Anti-angiogenic effect of α-mangostin

Abstract

Eleven known prenyl xanthones, isolated from the pericarp of Garcinia mangostana, were tested for their ability to inhibit the phosphorylation of kinase domain receptor (KDR) tyrosine kinase. α-Mangostin was found to inhibit phosphorylation of KDR. α-Mangostin also showed to inhibit phosphorylation of the Y1175 residue of KDR (10 μM). This is the first report that α-mangostin inhibited the phosphorylation of KDR tyrosine kinase and also the Y1175 residue of KDR. α-Mangostin also showed inhibitory effects on proliferation of human umbilical vein endothelial cells (HUVECs) (IC(50) 1.2 μM) and human umbilical artery endothelial cells (IC(50) 2.4 μM), as well as the migration (IC(50) 0.034 μM) and tubule formation (at the concentrations of 0.6 and 1.2 μM) of HUVECs. These results suggest that the inhibition of the phosphorylation of KDR tyrosine kinase is concerned in the anti-angiogenic activity of α-mangostin.

Anti-angiogenic actions of the mangosteen polyphenolic xanthone derivative α-mangostin

“…It has also been shown that VEGF increases cell proliferation and tube formation through phosphorylation of ERK1/2 in retinal microvascular endothelial cells and in a rat OIR model (Bullard et al, 2003). A recent study reported that α-mangostin treatment of human umbilical vein endothelial cells (HUVEC) inhibited their proliferation, migration and tube formation (Shiozaki et al, 2012). These investigators also reported that α-mangostin treatment prevented ATP-induced phosphorylation of the tyrosine 1175 residue in recombinant VEGFR2.…”

“…α-mangostin is the one of the major biological components of mangosteen. Recently, it has been shown that α-mangostin inhibited growth of umbilical vein endothelial cells and suppressed ATP-induced phosphorylation of recombinant VEGFR2 at Y1175 (Shiozaki et al, 2012). However, the effect of α-mangostin on VEGF signaling and VEGF-induced hyperpermeability and angiogenesis has not been studied.…”

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“…Jittiporn et al [102] found that α-MG dramatically and dose dependently suppressed VEGF-induced hyperpermeability, increased proliferation, migration, and tube formation in retinal endothelial cells, and limited vascular sprouting in the ex vivo aortic ring assay through suppressing VEGF-induced phosphorylation of VEGFR2 and ERK1/2 (a major downstream target of VEGFR2). Another study reported on its inhibitory effects on VEGF-induced proliferation, migration, and tubule formation of human umbilical vein endothelial cells [103]. This study also examined site-specific phosphorylation of VEGFR2 and revealed that α-MG inhibited ATP-induced phosphorylation of recombinant VEGFR2 at the Y1175.…”

“…Human breast cancer MCF-7 cell [94] Inhibition of angiogenic and metastatic progression VEGF expression↓ Breast cancer T47D cells [99] VEGF-A/SDF-1 secretion↓ Activated pancreatic stellate cells [101] VEGFR2↓, EKR1/2↓ Retinal microvascular endothelial cells [102] Phosphorylation of VEGFR2↓ Human umbilical vein endothelial cells [103] MMP-2/MMP-9/NF-κB/Akt1 expression↓ Human melanoma SK-MEL-28 cells [105] MMP-2/NF-κB expression↓, IκBα expression↑ Human squamous cell carcinoma A-431 cells [106] continued…”

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“…Mangosteen extracts, including α-mangostin, apparently have somewhat more effective anti-angiogenic properties in vivo in the mammary cancer model used in this study [21,23]; however, the mechanism of angiogenic inhibition by α-mangostin may be related to a reduction in Akt phosphorylation [19][20][21], rather than to antigenantibody interactions; phosphatidylinositol 3-kinase (PI3K) exerts regulatory functions on tumor growth and angiogenesis, as well as on cell proliferation, cell transformation and apoptosis, through downstream targeting of Akt [40]. α-Mangostin inhibited angiogenesis in human umbilical vein endothelial cells and was associated with inhibited phosphorylation of VEGFR2 in vitro [41].…”