26qAb0mxlMnamZk3wHs0si0KUXVdWRL05UFMM3xZMsxxtWvtUHsOSJK8rQsuKt_-BioZMa-qO0OKAmkirijjIKdpRxe-Sg1xdlnu5uixXl9cc_NJ_edRf9Ij9n5LfthLw-gioRPsdovLGpr9cBw19C0Hc2wOHtN4Hi3GdHj3ZaeM6fB_sv_r4CVvVyDk</recordid><startdate>20141215</startdate><enddate>20141215</enddate><creator>Chuang, Cheng-Hung</creator><creator>Liu, Chia-Hua</creator><creator>Lu, Ta-Jung</creator><creator>Hu, Miao-Lin</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</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>7U7</scope><scope>C1K</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20141215</creationdate><title>Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells</title><author>Chuang, Cheng-Hung ; Liu, Chia-Hua ; Lu, Ta-Jung ; Hu, Miao-Lin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-deeb8ef07cf7b8bbbb2bbce70a8aad554bec86945ed289b0522101b3cf6719323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>ACETIC ACID</topic><topic>ANGIOGENESIS</topic><topic>Angiogenesis Inhibitors - pharmacology</topic><topic>Animals</topic><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Adhesion - drug effects</topic><topic>CELL CULTURES</topic><topic>Cell invasion</topic><topic>Cell migration</topic><topic>Cell Movement - drug effects</topic><topic>Cells, Cultured</topic><topic>Chick Embryo</topic><topic>CHICKENS</topic><topic>Chorioallantoic Membrane - blood supply</topic><topic>Chorioallantoic Membrane - drug effects</topic><topic>Chorioallantoic Membrane - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Endothelium, Vascular - cytology</topic><topic>Endothelium, Vascular - drug effects</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Endothelium, Vascular - pathology</topic><topic>ENZYME IMMUNOASSAY</topic><topic>ENZYMES</topic><topic>ETHERS</topic><topic>FETAL MEMBRANES</topic><topic>Focal Adhesion Kinase 1 - antagonists & inhibitors</topic><topic>Focal Adhesion Kinase 1 - metabolism</topic><topic>GROWTH FACTORS</topic><topic>Human umbilical vein endothelial cells</topic><topic>Human Umbilical Vein Endothelial Cells - cytology</topic><topic>Humans</topic><topic>IN VITRO</topic><topic>INHIBITION</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Matrix Metalloproteinase 2 - chemistry</topic><topic>Matrix Metalloproteinase 2 - metabolism</topic><topic>Matrix metalloproteinase-2</topic><topic>Medical sciences</topic><topic>METASTASES</topic><topic>MIGRATION</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>NEOPLASMS</topic><topic>Neovascularization, Pathologic - metabolism</topic><topic>Neovascularization, Pathologic - pathology</topic><topic>Neovascularization, Pathologic - prevention & control</topic><topic>NM23 Nucleoside Diphosphate Kinases - chemistry</topic><topic>NM23 Nucleoside Diphosphate Kinases - metabolism</topic><topic>PLANT GROWTH</topic><topic>RECEPTORS</topic><topic>Tocopherols - pharmacology</topic><topic>Toxicology</topic><topic>Tumors</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - antagonists & inhibitors</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - agonists</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - metabolism</topic><topic>VEINS</topic><topic>VITAMIN E</topic><topic>α-Tocopherol ether-linked acetic acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chuang, Cheng-Hung</creatorcontrib><creatorcontrib>Liu, Chia-Hua</creatorcontrib><creatorcontrib>Lu, Ta-Jung</creatorcontrib><creatorcontrib>Hu, Miao-Lin</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chuang, Cheng-Hung</au><au>Liu, Chia-Hua</au><au>Lu, Ta-Jung</au><au>Hu, Miao-Lin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>2014-12-15</date><risdate>2014</risdate><volume>281</volume><issue>3</issue><spage>310</spage><epage>316</epage><pages>310-316</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><abstract>Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression.
Possible mechanisms of α-TEA on inhibited angiogenesis of human umbilical vein endothelial cells.
Brief summary
In the present study, we have demonstrated that VEGF-mediated angiogenesis is significantly inhibited by α-TEA, and that this effect involves inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways related to invasion and migration. [Display omitted]
•The anti-angiogenic effect and the mechanistic action of α-TEA were investigated.•α-TEA significantly inhibited VEGF-mediated angiogenesis both in vitro and ex vivo.•α-TEA down-regulated MMP-2 via VEGFR-2-mediated FAK and p38 signaling pathways.•α-TEA up-regulated TIMP-2 and nm23-H1 expression in relation to invasion and migration.•Further studies are warranted on the anti-angiogenesis potential of α-TEA.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>25447407</pmid><doi>10.1016/j.taap.2014.10.018</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0041-008X |
| ispartof | Toxicology and applied pharmacology, 2014-12, Vol.281 (3), p.310-316 |
| issn | 0041-008X 1096-0333 |
| language | eng |
| recordid | cdi_osti_scitechconnect_22439935 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 60 APPLIED LIFE SCIENCES ACETIC ACID ANGIOGENESIS Angiogenesis Inhibitors - pharmacology Animals Antimetabolites, Antineoplastic - pharmacology Biological and medical sciences Cell Adhesion - drug effects CELL CULTURES Cell invasion Cell migration Cell Movement - drug effects Cells, Cultured Chick Embryo CHICKENS Chorioallantoic Membrane - blood supply Chorioallantoic Membrane - drug effects Chorioallantoic Membrane - metabolism Dose-Response Relationship, Drug Endothelium, Vascular - cytology Endothelium, Vascular - drug effects Endothelium, Vascular - metabolism Endothelium, Vascular - pathology ENZYME IMMUNOASSAY ENZYMES ETHERS FETAL MEMBRANES Focal Adhesion Kinase 1 - antagonists & inhibitors Focal Adhesion Kinase 1 - metabolism GROWTH FACTORS Human umbilical vein endothelial cells Human Umbilical Vein Endothelial Cells - cytology Humans IN VITRO INHIBITION MAP Kinase Signaling System - drug effects Matrix Metalloproteinase 2 - chemistry Matrix Metalloproteinase 2 - metabolism Matrix metalloproteinase-2 Medical sciences METASTASES MIGRATION Multiple tumors. Solid tumors. Tumors in childhood (general aspects) NEOPLASMS Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - pathology Neovascularization, Pathologic - prevention & control NM23 Nucleoside Diphosphate Kinases - chemistry NM23 Nucleoside Diphosphate Kinases - metabolism PLANT GROWTH RECEPTORS Tocopherols - pharmacology Toxicology Tumors Vascular endothelial growth factor Vascular Endothelial Growth Factor A - antagonists & inhibitors Vascular Endothelial Growth Factor A - metabolism Vascular Endothelial Growth Factor Receptor-2 - agonists Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 - metabolism VEINS VITAMIN E α-Tocopherol ether-linked acetic acid |
| title | Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells |
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