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作者

Ya-jun Hou Dawei Li Weiqi Wang Leilei Mao Xiaoyan Fu Baoliang Sun Cundong Fan

作者单位

²Department of Neurology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong 250000, China ¹Department of Central Lab, Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong 271000, China

刊名

Biomedicine & Pharmacotherapy

年份

2022

卷号

Vol.153

页码

113502

ISSN

0753-3322

关键词

NT157 TRAIL Apoptosis DNA damage Cell cycle arrest Glioma

摘要

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...更多

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.收起

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