Procyanidin B2 3,3″-di-O-gallate Inhibits Endothelial Cells Growth and Motility by Targeting VEGFR2 and Integrin Signaling Pathways
Michael F. Wempe,
Targeting angiogenesis, one of the hallmarks of carcinogenesis, using non-toxic phytochemicals has
emerged as a translational opportunity for angioprevention and to control advanced stages of malignancy.
Herein, we investigated the inhibitory effects and associated mechanism/s of action of Procyanidin B2-3,3″-di-
O-gallate (B2G2), a major component of grape seed extract, on human umbilical vein endothelial cells
(HUVECs) and human prostate microvascular endothelial cells (HPMECs). Our results showed that B2G2
(10-40 μM) inhibits growth and induces death in both HUVECs and HPMECs. Additional studies revealed that B2G2
causes a G1 arrest in cell cycle progression of HUVECs by down-regulating cyclins (D1 and A), CDKs (Cdk2 and Cdc2)
and Cdc25c phosphatase and up-regulating CDK inhibitors (p21 and p27) expression. B2G2 also induced strong apoptotic
death in HUVECs through increasing p53, Bax and Smac/Diablo expression while decreasing Bcl-2 and survivin levels.
Additionally, B2G2 inhibited the growth factors-induced capillary tube formation in HUVECs and HPMECs.
Interestingly, conditioned media (CCM) from prostate cancer (PCA) cells (LNCaP and PC3) grown under normoxic
(~21% O2) and hypoxic (1% O2) conditions significantly enhanced the tube formation in HUVECs, which was
compromised in presence of conditioned media from B2G2-treated PCA cells. B2G2 also inhibited the motility and
invasiveness of both HUVECs and HPMECs. Mechanistic studies showed that B2G2 targets VEGFR2/PI3K/Akt and
integrin signaling molecules which are important for endothelial cells survival, proliferation, tube formation and motility.
Overall, we report that B2G2 inhibits several attributes of angiogenesis in cell culture; therefore, it warrants further
investigation for efficacy for angioprevention and cancer control.
Keywords: Angioprevention, apoptosis, B2G2, cell cycle, endothelial cells, integrin, VEGFR2.
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