藤黄酰胺通过非依赖于 TrkA 的方式抑制内皮细胞中的 VEGF/VEGFR2 抑制血管生成。
Gambogic amide inhibits angiogenesis by suppressing VEGF/VEGFR2 in endothelial cells in a TrkA-independent manner.
机构信息
State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, Kunming, China.
出版信息
Pharm Biol. 2021 Dec;59(1):1566-1575. doi: 10.1080/13880209.2021.1998140.
CONTEXT
Gambogic amide (GA-amide) is a non-peptide molecule that has high affinity for tropomyosin receptor kinase A (TrkA) and possesses robust neurotrophic activity, but its effect on angiogenesis is unclear.
OBJECTIVE
The study investigates the antiangiogenic effect of GA-amide on endothelial cells (ECs).
MATERIALS AND METHODS
The viability of endothelial cells (ECs) treated with 0.1, 0.15, 0.2, 0.3, 0.4, and 0.5 μM GA-amide for 48 h was detected by MTS assay. Wound healing and angiogenesis assays were performed on cells treated with 0.2 μM GA-amide. Chicken eggs at day 7 post-fertilization were divided into the dimethyl sulfoxide (DMSO), bevacizumab (40 μg), and GA-amide (18.8 and 62.8 ng) groups to assess the antiangiogenic effect for 3 days. mRNA and protein expression in cells treated with 0.1, 0.2, 0.4, 0.8, and 1.2 μM GA-amide for 6 h was detected by qRT-PCR and Western blots, respectively.
RESULTS
GA-amide inhibited HUVEC (IC = 0.1269 μM) and NhEC (IC = 0.1740 μM) proliferation, induced cell apoptosis, and inhibited the migration and angiogenesis at a relatively safe dose (0.2 μM) . GA-amide reduced the number of capillaries from 56 ± 14.67 (DMSO) to 20.3 ± 5.12 (62.8 ng) in chick chorioallantoic membrane (CAM) assay. However, inactivation of TrkA couldn't reverse the antiangiogenic effect of GA-amide. Moreover, GA-amide suppressed the expression of VEGF and VEGFR2, and decreased activation of the AKT/mTOR and PLCγ/Erk1/2 pathways.
CONCLUSIONS
Considering the antiangiogenic effect of GA-amide, it might be developed as a useful agent for use in clinical combination therapies.
背景
藤黄酰胺（GA-amide）是一种非肽类分子，对原肌球蛋白受体激酶 A（TrkA）具有高亲和力，具有强大的神经营养活性，但它对血管生成的影响尚不清楚。
目的
本研究探讨 GA-amide 对内皮细胞（ECs）的抗血管生成作用。
材料和方法
用 MTS 法检测 0.1、0.15、0.2、0.3、0.4 和 0.5μM GA-amide 处理 48h 后内皮细胞（ECs）的活力。用 0.2μM GA-amide 处理细胞进行划痕愈合和血管生成实验。将受精后 7 天的鸡卵分为二甲基亚砜（DMSO）、贝伐单抗（40μg）和 GA-amide（18.8 和 62.8ng）组，连续 3 天评估抗血管生成作用。用 qRT-PCR 和 Western blot 分别检测 0.1、0.2、0.4、0.8 和 1.2μM GA-amide 处理 6h 后细胞的 mRNA 和蛋白表达。
结果
GA-amide 抑制 HUVEC（IC=0.1269μM）和 NhEC（IC=0.1740μM）增殖，诱导细胞凋亡，并在相对安全剂量（0.2μM）下抑制迁移和血管生成。GA-amide 使鸡胚绒毛尿囊膜（CAM）试验中毛细血管数量从 56±14.67（DMSO）减少至 20.3±5.12（62.8ng）。然而，TrkA 的失活不能逆转 GA-amide 的抗血管生成作用。此外，GA-amide 抑制了 VEGF 和 VEGFR2 的表达，并降低了 AKT/mTOR 和 PLCγ/Erk1/2 通路的激活。
结论
鉴于 GA-amide 的抗血管生成作用，它可能被开发为临床联合治疗的有用药物。
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