The marine-derived oligosaccharide sulfate (MdOS), a novel multiple tyrosine kinase inhibitor, combats tumor angiogenesis both in vitro and in vivo
Despite the emerging success of multi-targeted protein tyrosine kinase (PTK) inhibitors in cancer therapy, significant side effects and resistance concerns seems to be avoided unlikely. The aim of the present study was to identify novel multi-targeting PTK inhibitors. The kinase enzymatic activities...
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| creator | Ma, Jingui Xin, Xianliang Meng, Linghua Tong, Linjiang Lin, Liping Geng, Meiyu Ding, Jian |
| description | Despite the emerging success of multi-targeted protein tyrosine kinase (PTK) inhibitors in cancer therapy, significant side effects and resistance concerns seems to be avoided unlikely. The aim of the present study was to identify novel multi-targeting PTK inhibitors. The kinase enzymatic activities were measured by enzyme-linked immunosorbent assay (ELISA). The antiproliferative activities in human microvascular endothelial cells (HMECs) were evaluated by sulforhodamine (SRB) assay. The phosphorylation of kinases and their downstream molecules was probed by western blot analysis. The binding mode between MdOS and PTKs was profiled by surface plasmon resonance (SPR) approach and molecular simulation. Tube formation assay, rat aortic ring method and chicken chorioallantoic membrane assay were combined to illustrate the in vitro and in vivo anti-angiogenic effects. Results indicated that MdOS, a novel marine-derived oligosaccharide sulfate, exhibited a broad-spectrum PTK inhibitory action. At an enzymatic level, MdOS inhibited HER2, EGFR, VEGFR, PDGFR, c-Kit, FGFR1 and c-Src, with little impact on FGFR2. In cellular settings, MdOS inhibited phosphorylation of PTKs, exemplified by HER2, EGFR and VEGFR2, and downstream molecules of Erk1/2 and AKT. Further studies demonstrated that MdOS acted as an ATP-competitive inhibitor via directly binding to the residues of entrance rather than those of the ATP-binding pocket. Furthermore, MdOS inhibited proliferation and tube formation of HMECs, arrested microvessel outgrowth of rat aortic rings and hindered the neovascularization of chick allantoic membrane. Taken together, results presented here indicated that MdOS exhibited anti-angiogenic activity in a PTK-dependent manner and make it a promising agent for further evaluation in PTK-associated cancer therapy. |
| doi_str_mv | 10.1371/journal.pone.0003774 |
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The aim of the present study was to identify novel multi-targeting PTK inhibitors. The kinase enzymatic activities were measured by enzyme-linked immunosorbent assay (ELISA). The antiproliferative activities in human microvascular endothelial cells (HMECs) were evaluated by sulforhodamine (SRB) assay. The phosphorylation of kinases and their downstream molecules was probed by western blot analysis. The binding mode between MdOS and PTKs was profiled by surface plasmon resonance (SPR) approach and molecular simulation. Tube formation assay, rat aortic ring method and chicken chorioallantoic membrane assay were combined to illustrate the in vitro and in vivo anti-angiogenic effects. Results indicated that MdOS, a novel marine-derived oligosaccharide sulfate, exhibited a broad-spectrum PTK inhibitory action. At an enzymatic level, MdOS inhibited HER2, EGFR, VEGFR, PDGFR, c-Kit, FGFR1 and c-Src, with little impact on FGFR2. In cellular settings, MdOS inhibited phosphorylation of PTKs, exemplified by HER2, EGFR and VEGFR2, and downstream molecules of Erk1/2 and AKT. Further studies demonstrated that MdOS acted as an ATP-competitive inhibitor via directly binding to the residues of entrance rather than those of the ATP-binding pocket. Furthermore, MdOS inhibited proliferation and tube formation of HMECs, arrested microvessel outgrowth of rat aortic rings and hindered the neovascularization of