The isoflavone metabolite 6-methoxyequol inhibits angiogenesis and suppresses tumor growth.
The isoflavone metabolite 6-methoxyequol inhibits angiogenesis and suppresses tumor growth.
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DOI：
10.1186/1476-4598-11-35
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发表时间：
2012-05-14
期刊：
影响因子：
37.3
通讯作者：
Fotsis T
中科院分区：
文献类型：
--
作者：
Bellou S;Karali E;Bagli E;Al-Maharik N;Morbidelli L;Ziche M;Adlercreutz H;Murphy C;Fotsis T
植物性饮食消费的增加与某些植物化学物质的存在有关，包括多酚类化合物，如黄酮类化合物。这些化合物中的几种通过抑制肿瘤血管生成发挥其保护作用。鉴定具有潜在抗血管生成活性的其他植物化学物质不仅对于理解预防作用的机制很重要，而且对于开发新的治疗干预措施也很重要。在试图确定植物化学物质有助于充分记录的预防作用的植物性饮食对癌症的发病率和死亡率，我们已经筛选了一组迄今为止未经测试的植物雌激素代谢物关于其抗血管生成的作用，使用内皮细胞增殖作为终点。在这里，我们发现，一种新的植物雌激素，6-甲氧基雌马酚（6-ME），抑制VEGF诱导的人脐静脉内皮细胞（HUVE）细胞的增殖，而VEGF诱导的迁移和生存的HUVE细胞保持不受影响。此外，6-ME抑制FGF-2诱导的牛脑毛细血管内皮细胞（BBCE）的增殖。与其在细胞增殖中的作用一致，6-ME抑制VEGF诱导的ERK 1/2 MAPK磷酸化，ERK 1/2 MAPK是VEGF诱导的内皮细胞增殖的关键级联反应。在这种情况下，6-ME以剂量依赖性方式抑制MEK 1/2的磷酸化，MEK 1/2是ERK 1/2唯一已知的上游激活剂。6-ME不改变VEGF诱导的p38 MAPK或AKT的磷酸化，这与缺乏对VEGF诱导的内皮细胞迁移和存活的影响相一致。在A-431异种移植肿瘤中的肿瘤周围注射6-ME导致与媒介物对照相比肿瘤生长减少且新血管形成受到抑制（P < 0.01）。6-ME通过靶向MEK 1/2及其下游底物ERK 1/2的磷酸化来抑制VEGF和FGF 2诱导的EC增殖，MEK 1/2和ERK 1/2都是促有丝分裂MAPK途径的关键组分。注射6-ME在小鼠A-431异种移植瘤中导致肿瘤具有减少的新血管生成和减小的肿瘤体积，这表明6-ME可能被开发为用于癌症治疗的新型抗血管生成剂。
Increased consumption of plant-based diets has been linked to the presence of certain phytochemicals, including polyphenols such as flavonoids. Several of these compounds exert their protective effect via inhibition of tumor angiogenesis. Identification of additional phytochemicals with potential antiangiogenic activity is important not only for understanding the mechanism of the preventive effect, but also for developing novel therapeutic interventions. In an attempt to identify phytochemicals contributing to the well-documented preventive effect of plant-based diets on cancer incidence and mortality, we have screened a set of hitherto untested phytoestrogen metabolites concerning their anti-angiogenic effect, using endothelial cell proliferation as an end point. Here, we show that a novel phytoestrogen, 6-methoxyequol (6-ME), inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVE) cells, whereas VEGF-induced migration and survival of HUVE cells remained unaffected. In addition, 6-ME inhibited FGF-2-induced proliferation of bovine brain capillary endothelial (BBCE) cells. In line with its role in cell proliferation, 6-ME inhibited VEGF-induced phosphorylation of ERK1/2 MAPK, the key cascade responsible for VEGF-induced proliferation of endothelial cells. In this context, 6-ME inhibited in a dose dependent manner the phosphorylation of MEK1/2, the only known upstream activator of ERK1/2. 6-ME did not alter VEGF-induced phosphorylation of p38 MAPK or AKT, compatible with the lack of effect on VEGF-induced migration and survival of endothelial cells. Peri-tumor injection of 6-ME in A-431 xenograft tumors resulted in reduced tumor growth with suppressed neovasularization compared to vehicle controls (P < 0.01). 6-ME inhibits VEGF- and FGF2-induced proliferation of ECs by targeting the phosphorylation of MEK1/2 and it downstream substrate ERK1/2, both key components of the mitogenic MAPK pathway. Injection of 6-ME in mouse A-431 xenograft tumors results to tumors with decreased neovascularization and reduced tumor volume suggesting that 6-ME may be developed to a novel anti-angiogenic agent in cancer treatment.
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影响因子：
2.5
作者：
Gómez, AR;López-Varea, A;de Celis, JF
通讯作者：
de Celis, JF
DOI：
10.1073/pnas.90.7.2690
发表时间：
1993-04-01
影响因子：
11.1
作者：
FOTSIS, T;PEPPER, M;SCHWEIGERER, L
通讯作者：
SCHWEIGERER, L
DOI：
10.1111/j.1432-1033.1983.tb07692.x
发表时间：
1983-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
GRAZIANI, Y;ERIKSON, E;ERIKSON, RL
通讯作者：
ERIKSON, RL
影响因子：
4.8
作者：
McMullen, ME;Bryant, PW;Pumiglia, KM
通讯作者：
Pumiglia, KM
分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.