Anti-angiogenic Activity and Intracellular Distribution of Epigallocatechin-3-gallate Analogs

Abstract

Tumor angiogenesis, a process of new blood vessel formation from pre-existing vessels, is crucial for the growth and development of tumors. It requires multiple interactions among endothelial cells, surrounding pericytes, and smooth muscle cells, extracellular matrix, and angiogenic cytokines/growth factors. [1][2][3] Since effective inhibition of tumor angiogenesis promises to provide crucial suppression of not only tumor growth but also tumor metastasis, the development of agents inhibiting angiogenic processes has become a matter of focus. (Ϫ)-Epigallocatechin-3-O-gallate (EGCG) is known as a major component of green tea extracts and to exhibit various biological activities including anti-viral, anti-microbial, and anti-oxidative ones. [4][5][6][7][8] Especially, the relationship between EGCG and anti-cancer activity is now the most notable, since cancer is the leading cause of human death in various countries. Previous studies demonstrated that EGCG suppresses tumor growth through the inhibition of tumor angiogenesis, and mechanistic studies on this anti-angiogenic effect of EGCG is now ongoing. Tang et al. demonstrated that EGCG inhibits vascular endothelial growth factor (VEGF)-induced Akt activation and VE-cadherin phosphorylation 9) ; and Rodriguez et al., that green tea catechin disrupts VEGF/VEGF receptor (VEGFR) complexes and subsequent signal transduction. 10) Also, Tachibana et al. directly identified the target molecule of EGCG as a 67-kDa laminin receptor by using surface plasmon resonance (SPR) assay, and they observed the suppression of tumor angiogenesis through the inhibition of the receptor-mediated signal transduction. 11,12) Our previous studies also demonstrated that EGCG suppresses tumor angiogenesis through the inhibition of membrane-type1 matrix metalloproteinase (MT1-MMP). 13,14) These findings indicate that EGCG, as a functional component of green tea, will become useful for cancer therapy and chemoprevention.Previous study demonstrated that 5,7-deoxyepigallocatechin gallate (DOEGCG), a synthetic EGCG derivative, possesses more potent anti-influenza infection activity than the original EGCG, suggesting that the phenolic hydroxyl groups on the A-ring in the flavan structure are not involved in the biological activity and that modification of A-ring of the EGCG structure does not abolish but rather enhances the functional ability of EGCG.15) Based on this and other structure-relationship studies, 16,17) we synthesized (Ϯ)-6-(5-aminopentyl)-5,7-deoxyepigallocatechin gallate (cis-APDOEGCG) and (Ϯ)-6-(5-aminopentyl)-5,7-deoxygallocatechin gallate (trans-APDOEGCG) as EGCG derivatives containing linkers and reactive amino groups added to the EGCG structure, as shown in Fig. 1. We compared their antiangiogenic activity with that of EGCG by examining the inhibitory effect on proliferation, migration, invasion, and tube formation by HUVECs. Then, we synthesized fluorescencelabeled EGCG by conjugating the fluorescent reagent TokyoGreen (TG) to (Ϯ)-cis-APDOEGCG (EGCG-TG) and examined the intracel...

Comparison of antiproliferative effect of epigallocatechin gallate when loaded into cationic solid lipid nanoparticles against different cell lines

“…EGCG has revealed several beneficial health effects, including anti-inflammatory (Cavet et al 2011), anti-carcinogenic (Farabegoli et al 2011;Santos et al 2013;Radhakrishnan et al 2016;Shin et al 2016), antioxidant (Cavet et al 2011;Zhou and Elias 2013), antiangiogenic (Yamakawa et al 2004;Piyaviriyakul et al 2011), anti-diabetic (Wolfram et al 2006;Chen N et al 2009) and anti-bacterial (Lee S et al 2017). It has also been reported its use as chondroprotective agent as it suppressed the inflammatory response in osteoarthritis models (Akhtar and Haqqi 2011;Min S-Y et al 2015), as well as a cardiovascular protector (Wolfram 2007;Oyama et al 2017) and neuroprotector (Lee JH et al 2015;Ortiz-López et al 2016).…”

PI3K/AKT/PTEN Signaling as a Molecular Target in Leukemia Angiogenesis

“…Angiogenesis is the process by which new blood capillaries are generated from the preexisting blood vessels [1, 2]. Tumor angiogenesis is essential for tumor growth, invasion, and metastasis [3, 4].…”

Detailed Analysis of Apoptosis and Delayed Luminescence of Human Leukemia Jurkat T Cells after Proton Irradiation and Treatments with Oxidant Agents and Flavonoids

“…In Jurkat cells, EGCG (50  μ M) produces intracellular H 2 O 2 , which induces apoptosis by a Fe 2+ -dependent mechanism, through generation of hydroxyl radicals via Fenton reactions [5]. In a different cell type, EGCG has been shown to associate with mitochondria and other yet unidentified cytoplasmic organelles [18]. …”