chick allantoic membrane. Taken together, results presented here indicated that MdOS exhibited anti-angiogenic activity in a PTK-dependent manner and make it a promising agent for further evaluation in PTK-associated cancer therapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0003774</identifier><identifier>PMID: 19020661</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>AKT protein ; Analysis ; Angiogenesis ; Animals ; Aorta ; Aorta - metabolism ; Assaying ; ATP ; Binding ; c-Kit protein ; Cancer ; Cancer therapies ; Cancer treatment ; Cell Biology/Cell Signaling ; Cell growth ; Cell Line, Tumor ; Chickens ; Chorioallantoic membrane ; Chorioallantoic Membrane - metabolism ; Endothelial cells ; Endothelium, Vascular - metabolism ; Enzymatic activity ; Enzyme inhibitors ; Enzyme-linked immunosorbent assay ; Enzymes ; Epidermal growth factor ; Epidermal growth factor receptors ; ErbB-2 protein ; Extracellular signal-regulated kinase ; Fibroblast growth factor receptor 1 ; Fibroblast growth factor receptor 2 ; Health aspects ; Humans ; In Vitro Techniques ; Inhibitors ; Kinases ; Kinetics ; Laboratories ; Ligands ; Lung cancer ; Microcirculation ; Microvasculature ; Mutation ; Neoplasms - drug therapy ; Neoplasms - metabolism ; Neovascularization ; Neovascularization, Pathologic ; Oligosaccharides - chemistry ; Oncology/Oncology Agents ; Pharmacology ; Pharmacology/Drug Development ; Phenols (Class of compounds) ; Phosphorylation ; Phosphotransferases ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Protein-tyrosine kinase ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Proteins ; Rats ; Rats, Sprague-Dawley ; Rodents ; Side effects ; Signal transduction ; Simulation ; Src protein ; Sulfates ; Sulfates - chemistry ; Sulforhodamine ; Surface plasmon resonance ; Therapy ; Tumors ; Tyrosine ; Tyrosine kinase inhibitors ; Vascular endothelial growth factor ; Vascular endothelial growth factor receptors ; Vascularization</subject><ispartof>PloS one, 2008-11, Vol.3 (11), p.e3774-e3774</ispartof><rights>COPYRIGHT 2008 Public Library of Science</rights><rights>2008 Ma et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Ma et al. 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c493t-9c7064fd6e5d6ea5fd350437e3e424cd074ad3733db13080173d0b5ed6a0dfb13</citedby><cites>FETCH-LOGICAL-c493t-9c7064fd6e5d6ea5fd350437e3e424cd074ad3733db13080173d0b5ed6a0dfb13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2582481/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2582481/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19020661$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ma, Jingui</creatorcontrib><creatorcontrib>Xin, Xianliang</creatorcontrib><creatorcontrib>Meng, Linghua</creatorcontrib><creatorcontrib>Tong, Linjiang</creatorcontrib><creatorcontrib>Lin, Liping</creatorcontrib><creatorcontrib>Geng, Meiyu</creatorcontrib><creatorcontrib>Ding, Jian</creatorcontrib><title>The marine-derived oligosaccharide sulfate (MdOS), a novel multiple tyrosine kinase inhibitor, combats tumor angiogenesis both in vitro and in vivo</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Despite the emerging success of multi-targeted protein tyrosine kinase (PTK) inhibitors in cancer therapy, significant side effects and resistance concerns seems to be avoided unlikely. The aim of the present study was to identify novel multi-targeting PTK inhibitors. The kinase enzymatic activities were measured by enzyme-linked immunosorbent assay (ELISA). The antiproliferative activities in human microvascular endothelial cells (HMECs) were evaluated by sulforhodamine (SRB) assay. The phosphorylation of kinases and their downstream molecules was probed by western blot analysis. The binding mode between MdOS and PTKs was profiled by surface plasmon resonance (SPR) approach and molecular simulation. Tube formation assay, rat aortic ring method and chicken chorioallantoic membrane assay were combined to