Tylophorine, a phenanthraindolizidine alkaloid isolated from Tylophora indica exerts antiangiogenic and antitumor activity by targeting vascular endothelial growth factor receptor 2-mediated angiogenesis.
Tylophorine, a phenanthraindolizidine alkaloid isolated from Tylophora indica exerts antiangiogenic and antitumor activity by targeting vascular endothelial growth factor receptor 2-mediated angiogenesis.
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DOI：
10.1186/1476-4598-12-82
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发表时间：
2013-07-29
期刊：
影响因子：
37.3
通讯作者：
Alhaider AA
中科院分区：
文献类型：
--
作者：
Saraswati S;Kanaujia PK;Kumar S;Kumar R;Alhaider AA
以VEGFR 2为靶点的抗血管生成已被认为是肿瘤治疗的重要策略。Tylophorine具有抗炎、抗肿瘤活性，但其在肿瘤血管生成中的作用及其分子机制尚不清楚。因此，我们在体外和体内研究其抗血管生成作用和机制。本研究采用体外培养的人脐静脉内皮细胞（HUVEC）和体内培养的埃利希腹水癌（EAC）细胞，观察了雷公藤甲素的抑制作用。Tylophorine显著抑制VEGF诱导的血管生成过程，包括内皮细胞的增殖、迁移和管形成。此外，它还能直接抑制血管内皮细胞中VEGFR 2酪氨酸激酶活性及其下游信号通路Akt、Erk和ROS。用HUVECs，我们证明，雷公藤甲素抑制VEGF刺激的炎症反应，包括IL-6，IL-8，TNF-α，IFN-γ，MMP-2和NO的分泌。在海绵移植血管生成实验中，娃儿藤碱能显著抑制新生血管的生成，在体内也能抑制肿瘤血管生成和肿瘤生长。分子对接模拟结果表明，在VEGFR 2激酶单元的ATP结合区域内，野牡丹碱可以形成氢键和芳香相互作用。Tylophorine通过VEGFR 2信号通路发挥抗血管生成作用，因此可能是抗血管生成和抗癌治疗的可行候选药物。
Anti-angiogenesis targeting VEGFR2 has been considered as an important strategy for cancer therapy. Tylophorine is known to possess anti-inflammatory and antitumor activity, but its roles in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is still unknown. Therefore, we examined its anti-angiogenic effects and mechanisms in vitro and in vivo. We used tylophorine and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro and Ehrlich ascites carcinoma (EAC) tumor in vivo. Tylophorine significantly inhibited a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation of endothelial cells. Besides, it directly inhibited VEGFR2 tyrosine kinase activity and its downstream signaling pathways including Akt, Erk and ROS in endothelial cells. Using HUVECs we demonstrated that tylophorine inhibited VEGF-stimulated inflammatory responses including IL-6, IL-8, TNF-α, IFN-γ, MMP-2 and NO secretion. Tylophorine significantly inhibited neovascularization in sponge implant angiogenesis assay and also inhibited tumor angiogenesis and tumor growth in vivo. Molecular docking simulation indicated that tylophorine could form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit. Tylophorine exerts anti-angiogenesis effects via VEGFR2 signaling pathway thus, may be a viable drug candidate in anti-angiogenesis and anti-cancer therapies.
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影响因子：
4.3
作者：
Agrawal, S. S.;Saraswati, Sarita;Pandey, Maneesha
通讯作者：
Pandey, Maneesha
影响因子：
2.7
作者：
Gao, Wenli;Bussom, Scott;Cheng, Yung-Chi
通讯作者：
Cheng, Yung-Chi
影响因子：
3.5
作者：
Ali, N;Yoshizumi, M;Tamaki, T
通讯作者：
Tamaki, T
DOI：
10.1152/ajpheart.00786.2003
发表时间：
2004-05-01
影响因子：
4.8
作者：
Cho, CH;Lee, CS;Koh, GY
通讯作者：
Koh, GY
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.