State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Pharmacy, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China.
Chem Biol Drug Des. 2024 Mar;103(3):e14503. doi: 10.1111/cbdd.14503.
Flubendazole, an FDA-approved anthelmintic, has been predicted to show strong VEGFR2 inhibitory activity in silico screening combined with in vitro experimental validation, and it has shown anti-cancer effects on some human cancer cell lines, but little is known about the anti-angiogenesis effects and anti-prostate cancer effects. In this study, we analyzed the binding modes and kinetic analysis of flubendazole with VEGFR2 and first demonstrated that flubendazole suppressed VEGF-stimulated cell proliferation, wound-healing migration, cell invasion and tube formation of HUVEC cells, and decreased the phosphorylation of extracellular signal-regulated kinase and serine/threonine kinase Akt, which are the downstream proteins of VEGFR2 that are important for cell growth. What's more, our results showed that flubendazole decreased PC-3 cell viability and proliferation ability, and suppressed PC-3 cell wound healing migration and invasion across a Matrigel-coated Transwell membrane in a concentration-dependent manner. The antiproliferative effects of flubendazole were due to induction of G2-M phase cell cycle arrest in PC-3 cells with decreasing expression of the Cyclin D1 and induction of cell apoptosis with the number of apoptotic cells increased after flubendazole treatment. These results indicated that flubendazole could exert anti-angiogenic and anticancer effects by inhibiting cell cycle and inducing cell apoptosis.
氟苯达唑是一种获得 FDA 批准的驱虫药，通过计算机模拟筛选结合体外实验验证，预测其具有很强的 VEGFR2 抑制活性，并且已显示出对某些人类癌细胞系的抗癌作用，但对其抗血管生成和抗前列腺癌作用知之甚少。在这项研究中，我们分析了氟苯达唑与 VEGFR2 的结合模式和动力学，并首次证明氟苯达唑抑制了 VEGF 刺激的 HUVEC 细胞增殖、划痕愈合迁移、细胞侵袭和管形成，降低了 VEGFR2 的下游蛋白细胞外信号调节激酶和丝氨酸/苏氨酸激酶 Akt 的磷酸化，这些蛋白对细胞生长很重要。更重要的是，我们的结果表明，氟苯达唑降低了 PC-3 细胞的活力和增殖能力，并呈浓度依赖性抑制了 PC-3 细胞的划痕愈合迁移和侵袭穿过 Matrigel 包被的 Transwell 膜。氟苯达唑的抗增殖作用是由于诱导 PC-3 细胞 G2-M 期细胞周期停滞，细胞周期蛋白 D1 的表达降低，并诱导细胞凋亡，氟苯达唑处理后凋亡细胞数量增加。这些结果表明，氟苯达唑通过抑制细胞周期和诱导细胞凋亡发挥抗血管生成和抗癌作用。
