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Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo
Heparan sulphate (HS), a ubiquitously expressed glycosaminoglycan (GAG), regulates multiple cellular functions by mediating interactions between numerous growth factors and their cell surface cognate receptors. However, the structural specificity of HS in these interactions remains largely undefined...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973927/ https://www.ncbi.nlm.nih.gov/pubmed/27490176 http://dx.doi.org/10.1371/journal.pone.0159739 |
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author | Avizienyte, Egle Cole, Claire L. Rushton, Graham Miller, Gavin J. Bugatti, Antonella Presta, Marco Gardiner, John M. Jayson, Gordon C. |
author_facet | Avizienyte, Egle Cole, Claire L. Rushton, Graham Miller, Gavin J. Bugatti, Antonella Presta, Marco Gardiner, John M. Jayson, Gordon C. |
author_sort | Avizienyte, Egle |
collection | PubMed |
description | Heparan sulphate (HS), a ubiquitously expressed glycosaminoglycan (GAG), regulates multiple cellular functions by mediating interactions between numerous growth factors and their cell surface cognate receptors. However, the structural specificity of HS in these interactions remains largely undefined. Here, we used completely synthetic, structurally defined, alternating N-sulfated glucosamine (NS) and 2-O-sulfated iduronate (IS) residues to generate dodecasaccharides ([NSIS](6)) that contained no, one or six glucosamine 6-O-sulfates (6S). The aim was to address how 6S contributes to the potential of defined HS dodecasaccharides to inhibit the angiogenic growth factors FGF2 and VEGF(165), in vitro and in vivo. We show that the addition of a single 6S at the non-reducing end of [NSIS](6), i.e. [NSIS6S]-[NSIS](5), significantly augments the inhibition of FGF2-dependent endothelial cell proliferation, migration and sprouting in vitro when compared to the non-6S variant. In contrast, the fully 6-O-sulfated dodecasaccharide, [NSIS6S](6), is not a potent inhibitor of FGF2. Addition of a single 6S did not significantly improve inhibitory properties of [NSIS](6) when tested against VEGF(165)-dependent endothelial cell functions.In vivo, [NSIS6S]-[NSIS](5) blocked FGF2-dependent blood vessel formation without affecting tumor growth. Reduction of non-FGF2-dependent ovarian tumor growth occurred when [NSIS6S]-[NSIS](5) was combined with cisplatin. The degree of inhibition by [NSIS6S]-[NSIS](5) in combination with cisplatin in vivo equated with that induced by bevacizumab and sunitinib when administered with cisplatin. Evaluation of post-treatment vasculature revealed that [NSIS6S]-[NSIS](5) treatment had the greatest impact on tumor blood vessel size and lumen formation. Our data for the first time demonstrate that synthetic, structurally defined oligosaccharides have potential to be developed as active anti-angiogenic agents that sensitize tumors to chemotherapeutic agents. |
format | Online Article Text |
id | pubmed-4973927 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49739272016-08-18 Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo Avizienyte, Egle Cole, Claire L. Rushton, Graham Miller, Gavin J. Bugatti, Antonella Presta, Marco Gardiner, John M. Jayson, Gordon C. PLoS One Research Article Heparan sulphate (HS), a ubiquitously expressed glycosaminoglycan (GAG), regulates multiple cellular functions by mediating interactions between numerous growth factors and their cell surface cognate receptors. However, the structural specificity of HS in these interactions remains largely undefined. Here, we used completely synthetic, structurally defined, alternating N-sulfated glucosamine (NS) and 2-O-sulfated iduronate (IS) residues to generate dodecasaccharides ([NSIS](6)) that contained no, one or six glucosamine 6-O-sulfates (6S). The aim was to address how 6S contributes to the potential of defined HS dodecasaccharides to inhibit the angiogenic growth factors FGF2 and VEGF(165), in vitro and in vivo. We show that the addition of a single 6S at the non-reducing end of [NSIS](6), i.e. [NSIS6S]-[NSIS](5), significantly augments the inhibition of FGF2-dependent endothelial cell proliferation, migration and sprouting in vitro when compared to the non-6S variant. In contrast, the fully 6-O-sulfated dodecasaccharide, [NSIS6S](6), is not a potent inhibitor of FGF2. Addition of a single 6S did not significantly improve inhibitory properties of [NSIS](6) when tested against VEGF(165)-dependent endothelial cell functions.In vivo, [NSIS6S]-[NSIS](5) blocked FGF2-dependent blood vessel formation without affecting tumor growth. Reduction of non-FGF2-dependent ovarian tumor growth occurred when [NSIS6S]-[NSIS](5) was combined with cisplatin. The degree of inhibition by [NSIS6S]-[NSIS](5) in combination with cisplatin in vivo equated with that induced by bevacizumab and sunitinib when administered with cisplatin. Evaluation of post-treatment vasculature revealed that [NSIS6S]-[NSIS](5) treatment had the greatest impact on tumor blood vessel size and lumen formation. Our data for the first time demonstrate that synthetic, structurally defined oligosaccharides have potential to be developed as active anti-angiogenic agents that sensitize tumors to chemotherapeutic agents. Public Library of Science 2016-08-04 /pmc/articles/PMC4973927/ /pubmed/27490176 http://dx.doi.org/10.1371/journal.pone.0159739 Text en © 2016 Avizienyte et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Avizienyte, Egle Cole, Claire L. Rushton, Graham Miller, Gavin J. Bugatti, Antonella Presta, Marco Gardiner, John M. Jayson, Gordon C. Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo |
title | Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo |
title_full | Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo |
title_fullStr | Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo |
title_full_unstemmed | Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo |
title_short | Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo |
title_sort | synthetic site-selectively mono-6-o-sulfated heparan sulfate dodecasaccharide shows anti-angiogenic properties in vitro and sensitizes tumors to cisplatin in vivo |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973927/ https://www.ncbi.nlm.nih.gov/pubmed/27490176 http://dx.doi.org/10.1371/journal.pone.0159739 |
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