illustrate the in vitro and in vivo anti-angiogenic effects. Results indicated that MdOS, a novel marine-derived oligosaccharide sulfate, exhibited a broad-spectrum PTK inhibitory action. At an enzymatic level, MdOS inhibited HER2, EGFR, VEGFR, PDGFR, c-Kit, FGFR1 and c-Src, with little impact on FGFR2. In cellular settings, MdOS inhibited phosphorylation of PTKs, exemplified by HER2, EGFR and VEGFR2, and downstream molecules of Erk1/2 and AKT. Further studies demonstrated that MdOS acted as an ATP-competitive inhibitor via directly binding to the residues of entrance rather than those of the ATP-binding pocket. Furthermore, MdOS inhibited proliferation and tube formation of HMECs, arrested microvessel outgrowth of rat aortic rings and hindered the neovascularization of chick allantoic membrane. Taken together, results presented here indicated that MdOS exhibited anti-angiogenic activity in a PTK-dependent manner and make it a promising agent for further evaluation in PTK-associated cancer therapy.</description><subject>AKT protein</subject><subject>Analysis</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Aorta</subject><subject>Aorta - metabolism</subject><subject>Assaying</subject><subject>ATP</subject><subject>Binding</subject><subject>c-Kit protein</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cancer treatment</subject><subject>Cell Biology/Cell Signaling</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Chickens</subject><subject>Chorioallantoic membrane</subject><subject>Chorioallantoic Membrane - metabolism</subject><subject>Endothelial cells</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Enzymatic activity</subject><subject>Enzyme inhibitors</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Enzymes</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>ErbB-2 protein</subject><subject>Extracellular signal-regulated kinase</subject><subject>Fibroblast growth factor receptor 1</subject><subject>Fibroblast growth factor receptor 2</subject><subject>Health aspects</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Kinetics</subject><subject>Laboratories</subject><subject>Ligands</subject><subject>Lung cancer</subject><subject>Microcirculation</subject><subject>Microvasculature</subject><subject>Mutation</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - metabolism</subject><subject>Neovascularization</subject><subject>Neovascularization, Pathologic</subject><subject>Oligosaccharides - chemistry</subject><subject>Oncology/Oncology Agents</subject><subject>Pharmacology</subject><subject>Pharmacology/Drug Development</subject><subject>Phenols (Class of compounds)</subject><subject>Phosphorylation</subject><subject>Phosphotransferases</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-tyrosine kinase</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rodents</subject><subject>Side effects</subject><subject>Signal transduction</subject><subject>Simulation</subject><subject>Src protein</subject><subject>Sulfates</subject><subject>Sulfates - chemistry</subject><subject>Sulforhodamine</subject><subject>Surface plasmon resonance</subject><subject>Therapy</subject><subject>Tumors</subject><subject>Tyrosine</subject><subject>Tyrosine kinase inhibitors</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular endothelial growth factor receptors</subject><subject>Vascularization</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUm1rFDEQXkSxtfoPRAOCKPTOvG1274tQii-FSj9YP4dsMruXM5tck-xBf4d_2Jy3aisSQpKZZ56ZyTxV9ZzgJWENebcJU_TKLbfBwxJjzJqGP6iOyYrRhaCYPbxzP6qepLTBuGatEI-rI7LCFAtBjqsf12tAo4rWw8JAtDswKDg7hKS0Xhe7AZQm16sM6M0Xc_X17SlSyIcdODROLtutA5RvY0iFAX23XiVA1q9tZ3OIp0iHsVM5oTyNISLlBxsG8JBsQl3I6wJFO5tjKC5zeOzC0-pRr1yCZ_N5Un37-OH6_PPi8urTxfnZ5ULzFcuLlW6w4L0RUJet6t6wGnPWAANOuTa44cqwhjHTEYZbTBpmcFeDEQqbvthOqpcH3q0LSc7_mSRhhDLS1kIUxMUBYYLayG205aduZVBW_jKEOEgVs9UOpG473nZUY9EBF3WjjNJ9U1NmOC1jUIXr_Zxt6kYwGnyOyt0jve_xdi2HsJO0bilv9-W-ngliuJkgZTnapME55SFMSYpVi5uW0gJ89Q_w_70tD6hBlfKt70PJqssyMFpdRNXbYj_jDa1rwQkrAfwQoMu0U4T-T-0Ey70kf6eRe0nKWZIl7MXdvv8GzRpkPwG51eGy</recordid><startdate>20081120</startdate><enddate>20081120</enddate><creator>Ma, Jingui</creator><creator>Xin, Xianliang</creator><creator>Meng, Linghua</creator><creator>Tong, Linjiang</creator><creator>Lin, Liping</creator><creator>Geng, Meiyu</creator><creator>Ding, Jian</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20081120</creationdate><title>The