title: Procyanidin B2 3,3″-di-O-gallate inhibits endothelial cells growth and motility by targeting VEGFR2 and integrin signaling pathways.
abstract: 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.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.forename: Gagan
authors.initials: G
authors.lastname: Deep
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: University of Colorado Denver, 12850 E. Montview Blvd, C238, Aurora, CO 80045, USA. Chapla.agarwal@ucdenver.edu.
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
mesh_terms: D000872:Anthocyanins / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D002470:Cell Survival; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000872:Anthocyanins; D016023:Integrins; C523197:procyanidin B2-3,3'-di-O-gallate; D040301:Vascular Endothelial Growth Factor Receptor-2