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

Abstract

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.

Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis

“…In addition, lower concentrations of DCA (6.25 and 12.5 mM) did not affect the HUVECs tube formation. These findings are consistent with a report by Schoonjans and coworkers, who demonstrated that 5 mM and 10 mM DCA did not affect HUVECs' tube formation in vitro [29]. In agreement with our data, DCA caused a reduction in the tumor microvessel density in treated rats, in which HIF1α suppression was also reported within the tumor cells [30].…”

Tumour endothelial cells for translational research and therapeutics

“…At present, there is no definite evidence to prove the role of glutamine metabolism in TECs. It has been studied that the combination of pyruvate dehydrogenase kinase inhibition with dichloroacetate and glutaminase‐1 (GLS‐1) inhibitor, bis‐2 ‐ (5‐phenylacetamide‐1,3,4‐thiadiazol‐2‐yl) ethyl sulfide (BPTES) is conducive to the normalization of tumour blood vessels 84 …”

The glycolytic process in endothelial cells and its implications

“…Glutamine metabolism (glutaminolysis), which involves the deamination of glutamine to glutamate by the enzyme glutaminase (GLS1), serves as a critical process in replenishing the carbon intermediates for maintaining the mitochondrial TCA cycle [ 26 ]. A stiff matrix, which mimics stiffness in hypertensive pulmonary arterioles, activates GLS1 and glycolysis, decreases oxidative phosphorylation, and restores cell proliferation in human pulmonary arterial endothelial cells than a soft matrix (mimicking stiffness in non-diseased pulmonary arterioles in rodents), whereas inhibition of GLS1 reduces glutaminolysis and attenuates cell proliferation [ 27 – 29 ]. Combined inhibition of GLS1 and PDH reduces endothelial proliferation, migration, and tube formation; these effects are coupled with normalized mitochondrial oxidation [ 27 ].…”