Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway.
Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway.
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膳食化合物异甘草素通过 VEGF/VEGFR-2 信号通路抑制乳腺癌新血管生成。
DOI：
10.1371/journal.pone.0068566
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Wang Z;Wang N;Han S;Wang D;Mo S;Yu L;Huang H;Tsui K;Shen J;Chen J
血管生成对肿瘤的发生、发展和转移起着至关重要的作用。以血管生成为靶点的天然植物药具有安全性高等优点，近年来在新药开发中备受关注。异甘草素(Isoliquiritigenin，ISL)是一种膳食查尔酮型黄酮类化合物，具有多种抗癌活性。然而，对异甘草素的抗血管生成活性及其潜在机制知之甚少。在此，我们发现ISL在无毒浓度下能显著抑制血管内皮生长因子诱导的人脐静脉内皮细胞的增殖。体外培养的人脐静脉内皮细胞血管形成、侵袭和迁移能力等一系列血管生成过程也被ISL阻断。此外，在体外模型中，ISL抑制了血管内皮生长因子治疗的主动脉环的萌芽形成。分子机制研究表明，ISL可通过促进缺氧诱导因子-1蛋白酶体的降解而显著抑制乳腺癌细胞中血管内皮生长因子的表达，并直接与α-2相互作用，阻断其激酶活性，从而抑制α的表达。体内研究进一步表明，ISL可以抑制乳腺癌的生长和新生血管生成，同时抑制VEGF/VEGFR-2信号转导，提高细胞凋亡率，毒性作用较小。分子对接模拟表明，ISL可以稳定地在VEGFR-2的ATP结合区形成氢键和芳香族相互作用。综上所述，我们的研究揭示了ISL作为一种通过VEGF/VEGFR-2途径抑制肿瘤血管生成的新型天然抑制剂的潜在应用。因此，未来ISL用于乳腺癌的化学预防或化学增敏的研究是有必要的。
Angiogenesis is crucial for cancer initiation, development and metastasis. Identifying natural botanicals targeting angiogenesis has been paid much attention for drug discovery in recent years, with the advantage of increased safety. Isoliquiritigenin (ISL) is a dietary chalcone-type flavonoid with various anti-cancer activities. However, little is known about the anti-angiogenic activity of isoliquiritigenin and its underlying mechanisms. Herein, we found that ISL significantly inhibited the VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) at non-toxic concentration. A series of angiogenesis processes including tube formation, invasion and migration abilities of HUVECs were also interrupted by ISL in vitro. Furthermore, ISL suppressed sprout formation from VEGF-treated aortic rings in an ex-vivo model. Molecular mechanisms study demonstrated that ISL could significantly inhibit VEGF expression in breast cancer cells via promoting HIF-1α (Hypoxia inducible factor-1α) proteasome degradation and directly interacted with VEGFR-2 to block its kinase activity. In vivo studies further showed that ISL administration could inhibit breast cancer growth and neoangiogenesis accompanying with suppressed VEGF/VEGFR-2 signaling, elevated apoptosis ratio and little toxicity effects. Molecular docking simulation indicated that ISL could stably form hydrogen bonds and aromatic interactions within the ATP-binding region of VEGFR-2. Taken together, our study shed light on the potential application of ISL as a novel natural inhibitor for cancer angiogenesis via the VEGF/VEGFR-2 pathway. Future studies of ISL for chemoprevention or chemosensitization against breast cancer are thus warranted.
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