Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling
Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling
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DOI：
10.1093/carcin/bgn070
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发表时间：
2008-05-01
期刊：
影响因子：
4.7
通讯作者：
Beliveu, Richard
中科院分区：
文献类型：
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作者：
Lamy, Sylvie;Beaulieu, Edith;Beliveu, Richard
大多数肿瘤依赖于肿瘤血管的生长，抑制肿瘤血管生成可能为延缓或阻断肿瘤生长提供有效的策略。最近，肿瘤血管靶向已扩大到不仅包括内皮细胞(ECs)，还包括平滑肌细胞(SMCs)，这些细胞有助于形成成熟的和功能强大的血管系统。我们以前已经报道过，浆果中的主要生物活性成分Delphinidin可以抑制血管内皮生长因子诱导的血管内皮生长因子受体-2的磷酸化，并在体内外阻止血管生成。在本研究中，我们发现飞雀素还抑制SMC中血小板衍生生长因子(PDGF)-BB受体-β[血小板衍生生长因子受体-β(PDGFR-β)]的激活，这种抑制作用可能与其抗肿瘤作用有关。Delphinidin对PDGFR-β的抑制作用非常迅速，可抑制PDGF-BB诱导的细胞外信号调节激酶(ERK)-1/2信号的激活和SMC的趋化运动，并在三维共培养体系中抑制EC和SMC向毛细血管样小管结构的分化和稳定。利用富含花青素的浆果提取物，在小鼠Matrigel Plug实验中，我们发现浆果提取物能够抑制碱性成纤维细胞生长因子-2和PDGF-BB对血管形成的协同诱导。口服浆果提取物也显著抑制了肺癌异种移植模型中的肿瘤生长。综上所述，这些结果为揭示飞蚊素抗血管生成活性的分子机制提供了新的视角，这将有助于开发以饮食为基础的化学预防策略。
Most cancers are dependent on the growth of tumor blood vessels and inhibition of tumor angiogenesis may thus provide an efficient strategy to retard or block tumor growth. Recently, tumor vascular targeting has expanded to include not only endothelial cells (ECs) but also smooth muscle cells (SMCs), which contribute to a mature and functional vasculature. We have reported previously that delphinidin, a major biologically active constituent of berries, inhibits the vascular endothelial growth factor-induced phosphorylation of vascular endothelial growth factor receptor-2 and blocks angiogenesis in vitro and in vivo. In the present study, we show that delphinidin also inhibits activation of the platelet-derived growth factor (PDGF)-BB receptor-beta [platelet-derived growth factor receptor-beta (PDGFR-beta)] in SMC and that this inhibition may contribute to its antitumor effect. The inhibitory effect of delphinidin on PDGFR-beta was very rapid and led to the inhibition of PDGF-BB-induced activation of extracellular signal-regulated kinase (ERK)-1/2 signaling and of the chemotactic motility of SMC, as well as the differentiation and stabilization of EC and SMC into capillary-like tubular structures in a three-dimensional coculture system. Using an anthocyan-rich extract of berries, we show that berry extracts were able to suppress the synergistic induction of vessel formation by basic fibroblast growth factor-2 and PDGF-BB in the mouse Matrigel plug assay. Oral administration of the berry extract also significantly retarded tumor growth in a lung carcinoma xenograft model. Taken together, these results provide new insight into the molecular mechanisms underlying the antiangiogenic activity of delphinidin that will be helpful for the development of dietary-based chemopreventive strategies.