化学
粒体自噬
功能(生物学)
癌细胞
细胞毒性
药理学
自噬
癌症研究
立体化学
癌症
体外
细胞凋亡
生物化学
细胞生物学
遗传学
生物
作者
Yaxu Wang,Liwei Gu,Jichong Li,Ruqi Wang,Yuan Zhuang,Wei He,Xinye Wang,Jun Zhe Zhang,Qingbo Liu,Jigang Wang,Shao‐Jiang Song
标识
DOI:10.1016/j.ejmech.2024.116312
摘要
Ingenol diterpenoids continue to attract the attention for their extensive biological activity and novel structural features. To further explore this type of compound as anti-tumor agent, 13-oxyingenol dodecanoate (13-OD) was prepared by a standard chemical transformation from an Euphorbia kansui extract, and 29 derivatives were synthesized through parent 13-OD. Their inhibition activities against different types of cancer were screened and some derivatives showed superior anti-non-small cell lung cancer (NSCLC) cells cytotoxic potencies than oxaliplatin. In addition, TMBIM6 was identified as a crucial cellular target of 13-OD using ABPP target angling technique, and subsequently was verified by pull down, siRNA interference, BLI and CETSA assays. With modulating the function of TMBIM6 protein by 13-OD and its derivatives, Ca2+ release function was affected, causing mitochondrial Ca2+ overload, depolarisation of membrane potential. Remarkably, 13-OD, B6, A2, and A10–2 induced mitophagy and ferroptosis. In summary, our results reveal that 13-OD, B6, A2, and A10–2 holds great potential in developing anti-tumor agents for targeting TMBIM6.
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