Identification of H7 as a novel peroxiredoxin I inhibitor to induce differentiation of leukemia cells
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Wei Wei1,*, Chunmin Ma1,*, Yang Cao1,*, Li Yang1,*, Zhimin Huang1,*, Dongjun Qin1, Yingyi Chen1, Chuanxu Liu2, Li Xia1, Tongdan Wang1, Hu Lei1, Yun Yu1, Min Huang1, Yin Tong4, Hanzhang Xu1, Fenghou Gao3, Jian Zhang1,*, Ying-Li Wu1,*
1Hongqiao 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
2Department of Hematology, Xinhua Hospital Shanghai Jiao-Tong University School of Medicine, Shanghai, 200092, China
3Institute of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
4Department of Hematology, Shanghai First People's Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200081, China
*These authors contributed equally to this work
Ying-Li Wu, e-mail: [email protected]
Jian Zhang, e-mail: [email protected]
Keywords: peroxiredoxin, leukemia, cell differentiation, reactive oxygen species
Received: June 09, 2015 Accepted: November 28, 2015 Published: December 26, 2015
Identifying novel targets to enhance leukemia-cell differentiation is an urgent requirment. 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.
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