marine-derived oligosaccharide sulfate (MdOS), a novel multiple tyrosine kinase inhibitor, combats tumor angiogenesis both in vitro and in vivo</title><author>Ma, Jingui ; Xin, Xianliang ; Meng, Linghua ; Tong, Linjiang ; Lin, Liping ; Geng, Meiyu ; Ding, Jian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c493t-9c7064fd6e5d6ea5fd350437e3e424cd074ad3733db13080173d0b5ed6a0dfb13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>AKT protein</topic><topic>Analysis</topic><topic>Angiogenesis</topic><topic>Animals</topic><topic>Aorta</topic><topic>Aorta - metabolism</topic><topic>Assaying</topic><topic>ATP</topic><topic>Binding</topic><topic>c-Kit protein</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cancer treatment</topic><topic>Cell Biology/Cell Signaling</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Chickens</topic><topic>Chorioallantoic membrane</topic><topic>Chorioallantoic Membrane - metabolism</topic><topic>Endothelial cells</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Enzymatic activity</topic><topic>Enzyme inhibitors</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Enzymes</topic><topic>Epidermal growth factor</topic><topic>Epidermal growth factor receptors</topic><topic>ErbB-2 protein</topic><topic>Extracellular signal-regulated kinase</topic><topic>Fibroblast growth factor receptor 1</topic><topic>Fibroblast growth factor receptor 2</topic><topic>Health aspects</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Kinetics</topic><topic>Laboratories</topic><topic>Ligands</topic><topic>Lung cancer</topic><topic>Microcirculation</topic><topic>Microvasculature</topic><topic>Mutation</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - metabolism</topic><topic>Neovascularization</topic><topic>Neovascularization, Pathologic</topic><topic>Oligosaccharides - chemistry</topic><topic>Oncology/Oncology Agents</topic><topic>Pharmacology</topic><topic>Pharmacology/Drug Development</topic><topic>Phenols (Class of compounds)</topic><topic>Phosphorylation</topic><topic>Phosphotransferases</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-tyrosine kinase</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Proteins</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Rodents</topic><topic>Side effects</topic><topic>Signal transduction</topic><topic>Simulation</topic><topic>Src protein</topic><topic>Sulfates</topic><topic>Sulfates - chemistry</topic><topic>Sulforhodamine</topic><topic>Surface plasmon resonance</topic><topic>Therapy</topic><topic>Tumors</topic><topic>Tyrosine</topic><topic>Tyrosine kinase inhibitors</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular endothelial growth factor receptors</topic><topic>Vascularization</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ma, Jingui</creatorcontrib><creatorcontrib>Xin, Xianliang</creatorcontrib><creatorcontrib>Meng, Linghua</creatorcontrib><creatorcontrib>Tong, Linjiang</creatorcontrib><creatorcontrib>Lin, Liping</creatorcontrib><creatorcontrib>Geng, Meiyu</creatorcontrib><creatorcontrib>Ding, Jian</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ma, Jingui</au><au>Xin, Xianliang</au><au>Meng, Linghua</au><au>Tong, Linjiang</au><au>Lin, Liping</au><au>Geng, Meiyu</au><au>Ding, Jian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The marine-derived oligosaccharide sulfate (MdOS), a novel multiple tyrosine kinase inhibitor, combats tumor angiogenesis both in vitro and in