Identification and characterization of isocitrate dehydrogenase 1(IDH1) as a functional target of marine natural product grincamycin B

• 作者: Zheng Wang Zeng-xia Li Wen-cao Zhao Hong-bo Huang Jia-qi Wang Hao Zhang Jun-yan Lu Rui-na Wang Wei Li Zhao Cheng Wen-long Xu Di Zhu Li-sha Zhou Wei Jiang Long Yu Jun-yan Liu Cheng Luo Heng Zhu Dan Ye Wei-jun Pan Jian-hua Ju Yong-jun Dang
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（5）
• 所属期刊栏目: Chemotherapy
• 页码范围: 801-813
• 页数: 13页
• 语种: 英文

摘要

Grincamycins (GCNs) are a class of angucycline glycosides isolated from actinomycete Streptomyces strains that have potent antitumor activities,but their antitumor mechanisms remain unknown.In this study,we tried to identify the cellular target of grincamycin B (GCN B),one of most dominant and active secondary metabolites,using a combined strategy.We showed that GCN B-selective-induced apoptosis of human acute promyelocytic leukemia (APL) cell line NB4 through increase of ER stress and intracellular reactive oxygen species (ROS) accumulation.Using a strategy of combining phenotype,transcriptomics and protein microarray approaches,we identified that isocitrate dehydrogenase 1(IDH1) was the putative target of GCN B,and confirmed that GCNs were a subset of selective inhibitors targeting both wild-type and mutant IDH1 in vitro.It is well-known that IDH1 converts isocitrate to 2-oxoglutarate (2-OG),maintaining intracellular 2-OG homeostasis.IDH1 and its mutant as the target ofGCN B were validated in NB4 cells and zebrafish model.Knockdown of IDH1 in NB4 cells caused the similar phenotype as GCN B treatment,and supplementation of N-acetylcysteine partially rescued the apoptosis caused by IDH1 interference in NB4 cells.In zebrafish model,GCN B effectively restored myeloid abnormality caused by overexpression of mutant IDH1 (R132C).Taken together,we demonstrate that IDH1 is one of the antitumor targets of GCNs,suggesting wild-type IDH1 may be a potential target for hematological malignancies intervention in the future.