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Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1

Targeting endothelial cell (EC) metabolism should impair angiogenesis, regardless of how many angiogenic signals are present. The dependency of proliferating ECs on glucose and glutamine for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer. The aim of the p...

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Autores principales: Schoonjans, Céline A., Mathieu, Barbara, Joudiou, Nicolas, Zampieri, Luca X., Brusa, Davide, Sonveaux, Pierre, Feron, Olivier, Gallez, Bernard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602423/
https://www.ncbi.nlm.nih.gov/pubmed/33076309
http://dx.doi.org/10.3390/jcm9103308
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author Schoonjans, Céline A.
Mathieu, Barbara
Joudiou, Nicolas
Zampieri, Luca X.
Brusa, Davide
Sonveaux, Pierre
Feron, Olivier
Gallez, Bernard
author_facet Schoonjans, Céline A.
Mathieu, Barbara
Joudiou, Nicolas
Zampieri, Luca X.
Brusa, Davide
Sonveaux, Pierre
Feron, Olivier
Gallez, Bernard
author_sort Schoonjans, Céline A.
collection PubMed
description Targeting endothelial cell (EC) metabolism should impair angiogenesis, regardless of how many angiogenic signals are present. The dependency of proliferating ECs on glucose and glutamine for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer. The aim of the present study was to investigate the role of pyruvate dehydrogenase kinase (PDK) inhibition with dichloroacetate (DCA), alone or in combination with the glutaminase-1 (GLS-1) inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), on Human umbilical vein endothelial cells (HUVECs) metabolism, proliferation, apoptosis, migration, and vessel formation. We demonstrated that both drugs normalize HUVECs metabolism by decreasing glycolysis for DCA and by reducing glutamate production for BPTES. DCA and BPTES reduced HUVECs proliferation and migration but have no impact on tube formation. While DCA increased HUVECs respiration, BPTES decreased it. Using both drugs in combination further reduced HUVECs proliferation while normalizing respiration and apoptosis induction. Overall, we demonstrated that DCA, a metabolic drug under study to target cancer cells metabolism, also affects tumor angiogenesis. Combining DCA and BPTES may reduce adverse effect of each drug alone and favor tumor angiogenesis normalization.
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spelling pubmed-76024232020-11-01 Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1 Schoonjans, Céline A. Mathieu, Barbara Joudiou, Nicolas Zampieri, Luca X. Brusa, Davide Sonveaux, Pierre Feron, Olivier Gallez, Bernard J Clin Med Article Targeting endothelial cell (EC) metabolism should impair angiogenesis, regardless of how many angiogenic signals are present. The dependency of proliferating ECs on glucose and glutamine for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer. The aim of the present study was to investigate the role of pyruvate dehydrogenase kinase (PDK) inhibition with dichloroacetate (DCA), alone or in combination with the glutaminase-1 (GLS-1) inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), on Human umbilical vein endothelial cells (HUVECs) metabolism, proliferation, apoptosis, migration, and vessel formation. We demonstrated that both drugs normalize HUVECs metabolism by decreasing glycolysis for DCA and by reducing glutamate production for BPTES. DCA and BPTES reduced HUVECs proliferation and migration but have no impact on tube formation. While DCA increased HUVECs respiration, BPTES decreased it. Using both drugs in combination further reduced HUVECs proliferation while normalizing respiration and apoptosis induction. Overall, we demonstrated that DCA, a metabolic drug under study to target cancer cells metabolism, also affects tumor angiogenesis. Combining DCA and BPTES may reduce adverse effect of each drug alone and favor tumor angiogenesis normalization. MDPI 2020-10-15 /pmc/articles/PMC7602423/ /pubmed/33076309 http://dx.doi.org/10.3390/jcm9103308 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Schoonjans, Céline A.
Mathieu, Barbara
Joudiou, Nicolas
Zampieri, Luca X.
Brusa, Davide
Sonveaux, Pierre
Feron, Olivier
Gallez, Bernard
Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1
title Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1
title_full Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1
title_fullStr Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1
title_full_unstemmed Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1
title_short Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1
title_sort targeting endothelial cell metabolism by inhibition of pyruvate dehydrogenase kinase and glutaminase-1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602423/
https://www.ncbi.nlm.nih.gov/pubmed/33076309
http://dx.doi.org/10.3390/jcm9103308
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