@article{APS10322,
author = {Zheng Wang and Zeng-xia Li and Wen-cao Zhao and Hong-bo Huang and Jia-qi Wang and Hao Zhang and Jun-yan Lu and Rui-na Wang and Wei Li and Zhao Cheng and Wen-long Xu and Di Zhu and Li-sha Zhou and Wei Jiang and Long Yu and Jun-yan Liu and Cheng Luo and Heng Zhu and Dan Ye and Wei-jun Pan and Jian-hua Ju and Yong-jun Dang},
title = {Identification and characterization of isocitrate dehydrogenase 1 (IDH1) as a functional target of marine natural product grincamycin B},
journal = {Acta Pharmacologica Sinica},
volume = {42},
number = {5},
year = {2021},
keywords = {},
abstract = {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 of GCN 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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/10322}
}