神经生长因子IB
化学
癌症研究
体内
空泡化
体外
细胞质
药理学
细胞生物学
生物化学
核受体
生物
转录因子
内分泌学
基因
生物技术
作者
Baicun Li,Jiangang Huang,Jie Liu,Fengming He,Fangfang Wen,Changming Yang,Wang Wang,Tong Wu,Taige Zhao,Jie Yao,Shun-Zhi Liu,Ying‐Kun Qiu,Meijuan Fang,Jin-Zhang Zeng,Zhixian Wu
标识
DOI:10.1016/j.bioorg.2022.105651
摘要
Nur77, an orphan nuclear receptor, has antitumor activity in hepatocellular carcinoma (HCC). However, its antitumor mechanisms of action in HCC are complicated and rarely reported. Our recent work demonstrated that certain quinoline-Schiff-base derivatives were good Nur77 mediators that exerted excellent anti-HCC activities in vitro and in vivo. Interestingly, these compounds shared similar chemical structures, but they displayed different Nur77-targeted anticancer mechanisms of action. As a continuous work, we synthesized a series of 4-(quinoline-4-amino) benzoylhydrazide derivatives and evaluated their anti-HCC activity and binding affinity to Nur77 in vitro. Compound 4-PQBH emerged as the best Nur77 binder (KD = 1.17 μM) and has potentially selective cytotoxicity to HCC cells. Mechanistically, 4-PQBH extensively induced caspase-independent cytoplasmic vacuolization and paraptosis through Nur77-mediated ER stress and autophagy. Moreover, 4-PQBH exhibited an effective xenograft tumor inhibition by modulating Nur77-dependent cytoplasmic vacuolation and paraptosis. This paper is the first to disclose that chemotherapeutic agents targeting Nur77-mediated cytoplasmic vacuolization and paraptosis may provide a promising strategy to combat HCC that frequently evade the apoptosis program.
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