vivo</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2008-11-20</date><risdate>2008</risdate><volume>3</volume><issue>11</issue><spage>e3774</spage><epage>e3774</epage><pages>e3774-e3774</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Despite the emerging success of multi-targeted protein tyrosine kinase (PTK) inhibitors in cancer therapy, significant side effects and resistance concerns seems to be avoided unlikely. The aim of the present study was to identify novel multi-targeting PTK inhibitors. The kinase enzymatic activities were measured by enzyme-linked immunosorbent assay (ELISA). The antiproliferative activities in human microvascular endothelial cells (HMECs) were evaluated by sulforhodamine (SRB) assay. The phosphorylation of kinases and their downstream molecules was probed by western blot analysis. The binding mode between MdOS and PTKs was profiled by surface plasmon resonance (SPR) approach and molecular simulation. Tube formation assay, rat aortic ring method and chicken chorioallantoic membrane assay were combined to illustrate the in vitro and in vivo anti-angiogenic effects. Results indicated that MdOS, a novel marine-derived oligosaccharide sulfate, exhibited a broad-spectrum PTK inhibitory action. At an enzymatic level, MdOS inhibited HER2, EGFR, VEGFR, PDGFR, c-Kit, FGFR1 and c-Src, with little impact on FGFR2. In cellular settings, MdOS inhibited phosphorylation of PTKs, exemplified by HER2, EGFR and VEGFR2, and downstream molecules of Erk1/2 and AKT. Further studies demonstrated that MdOS acted as an ATP-competitive inhibitor via directly binding to the residues of entrance rather than those of the ATP-binding pocket. Furthermore, MdOS inhibited proliferation and tube formation of HMECs, arrested microvessel outgrowth of rat aortic rings and hindered the neovascularization of chick allantoic membrane. Taken together, results presented here indicated that MdOS exhibited anti-angiogenic activity in a PTK-dependent manner and make it a promising agent for further evaluation in PTK-associated cancer therapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>19020661</pmid><doi>10.1371/journal.pone.0003774</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2008-11, Vol.3 (11), p.e3774-e3774 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1312318566 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | AKT protein Analysis Angiogenesis Animals Aorta Aorta - metabolism Assaying ATP Binding c-Kit protein Cancer Cancer therapies Cancer treatment Cell Biology/Cell Signaling Cell growth Cell Line, Tumor Chickens Chorioallantoic membrane Chorioallantoic Membrane - metabolism Endothelial cells Endothelium, Vascular - metabolism Enzymatic activity Enzyme inhibitors Enzyme-linked immunosorbent assay Enzymes Epidermal growth factor Epidermal growth factor receptors ErbB-2 protein Extracellular signal-regulated kinase Fibroblast growth factor receptor 1 Fibroblast growth factor receptor 2 Health aspects Humans In Vitro Techniques Inhibitors Kinases Kinetics Laboratories Ligands Lung cancer Microcirculation Microvasculature Mutation Neoplasms - drug therapy Neoplasms - metabolism Neovascularization Neovascularization, Pathologic Oligosaccharides - chemistry Oncology/Oncology Agents Pharmacology Pharmacology/Drug Development Phenols (Class of compounds) Phosphorylation Phosphotransferases Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein-tyrosine kinase Protein-Tyrosine Kinases - antagonists & inhibitors Proteins Rats Rats, Sprague-Dawley Rodents Side effects Signal transduction Simulation Src protein Sulfates Sulfates - chemistry Sulforhodamine Surface plasmon resonance Therapy Tumors Tyrosine Tyrosine kinase inhibitors Vascular endothelial growth factor Vascular endothelial growth factor receptors Vascularization |
| title | The marine-derived oligosaccharide sulfate (MdOS), a novel multiple tyrosine kinase inhibitor, combats tumor angiogenesis both in vitro and in vivo |
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