苯甲双胍
双胍
二甲双胍
糖酵解
安普克
乳酸性酸中毒
氧化磷酸化
化学
PI3K/AKT/mTOR通路
线粒体
药理学
癌症研究
细胞凋亡
生物化学
生物
内分泌学
磷酸化
胰岛素
新陈代谢
蛋白激酶A
作者
Jia‐Miao Fu,Siyu Liu,Minqiang Hu,Ximing Liao,Xiaoquan Wang,Zhengshuang Xu,Qinkai Li,Junmin Quan
出处
期刊:ChemMedChem
[Wiley]
日期:2022-01-18
卷期号:17 (6)
被引量:5
标识
DOI:10.1002/cmdc.202100674
摘要
Abstract Metformin and other biguanides represent a new class of inhibitors of mitochondrial complex I that show promising antitumor effects. However, stronger inhibition of mitochondrial complex I is generally associated with upregulation of glycolysis and higher risk of lactic acidosis. Herein we report a novel biguanide derivative, N ‐cystaminylbiguanide (MC001), which was found to inhibit mitochondrial complex I with higher potency while inducing lactate production to a similar degree as metformin.Furthermore, MC001 was found to efficiently inhibit a panel of colorectal cancer (CRC) cells in vitro and to suppress tumor growth in a HCT116 xenograft nude mouse model, while not enhancing lactate production relative to metformin, exhibiting a superior safety profile to other potent biguanides such as phenformin. Mechanistically, MC001 efficiently inhibits mitochondrial complex I, activates AMPK, and represses mTOR, leading to cell‐cycle arrest and apoptosis. Notably, MC001 inhibits both oxidative phosphorylation (OXPHOS) and glycolysis. We therefore propose that MC001 warrants further investigation in cancer treatment.
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