Nam Le Ba, Choi Won Jun, Keum Young-Sam
College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University, Goyang, South Korea.
Panacea Co., Goyang, South Korea.
Front Pharmacol. 2021 Sep 8;12:680167. doi: 10.3389/fphar.2021.680167. eCollection 2021.
We have identified triptolide as a novel NRF2 inhibitor, which significantly attenuates ARE-luciferase activity at nanomolar concentrations. Triptolide did not affect the level of NRF2, but significantly inhibited the expression of NRF2 target genes in A549 cells. We found that NRF2 possesses a previously unrecognized NES in the Neh2 domain, and that triptolide promotes an interaction between NRF2 and CRM1. Triptolide also decreased nuclear accumulation of NRF2, suggesting that it promotes nuclear export of NRF2. In addition, we show that triptolide decreased the expression of NRF2 target genes and increased intracellular oxidative stress, suppressing invasion and promoting cisplatin-induced apoptosis in A549 cells. Finally, oral administration of triptolide suppressed the growth of A549 xenografts in athymic mice by decreasing the expression of NRF2 target genes and promoting oxidative damages via the nuclear export of NRF2 and CRM1 . To the best of our knowledge, triptolide is the first type of compound to inhibit NRF2 by increasing cytoplasmic localization of NRF2.
我们已确定雷公藤甲素是一种新型的NRF2抑制剂，它在纳摩尔浓度下能显著减弱ARE荧光素酶活性。雷公藤甲素不影响NRF2的水平，但能显著抑制A549细胞中NRF2靶基因的表达。我们发现NRF2在Neh2结构域中拥有一个此前未被识别的核输出信号（NES），并且雷公藤甲素能促进NRF2与CRM1之间的相互作用。雷公藤甲素还减少了NRF2的核内积累，表明它促进了NRF2的核输出。此外，我们表明雷公藤甲素降低了NRF2靶基因的表达并增加了细胞内氧化应激，抑制了A549细胞的侵袭并促进了顺铂诱导的凋亡。最后，雷公藤甲素口服给药通过降低NRF2靶基因的表达并通过NRF2和CRM1的核输出促进氧化损伤，抑制了无胸腺小鼠体内A549异种移植物的生长。据我们所知，雷公藤甲素是第一种通过增加NRF2的细胞质定位来抑制NRF2的化合物类型。
