Sun Jing-Yi, Hou Ya-Jun, Cui Hai-Juan, Zhang Cheng, Yang Ming-Feng, Wang Feng-Ze, Sun Zheng, Fan Cun-Dong, Sun Bao-Liang, Oh Jin Rok
Department of Orthopedics, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Gangwon, 26426, Korea.
Department of Neurology, Second Affiliated Hospital; Key Lab of Cerebral Microcirculation in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, China.
Curr Cancer Drug Targets. 2020;20(8):616-623. doi: 10.2174/1568009620666200414150353.
Activation of the PI3K/mTOR signaling pathway plays a key role in the progression of human osteosarcoma. Studies have confirmed that VS-5584 was a novel inhibitor of the PI3K/mTOR pathway, and displayed potential anticancer activity.
To explore the anticancer effect and underlying mechanism of VS-5584 against the growth of human osteosarcoma cells.
U2OS and MG-63 human osteosarcoma cells were cultured and the cytotoxicity, cell apoptosis in VS-5584-treated cells were explored by the CCK8 assay, flow cytometric analysis and western blot. Cell migration and tube formation were also employed to examine the anticancer potential.
The results showed that VS-5584 treatment dose-dependently inhibited the growth of U2OS and MG-63 cells by induction of G1-phase arrest through regulating p21, p27, Cyclin B1 and Cdc2. Further investigation revealed that VS-5584 treatment effectively inhibited the PI3K/mTOR signaling pathway and triggered MAPK phosphorylation. Moreover, VS-5584 treatment dramatically suppressed cell migration and tube formation of HUVECs, followed by the down-regulation of HIF-1α and VEGF.
Our findings validated that VS-5584 may be a promising anticancer agent with potential application in the chemotherapy and chemoprevention of human osteosarcoma.
PI3K/mTOR信号通路的激活在人类骨肉瘤进展中起关键作用。研究证实VS-5584是一种新型的PI3K/mTOR通路抑制剂，并显示出潜在的抗癌活性。
探讨VS-5584对人骨肉瘤细胞生长的抗癌作用及潜在机制。
培养U2OS和MG-63人骨肉瘤细胞，通过CCK8法、流式细胞术分析和蛋白质印迹法探讨VS-5584处理细胞后的细胞毒性、细胞凋亡情况。还采用细胞迁移和管腔形成实验检测其抗癌潜力。
结果显示，VS-5584处理通过调节p21、p27、细胞周期蛋白B1和细胞分裂周期蛋白2诱导G1期阻滞，从而剂量依赖性地抑制U2OS和MG-63细胞的生长。进一步研究表明，VS-5584处理可有效抑制PI3K/mTOR信号通路并触发丝裂原活化蛋白激酶（MAPK）磷酸化。此外，VS-5584处理显著抑制人脐静脉内皮细胞（HUVECs）的细胞迁移和管腔形成，随后下调缺氧诱导因子-1α（HIF-1α）和血管内皮生长因子（VEGF）。
我们的研究结果证实，VS-5584可能是一种有前景的抗癌药物，在人类骨肉瘤的化疗和化学预防中具有潜在应用价值。
