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.
Highlights
Several studies have described the association between the growth of malignant tumors and the development and growth of new blood growth vessels [1,2,3]
DOPAL at 100 μM was capable of inhibiting VEGF receptor-2 (VEGFR-2) activation by 46%
We explore the bioactivity of HT endogenous metabolites such as DOPAL, MOPAL and MOPET and other L-TRP metabolites such as indole pyruvic acid (IPy), indole propionic acid (IPA), indole lactic acid (ILA) and indole butyric acid (IBA)
Summary
Several studies have described the association between the growth of malignant tumors and the development and growth of new blood growth vessels [1,2,3]. Tumors express various pro-angiogenic factors among them, the main one being VEGF which binds to VEGFR-2 [5]. It is worth noticing that certain anti-VEGF drugs, such as bevacizumab, sorafenib and sunitinib, cause hypertension as a side effect [7,8,9]. This is related to a nitric oxide (NO) reduction
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