title: Identification of H7 as a novel peroxiredoxin I inhibitor to induce differentiation of leukemia cells.
abstract: Identifying novel targets to enhance leukemia-cell differentiation is an urgent requirement. We have recently proposed that inhibiting the antioxidant enzyme peroxiredoxin I (Prdx I) may induce leukemia-cell differentiation. However, this concept remains to be confirmed. In this work, we identified H7 as a novel Prdx I inhibitor through virtual screening, in vitro activity assay, and surface plasmon resonance assay. Cellular thermal shift assay showed that H7 directly bound to Prdx I but not to Prdxs II-V in cells. H7 treatment also increased reactive oxygen species (ROS) level and cell differentiation in leukemia cells, as reflected by the upregulation of the cell surface differentiation marker CD11b/CD14 and the morphological maturation of cells. The differentiation-induction effect of H7 was further observed in some non-acute promyelocytic leukemia (APL) and primary leukemia cells apart from APL NB4 cells. Moreover, the ROS scavenger N-acetyl cysteine significantly reversed the H7-induced cell differentiation. We demonstrated as well that H7-induced cell differentiation was associated with the activation of the ROS-Erk1/2-C/EBPβ axis. Finally, we showed H7 treatment induced cell differentiation in an APL mouse model. All of these data confirmed that Prdx I was novel target for inducing leukemia-cell differentiation and that H7 was a novel lead compound for optimizing Prdx I inhibition.
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Chunmin
authors.initials: C
authors.lastname: Ma
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Qin
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Hematology, Xinhua Hospital Shanghai Jiao-Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Chuanxu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xia
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Tongdan
authors.initials: T
authors.lastname: Wang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Lei
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Hematology, Shanghai First People's Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200081, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Hanzhang
authors.initials: H
authors.lastname: Xu
authors.affiliation: Institute of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: Fenghou
authors.initials: F
authors.lastname: Gao
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D020349:Surface Plasmon Resonance; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013449:Sulfonamides; C515940:PRDX1 protein, human; D054464:Peroxiredoxins
keywords: cell differentiation; leukemia; peroxiredoxin; reactive oxygen species