Oncotarget

Research Papers:

Identification of H7 as a novel peroxiredoxin I inhibitor to induce differentiation of leukemia cells

Wei Wei, Chunmin Ma, Yang Cao, Li Yang, Zhimin Huang, Dongjun Qin, Yingyi Chen, Chuanxu Liu, Li Xia, Tongdan Wang, Hu Lei, Yun Yu, Min Huang, Yin Tong, Hanzhang Xu, Fenghou Gao, Jian Zhang, Ying-Li Wu _

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Abstract

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

Correspondence to:

Ying-Li Wu, e-mail: wuyingli@shsmu.edu.cn

Jian Zhang, e-mail: jian.zhang@sjtu.edu.cn

Keywords: peroxiredoxin, leukemia, cell differentiation, reactive oxygen species

Received: June 09, 2015     Accepted: November 28, 2015     Published: December 26, 2015

ABSTRACT

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.

Author Information

Wei Wei

Chunmin Ma

Yang Cao

Li Yang

Zhimin Huang

Dongjun Qin

Yingyi Chen

Chuanxu Liu

Li Xia

Tongdan Wang

Hu Lei

Yun Yu

Min Huang

Yin Tong

Hanzhang Xu

Fenghou Gao

Jian Zhang

Ying-Li Wu
Primary Contact  _


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