School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, P.R. China.
Anticancer Agents Med Chem. 2024;24(19):1419-1430. doi: 10.2174/0118715206313028240819103933.
Non-Small Cell Lung Cancer (NSCLC) has attracted much attention on account of the high incidence and mortality of cancers. Vascular Endothelial Growth Factor Receptor 3 (VEGFR3/FLT4), which is a highly expressed receptor in NSCLC, greatly regulates cancer proliferation and migration. Pseudolaric Acid B (PAB) is a diterpenoid acid with antitumor activity isolated from This study aimed to explore the inhibitory effect of PAB targeting FLT4 in NSCLC.
Cell membrane chromatography was used to evaluate the affinity of PAB binding on FLT4. NCIH1299 cells were used in this study, and an MTT assay was performed to determine the anti-proliferation effect of PAB. Cell cycle analysis was conducted to study the cycle arrest of PAB. Wound healing and Transwell assays assessed the rate of cell migration. Western blot analysis evaluated the expression of related proteins.
PAB showed strong affinity to FLT4 with a value of 3.01 × 10 M. Targeting FLT4 by PAB inactivated downstream P38MAPK and PI3K/AKT pathways, which inhibited the proliferation of NCI-H1299 cells. Meanwhile, PAB promoted G2/M phase arrest by influencing CyclinB1 and CDK1 complex formation to inhibit NCI-H1299 cell growth, but the effect was attenuated by knocking down the FLT4. Besides, PAB regulated MMP9 secretion through the Wnt/β-catenin signaling pathway to inhibit NCI-H1299 cell migration. However, the ability of PAB to inhibit migration was significantly weakened by FLT4 knockdown in NCI-H1299 cells.
PAB can inhibit the proliferation and migration of NSCLC cells through targeting FLT4 and is expected to be a promising FLT4 inhibitor for NSCLC treatment.
非小细胞肺癌（NSCLC）发病率和死亡率高，引起了广泛关注。血管内皮生长因子受体 3（VEGFR3/FLT4）在 NSCLC 中高度表达，极大地调节了癌症的增殖和迁移。白头翁素 B（PAB）是一种从白头翁中分离得到的具有抗肿瘤活性的二萜酸。本研究旨在探讨 PAB 靶向 FLT4 对 NSCLC 的抑制作用。
采用细胞膜色谱法评价 PAB 与 FLT4 的结合亲和力。本研究采用 NCIH1299 细胞，通过 MTT 法测定 PAB 的抗增殖作用。通过细胞周期分析研究 PAB 引起的细胞周期阻滞。通过划痕愈合和 Transwell 实验评估细胞迁移率。Western blot 分析评估相关蛋白的表达。
PAB 与 FLT4 具有很强的亲和力， 值为 3.01×10 M。PAB 靶向 FLT4 可使下游 P38MAPK 和 PI3K/AKT 通路失活，从而抑制 NCI-H1299 细胞的增殖。同时，PAB 通过影响 CyclinB1 和 CDK1 复合物的形成促进 G2/M 期阻滞，从而抑制 NCI-H1299 细胞生长，但这种作用在 FLT4 敲低时被减弱。此外，PAB 通过 Wnt/β-catenin 信号通路调节 MMP9 分泌，从而抑制 NCI-H1299 细胞迁移。然而，在 NCI-H1299 细胞中敲低 FLT4 后，PAB 抑制迁移的能力显著减弱。
PAB 通过靶向 FLT4 抑制 NSCLC 细胞的增殖和迁移，有望成为治疗 NSCLC 的有前途的 FLT4 抑制剂。
