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Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression
Ulrich Pfeffer1, Nicoletta Ferrari, Raffaella Dell'Eva
1Functional Genomics Unit, National Cancer Research Institute, Genova, Italy.
Abstract:
The anti-oxidants N-acetyl-l-cysteine (NAC) and (-)-epigallocatechin-3-gallate (EGCG) inhibit tumor vascularization by reducing endothelial cell migration and invasion in a similar, non additive and non synergistic manner but do not alter the growth of human umbilical vein endothelial cells. Here we address the effects of the two chemopreventive drugs on endothelial cell signaling by means of expression profiling and real-time PCR validation. We identify a series of angiogenesis related genes that are similarly regulated by the two drugs. Anti-oxidant treated endothelial cells show gene expression profiles compatible with a less activated, less apoptosis prone and less migratory phenotype. The anti-oxidants affect expression of several components of the TNFalpha response pathway including downstream genes that are regulated in the opposite direction in the absence of the inflammatory cytokine. The interference with the TNFalpha pathway is reflected by reduced NFkappaB activation in anti-oxidants treated cells but the compounds are not able to contrast TNFalpha mediated activation of NFkappaB. The chemopreventive action of these compounds thus relies on a reduction of basal levels of endothelial cell activation. Down-regulation of the TNFalpha responsive pro-metastatic, pro-inflammatory genes, urokinase plasminogen activator and selectin E, further implies anti-metastatic effects for these drugs.
Insights
The antioxidants N-acetyl-l-cysteine (NAC) and epigallocatechin-3-gallate (EGCG) reduce tumor vascularization by inhibiting endothelial cell migration. These compounds lower basal endothelial cell activation, suggesting chemopreventive and anti-metastatic effects.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- N-acetyl-l-cysteine (NAC) and epigallocatechin-3-gallate (EGCG) are antioxidants with potential chemopreventive properties.
- These compounds have been shown to inhibit tumor vascularization by affecting endothelial cell migration and invasion.
Purpose of the Study:
- To investigate the effects of NAC and EGCG on endothelial cell signaling pathways.
- To identify angiogenesis-related genes regulated by these antioxidants.
- To elucidate the mechanism underlying their chemopreventive action.
Main Methods:
- Gene expression profiling of endothelial cells treated with NAC and EGCG.
- Real-time PCR validation of identified gene expression changes.
- Analysis of the TNFalpha response pathway and NF-kappaB activation.
Main Results:
- NAC and EGCG similarly regulate a set of angiogenesis-related genes.
- Antioxidant treatment leads to gene expression profiles indicative of reduced endothelial cell activation, apoptosis, and migration.
- Interference with the TNFalpha pathway and reduced basal NF-kappaB activation were observed.
- Down-regulation of urokinase plasminogen activator and selectin E suggests anti-metastatic potential.
Conclusions:
- The chemopreventive effects of NAC and EGCG are attributed to the reduction of basal endothelial cell activation.
- These antioxidants exhibit anti-metastatic potential by down-regulating pro-inflammatory and pro-metastatic genes.
- NAC and EGCG offer a promising therapeutic strategy for inhibiting tumor vascularization and metastasis.
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