摘要
靶向肿瘤血管的新生是细胞癌变的标志之一,采用无毒的植物化学物质已成为预防癌变和控制恶性肿瘤晚期的可替代性方法。本研究论文中,我们研究了原花青素B-2-3,3″二-氧-没食子酸酯(B2G2)对人脐静脉内皮细胞(HUVECs)和人前列腺微血管内皮细胞(HPMECs)的抑制作用和相关机制,而B2G2是葡萄籽提取物的主要成分。结果表明,B2G2 (10-40 μM)对HUVECs和HPMECs均具有抑制生长和诱导凋亡作用。进一步的研究发现,在HUVECs中,B2G2通过下调细胞周期蛋白(D1和A) 、CDKs(Cdk2和Cdc2)以及Cdc25c磷酸酯酶表达,上调CDK抑制剂(p21 和 p27)的表达从而导致HUVECs细胞周期中G1期阻滞;B2G2也能通过增加p53, Bax and Smac/Diablo的表达,降低Bcl-2和survivin表达水平来诱导显著的凋亡作用。另外,在HUVECs和 HPMECs中,B2G2能抑制生长因子诱导的毛细血管生成。有趣的是,前列腺癌(PCA)细胞(LNCaP 和PC3) 生长在常氧(~21% 氧气)和缺氧(~ 1%氧气)下的条件培养基(CCM)显著增强HUVECs管腔形成,B2G2处理前列腺癌细胞后的条件培养基却能使该增强现象减弱。B2G2也都能够抑制HUVECs 和HPMECs的侵袭和迁移,进一步的机理研究表明,该作用是通过B2G2作用于VEGFR2/PI3K/Akt和整合素信号分子而产生,该信号通路对于内皮细胞存活、增殖、血管形成和迁移是非常重要的。总的来说,本研究报道在细胞培养的条件下B2G2抑制肿瘤血管生成的几个特性,值得进一步研究B2G2预防癌变和控制癌症的效果。
关键词: 抗血管生成;凋亡;原花青素B-2-3
图形摘要
Current Cancer Drug Targets
Title:Procyanidin B2 3,3″-di-O-gallate Inhibits Endothelial Cells Growth and Motility by Targeting VEGFR2 and Integrin Signaling Pathways
Volume: 15 Issue: 1
Author(s): Rahul Kumar, Gagan Deep, Michael F. Wempe, Rajesh Agarwal and Chapla Agarwal
Affiliation:
关键词: 抗血管生成;凋亡;原花青素B-2-3
摘要: 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.
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Cite this article as:
Rahul Kumar, Gagan Deep, Michael F. Wempe, Rajesh Agarwal and Chapla Agarwal , Procyanidin B2 3,3″-di-O-gallate Inhibits Endothelial Cells Growth and Motility by Targeting VEGFR2 and Integrin Signaling Pathways, Current Cancer Drug Targets 2015; 15 (1) . https://dx.doi.org/10.2174/1568009614666141229102254
DOI https://dx.doi.org/10.2174/1568009614666141229102254 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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