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Design and optimize N‐substituted EF 24 as effective and low toxicity NF ‐κB inhibitor for lung cancer therapy via apoptosis‐to‐pyroptosis switch
Author(s) -
Chen Liping,
Li Qian,
Zheng Zhiwei,
Xie Jingwen,
Lin Xiaoming,
Jiang Chengxi,
Xu Haineng,
Wu Xiaoping,
Wu Jianzhang,
Zhang Huajie
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13514
Subject(s) - pyroptosis , apoptosis , toxicity , cytotoxicity , nf κb , cell cycle checkpoint , chemistry , cell cycle , pharmacology , programmed cell death , cancer research , biology , biochemistry , in vitro , organic chemistry
As NF ‐κB signaling pathway is constitutively activated in lung cancer, targeting NF ‐κB has a potential for the treatment. EF 24 has been proved to be a NF ‐κB inhibitor with good antitumor activity, while whose toxicity possibly became one of the obstacles to enter into clinical application. In order to find high efficiency and low toxicity NF ‐κB inhibitors, EF 24 was modified and 13d was screened out. It was proved that 13d possessed an effective combination of inhibiting NF ‐κB pathway and showing lower cytotoxicity on normal cells as well as less toxicity in acute toxicity experiment compared with the lead compound of EF 24. In addition, 13d was found to inhibit cell vitality, arrest cell cycle in G2/M phase, promote cell apoptosis, and suppress the xenograft tumor growth. Furthermore, 13d was elucidated to induce pyroptosis developing from apoptosis, which was associated with the inhibition of NF ‐κB. Taken together, it was suggested that 13d was a potent antitumor agent.