Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3'-kinase activity
Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3'-kinase activity
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DOI：
10.1158/0008-5472.can-03-3104
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发表时间：
2004-11-01
期刊：
影响因子：
11.2
通讯作者：
Fotsis, T
中科院分区：
文献类型：
--
作者：
Bagli, E;Stefaniotou, M;Fotsis, T
为了确定植物化学物质有助于植物性饮食对癌症发病率和死亡率的预防作用，我们之前已经证明某些黄酮类化合物会抑制体外血管生成。在这里，我们证明黄酮类木犀草素在小鼠异种移植模型中抑制肿瘤生长和血管生成。此外，在兔角膜试验中，木犀草素可抑制血管内皮生长因子 (VEGF) 诱导的体内血管生成。与此一致，木犀草素抑制 VEGF 诱导的人脐静脉内皮细胞 (HUVEC) 的存活和增殖，IC50 约为 5 μmol/L。木犀草素抑制 HUVEC 中 VEGF 诱导的磷脂酰肌醇 3'-激酶 (PI3K) 活性，这种抑制对于该化合物的抗存活和抗有丝分裂作用至关重要。事实上，木犀草素消除了 VEGF 诱导的 Akt 激活，Akt 是传递生存和有丝分裂下游信号的 PI3K 下游靶标。由于 Akt 组成型活性形式的过度表达只能使 HUVEC 免受木犀草素的抗生存作用的影响，因此结果表明木犀草素主要针对 PI3K/Akt 途径的生存信号。就其抗有丝分裂活性而言，木犀草素可抑制 VEGF 诱导的 p70 S6 激酶 (S6K) 磷酸化，p70 S6 激酶 (S6K) 是负责 G1 进展的 PI3K 下游效应子。事实上，VEGF 诱导的 HUVEC 增殖对雷帕霉素（一种 p70 S6K 激活抑制剂）敏感。令人惊讶的是，木犀草素并不影响 VEGF 诱导的细胞外信号调节激酶 1/2 有丝分裂原激活蛋白激酶的磷酸化，这一途径被认为对 VEGF 有丝分裂作用很重要。因此，木犀草素对 PI3K 的阻断是该化合物对 VEGF 诱导的 HUVEC 存活和增殖的抑制作用的原因。木犀草素的抗存活作用是通过阻断 PI3K/Akt 依赖性途径介导的，而抑制 PI3K/p70 S6K 途径则介导该化合物的抗有丝分裂作用。
In an attempt to identify phytochemicals contributing to the well-documented preventive effect of plant-based diets on cancer incidence and mortality, we have previously shown that certain flavonoids inhibit in vitro angiogenesis. Here, we show that the flavonoid luteolin inhibited tumor growth and angiogenesis in a murine xenograft model. Furthermore, luteolin inhibited vascular endothelial growth factor (VEGF)-induced in vivo angiogenesis in the rabbit corneal assay. In agreement, luteolin inhibited both VEGF-induced survival and proliferation of human umbilical vein endothelial cells (HUVECs) with an IC50 of about 5 mumol/L. Luteolin inhibited VEGF-induced phosphatidylinositol 3'-kinase (PI3K) activity in HUVECs, and this inhibition was critical for both the antisurvival and antimitotic affects of the compound. Indeed, luteolin abolished VEGF-induced activation of Akt, a downstream target of PI3K conveying both survival and mitotic downstream signals. Because overexpression of a constitutively active form of Akt rescued HUVECs only from the antisurvival effects of luteolin, the result indicated that luteolin targeted mainly the survival signals of the PI3K/Akt pathway. With regard to its antimitotic activity, luteolin inhibited VEGF-induced phosphorylation of p70 S6 kinase (S6K), a downstream effector of PI3K responsible for G, progression. Indeed, VEGF-induced proliferation of HUVECs was sensitive to rapamycin, an inhibitor of p70 S6K activation. Surprisingly, luteolin did not affect VEGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases, a pathway that is considered important for the mitotic effects of VEGF. Thus, blockade of PI3K by luteolin was responsible for the inhibitory effects of the compound on VEGF-induced survival and proliferation of HUVECs. The antisurvival effects of luteolin were mediated via blockage of PI3K/Akt-dependent pathways, whereas inhibition of the PI3K/p70 S6K pathway mediated the antimitotic effects of the compound.