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: 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
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 4 Pg. 3873-83 (Jan 26 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26716647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Small Molecule Libraries
• Sulfonamides
• PRDX1 protein, human
• Peroxiredoxins

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Differentiation (drug effects)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Female
• High-Throughput Screening Assays
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Leukemia, Promyelocytic, Acute (drug therapy, metabolism, pathology)
• Mice
• Mice, Transgenic
• Peroxiredoxins (antagonists & inhibitors)
• Small Molecule Libraries (pharmacology)
• Sulfonamides (pharmacology)
• Surface Plasmon Resonance
• Tumor Cells, Cultured