Department of Central Lab, Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong 271000, China.
Department of Neurology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong 250000, China.
Biomed Pharmacother. 2022 Sep;153:113502. doi: 10.1016/j.biopha.2022.113502. Epub 2022 Aug 4.
NT157, a small-molecule tyrosine kinase inhibitor, exhibits broad-spectrum anti-tumor activity. However, NT157-mediated inhibition against glioma has not been explored yet. Herein, the anticancer effects and underlying mechanism of NT157 against human giloma growth were evaluated. The results showed that NT157 alone significantly inhibited glioma cells growth in vitro by lunching cell cycle arrest through up-regulating p21 and p27, and down-regulating cell cycle-related factors. NT157 alone also induced significant glioma cells apoptosis, followed by PARP cleavage and caspase-3 activation. Our findings further revealed that NT157 triggered significant DNA damage and dysfunction of PI3K/AKT, MAPKs and EGFR-STAT3 signaling pathways. Addition of several kinases inhibitors effectively abrogated NT157-induced DR5 up-regulation, which further confirmed the significant role of DR5 pathway. Moreover, combined treatment of NT157 and TRAIL showed enhanced apoptosis against U251 and U87 cells. However, Knockdown of DR5 expression significantly attenuated combined treatment-induced PARP cleavage and caspase-3 activation. Importantly, combined administration of NT157 and TRAIL in vivo effectively inhibited glioma xenograft growth of nude mice by inhibiting cell proliferation and angiogenesis, and inducing DNA damage and apoptosis. Taken together, our findings validated the rational design that combined strategy of NT157 and TRAIL to trigger DNA damage and apoptosis by up-regulating DR5 could be a high efficient way to combat human glioma.
NT157 是一种小分子酪氨酸激酶抑制剂，具有广谱的抗肿瘤活性。然而，NT157 对神经胶质瘤的抑制作用尚未被探索。在此，我们评估了 NT157 对人神经胶质瘤生长的抗癌作用及其潜在机制。结果表明，NT157 单独使用可通过上调 p21 和 p27 以及下调细胞周期相关因子，在体外显著抑制神经胶质瘤细胞的生长，从而引发细胞周期停滞。NT157 单独使用还可诱导显著的神经胶质瘤细胞凋亡，随后出现 PARP 切割和 caspase-3 激活。我们的研究结果进一步表明，NT157 可引发显著的 DNA 损伤以及 PI3K/AKT、MAPKs 和 EGFR-STAT3 信号通路的功能障碍。添加几种激酶抑制剂可有效阻断 NT157 诱导的 DR5 上调，这进一步证实了 DR5 通路的重要作用。此外，NT157 和 TRAIL 的联合治疗对 U251 和 U87 细胞表现出增强的凋亡作用。然而，DR5 表达的敲低显著减弱了联合治疗诱导的 PARP 切割和 caspase-3 激活。重要的是，NT157 和 TRAIL 的体内联合给药通过抑制细胞增殖和血管生成以及诱导 DNA 损伤和凋亡，有效地抑制了裸鼠神经胶质瘤异种移植的生长。总之，我们的研究结果验证了联合使用 NT157 和 TRAIL 通过上调 DR5 引发 DNA 损伤和凋亡的合理设计，可能是对抗人类神经胶质瘤的一种高效方法。
