Anti-VEGF Effect of Bioactive Indolic Compounds and Hydroxytyrosol Metabolites

Abstract

Angiogenesis is a key process involved in both cancer and cardiovascular diseases, the vascular endothelial growth factor (VEGF) and its VEGF receptor-2 (VEGFR-2) being the main triggers. The aim of this study was to determine the molecular mechanism underlying the potent inhibition of VEGF signaling by hydroxytyrosol (HT) metabolites and indolic compounds and establish a relation between their structure and bioactivity. Experiments involved the evaluation of their potential to inhibit VEGF on human umbilical vein endothelial cells (HUVECs) by ELISA assay and their subsequent effect on the downstream signaling pathway (PLCγ1, Akt, and endothelial nitric oxide synthetase (eNOS)) by Western blot. Respectively, 3,4-dihydroxyphenylacetaldehyde (DOPAL) (100 µM) and indole pyruvic acid (IPy) (1 mM) were capable of inhibiting VEGFR-2 activation with an IC50 value of 119 µM and 1.037 mM. The anti-angiogenic effect of DOPAL and IPy is mediated via PLCγ1. Additionally, DOPAL significantly increases eNOS phosphorylation, while IPy maintained it. These data provide for the first time evidence of the anti-angiogenic effect of DOPAL and IPy for future use as potential bioactive food ingredients.

Anti-Cancer, Anti-Angiogenic, and Anti-Atherogenic Potential of Key Phenolic Compounds from Virgin Olive Oil

“…Hydroxytyrosol can inhibit cyclooxygenase 2 (COX-2) activ-ity [107]. In addition, data support a reduction in the AKT [88,108], nuclear factor-kappa B (NF-κB) [88], and vascular endothelial growth factor receptor (VEGFR) signaling pathways [108] by this molecule. Remarkably, our research group demonstrated that hydroxytyrosol exhibited anti-angiogenic effects by targeting extracellular remodeling and reducing matrix metalloproteinases' (MMPs) production [71,109], in alignment with the findings of Scoditti and colleagues [107].…”

“…Reduction in pro-angiogenic signaling Inhibition of COX-2 [107] Inhibition of the pro-survival AKT pathway [88,108] Inhibition of VEGFR signaling [108] Inhibition of NF-κB signaling [88] Decrease in extracellular remodeling capacity Reduction in MMP expression [71,107,109] HT alkyl ethers Cytotoxic Induction of apoptosis [110] Reduction in endothelial cell migration and tube formation - [110] (-)-Oleocanthal Reduction in endothelial cell migration, invasion, and tube formation Inhibition of AKT and ERK1/2 signaling [111] Inhibition of STAT3 signaling [97] (-)-Oleacein Reduction in endothelial cell migration, invasion, and tube formation Inhibition of AKT and ERK1/2 signaling [111] COX-2: cyclooxygenase 2; VEGFR: vascular endothelial growth factor receptor; NF-κB: nuclear factor-kappa B; MMP: matrix metalloproteinase.…”

Antineoplastic indole-containing compounds with potential VEGFR inhibitory properties

“… 95–97 Vindesine (Eldisine) 41 is a Vinca alkaloid with efficacy against acute lymphocytic leukemia. 95,98 3-Indole acetic acid 42, which is present in wine, and 3-indole pyruvic acid 43 (human metabolite) exhibited inhibitory properties against VEGFR-2 with IC 50 = 0.9704 and 1.037 mM, respectively 99 ( Fig. 8 ).…”

Antiangiogenic Effect of Dopamine and Dopaminergic Agonists as an Adjuvant Therapeutic Option in the Treatment of Cancer, Endometriosis, and Osteoarthritis

“…The signal transduction cascade begins when VEGF binds to VEGFR 2, leading to a conformational change, dimerization, and phosphorylation of tyrosine residues of the receptor, which leads to the activation of several intracellular molecules that serve as downstream signaling elements that propagate the signal to activate angiogenesis [ 72 ]. This system mediates angiogenesis through the proliferation, migration, and survival of endothelial cells, promoting new vessel formation ( Figure 1 ) [ 74 , 75 ]. The potent proangiogenic activity of VEGF was first described as essential for vascular endothelial cells; however, VEGF and VEGF receptors are expressed on numerous nonendothelial cells, including tumor cells [ 72 , 76 ].…”

“…The potent proangiogenic activity of VEGF was first described as essential for vascular endothelial cells; however, VEGF and VEGF receptors are expressed on numerous nonendothelial cells, including tumor cells [ 72 , 76 ]. In addition, VEGFR 2 is associated with the mitogenic, angiogenic, and permeability-enhancing effects of VEGF in a wide variety of tissues [ 75 , 77 ].…”