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Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells
The anti-angiogenic activity of chemotherapy is both dose- and schedule-dependent. While conventional maximum tolerated dose (MTD) chemotherapy exerts only mild and reversible anti-angiogenic effects, low-dose metronomic (LDM) chemotherapy was developed to specifically target tumour angiogenesis. Ho...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Netherlands
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595478/ https://www.ncbi.nlm.nih.gov/pubmed/23143659 http://dx.doi.org/10.1007/s10456-012-9321-x |
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author | Pasquier, Eddy Tuset, Maria-Pia Street, Janine Sinnappan, Snega MacKenzie, Karen L. Braguer, Diane Andre, Nicolas Kavallaris, Maria |
author_facet | Pasquier, Eddy Tuset, Maria-Pia Street, Janine Sinnappan, Snega MacKenzie, Karen L. Braguer, Diane Andre, Nicolas Kavallaris, Maria |
author_sort | Pasquier, Eddy |
collection | PubMed |
description | The anti-angiogenic activity of chemotherapy is both dose- and schedule-dependent. While conventional maximum tolerated dose (MTD) chemotherapy exerts only mild and reversible anti-angiogenic effects, low-dose metronomic (LDM) chemotherapy was developed to specifically target tumour angiogenesis. However, the long-term effects of either MTD or LDM chemotherapy on vascular endothelial cells have never been investigated. Here, we demonstrated that repeated exposure to MTD and LDM chemotherapy differentially impact on the angiogenic potential and chemosensitivity of immortalized endothelial cells. Repeated MTD vinblastine treatment of vascular endothelial cells led to an increased proliferation rate and resistance to paclitaxel. In contrast, repeated LDM treatment with vinblastine or etoposide impaired the angiogenic potential of endothelial cells and increased their chemosensitivity. This effect was associated with a significant decrease in βII- and βIII-tubulin expression. Functional analysis using siRNA showed that silencing the expression of βIII-tubulin in endothelial cells significantly decreased their capacity to form vascular structures and increased their sensitivity to the anti-angiogenic and vascular-disrupting effects of chemotherapy, whereas silencing βII-tubulin expression had no effect. Collectively our results show that LDM chemotherapy impairs the angiogenic potential of endothelial cells while increasing their chemosensitivity—an effect at least in part mediated by the down-regulation of βIII-tubulin expression. Furthermore, our study suggests that βIII-tubulin represents an attractive therapeutic target to increase the anti-angiogenic effects of chemotherapy and overall anti-tumour efficacy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10456-012-9321-x) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-3595478 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-35954782013-03-13 Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells Pasquier, Eddy Tuset, Maria-Pia Street, Janine Sinnappan, Snega MacKenzie, Karen L. Braguer, Diane Andre, Nicolas Kavallaris, Maria Angiogenesis Original Paper The anti-angiogenic activity of chemotherapy is both dose- and schedule-dependent. While conventional maximum tolerated dose (MTD) chemotherapy exerts only mild and reversible anti-angiogenic effects, low-dose metronomic (LDM) chemotherapy was developed to specifically target tumour angiogenesis. However, the long-term effects of either MTD or LDM chemotherapy on vascular endothelial cells have never been investigated. Here, we demonstrated that repeated exposure to MTD and LDM chemotherapy differentially impact on the angiogenic potential and chemosensitivity of immortalized endothelial cells. Repeated MTD vinblastine treatment of vascular endothelial cells led to an increased proliferation rate and resistance to paclitaxel. In contrast, repeated LDM treatment with vinblastine or etoposide impaired the angiogenic potential of endothelial cells and increased their chemosensitivity. This effect was associated with a significant decrease in βII- and βIII-tubulin expression. Functional analysis using siRNA showed that silencing the expression of βIII-tubulin in endothelial cells significantly decreased their capacity to form vascular structures and increased their sensitivity to the anti-angiogenic and vascular-disrupting effects of chemotherapy, whereas silencing βII-tubulin expression had no effect. Collectively our results show that LDM chemotherapy impairs the angiogenic potential of endothelial cells while increasing their chemosensitivity—an effect at least in part mediated by the down-regulation of βIII-tubulin expression. Furthermore, our study suggests that βIII-tubulin represents an attractive therapeutic target to increase the anti-angiogenic effects of chemotherapy and overall anti-tumour efficacy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10456-012-9321-x) contains supplementary material, which is available to authorized users. Springer Netherlands 2012-11-10 2013 /pmc/articles/PMC3595478/ /pubmed/23143659 http://dx.doi.org/10.1007/s10456-012-9321-x Text en © The Author(s) 2012 https://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Original Paper Pasquier, Eddy Tuset, Maria-Pia Street, Janine Sinnappan, Snega MacKenzie, Karen L. Braguer, Diane Andre, Nicolas Kavallaris, Maria Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells |
title | Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells |
title_full | Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells |
title_fullStr | Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells |
title_full_unstemmed | Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells |
title_short | Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells |
title_sort | concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595478/ https://www.ncbi.nlm.nih.gov/pubmed/23143659 http://dx.doi.org/10.1007/s10456-012-9321-x |
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