The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-kB pathway
The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-kB pathway
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新型血管生成抑制剂（八氢萘衍生物）同时靶向 VEGF 受体和 NF-kB 通路的抗肿瘤作用
DOI：
10.1002/ijc.26356
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发表时间：
2012
影响因子：
6.4
通讯作者：
M.
中科院分区：
文献类型：
--
作者：
Watari;K.;Nakamura;M.;Fukunaga;Y.;Furuno;A.;Shibata;T.;Kawahara;A.;Hosoi;F.;Kuwano T.;Kuwano;M.;Ono;M.
一种新型血管生成抑制剂的开发将对进一步改善癌症患者的治疗方法至关重要。我们研究了八氢萘衍生物AMF - 26是否可以阻断血管内皮细胞对血管内皮生长因子（VEGF）和/或炎症细胞因子的血管生成，AMF - 26被筛选为血管内皮细胞炎症刺激刺激下细胞间粘附分子1 （ICAM - 1）产生的抑制剂。低剂量AMF‐26能有效抑制人脐血管内皮细胞（HUVECs）中肿瘤坏死因子α （TNF‐α）或白细胞介素- 1β （IL‐1β）诱导的ICAM‐1的产生。我们发现，在内皮细胞和癌细胞中，TNF‐α诱导的κB轻多肽基因增强子核因子磷酸化、α (i - κBα)和p65核易位被AMF‐26破坏。AMF‐26可以抑制HUVECs中VEGF受体1 （VEGFR1）、VEGFR2和下游信号分子Akt、细胞外信号调节激酶（ERK）1/2的磷酸化。因此，VEGF诱导的血管内皮细胞的增殖、迁移和管状形成极易受到AMF - 26的抑制。口服AMF - 26可显著阻断VEGF -或IL - 1β -诱导的小鼠角膜血管生成，以及肿瘤血管生成和生长。总之，我们的研究结果表明，当受到VEGF或炎症细胞因子刺激时，AMF‐26通过抑制VEGFR1/2和核因子κB （NF‐κB）信号通路抑制血管生成。AMF - 26可能是一种有前景的新型癌症治疗候选药物。
Development of a novel type of angiogenesis inhibitor will be essential for further improvement of therapeutics against cancer patients. We examined whether an octahydronaphthalene derivative, AMF‐26, which was screened as an inhibitor of intercellular adhesion molecule‐1 (ICAM‐1) production stimulated by inflammatory stimuli in vascular endothelial cells, could block angiogenesis in response to vascular endothelial growth factor (VEGF) and/or inflammatory cytokines. Low dose AMF‐26 effectively inhibited the tumor necrosis factor‐α (TNF‐α)‐ or the interleukin‐1β (IL‐1β)‐induced production of ICAM‐1 in human umbilical vascular endothelial cells (HUVECs). We found that the TNF‐α‐induced phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B‐cells inhibitor, alpha (IκBα) and nuclear translocation of p65 were impaired by AMF‐26 in both endothelial cells and cancer cells. AMF‐26 was found to inhibit the phosphorylation of VEGF receptor 1 (VEGFR1), VEGFR2 and the downstream signaling molecules Akt, extracellular signal‐regulated kinase (ERK)1/2 stimulated by VEGF in HUVECs. Therefore, the VEGF‐induced proliferation, migration and tube formation of vascular endothelial cells was highly susceptible to inhibition by AMF‐26. Oral administration of AMF‐26 significantly blocked VEGF‐ or IL‐1β‐induced angiogenesis in the mouse cornea, and also tumor angiogenesis and growth. Together, our results indicate that AMF‐26 inhibits angiogenesis through suppression of both VEGFR1/2 and nuclear factor‐κB (NF‐κB) signaling pathways when stimulated by VEGF or inflammatory cytokines. AMF‐26 could be a promising novel candidate drug for cancer treatments.