Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells

Chuan-Xu Liu; Qian-Qian Yin; Hu-Chen Zhou; Ying-Li Wu; Jian-Xin Pu; Li Xia; Wei Liu; Xin Huang; Tao Jiang; Ming-Xuan Wu; Li-Cai He; Ya-Xue Zhao; Xiao-Lin Wang; Wei-Lie Xiao; Hong-Zhuan Chen; Qian Zhao; Ai-Wu Zhou; Li-Shun Wang; Han-Dong Sun; Guo-Qiang Chen

doi:10.1038/nchembio.935

Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells

Nat Chem Biol. 2012 Apr 8;8(5):486-93. doi: 10.1038/nchembio.935.

Affiliation

¹ Department of Pathophysiology, Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

PMID: 22484541
DOI: 10.1038/nchembio.935

Abstract

Peroxiredoxins (Prxs) are potential therapeutic targets for major diseases such as cancers. However, isotype-specific inhibitors remain to be developed. We report that adenanthin, a diterpenoid isolated from the leaves of Rabdosia adenantha, induces differentiation of acute promyelocytic leukemia (APL) cells. We show that adenanthin directly targets the conserved resolving cysteines of Prx I and Prx II and inhibits their peroxidase activities. Consequently, cellular H(2)O(2) is elevated, leading to the activation of extracellular signal-regulated kinases and increased transcription of CCAAT/enhancer-binding protein β, which contributes to adenanthin-induced differentiation. Adenanthin induces APL-like cell differentiation, represses tumor growth in vivo and prolongs the survival of mouse APL models that are sensitive and resistant to retinoic acid. Thus, adenanthin can serve as what is to our knowledge the first lead natural compound for the development of Prx I- and Prx II-targeted therapeutic agents, which may represent a promising approach to inducing differentiation of APL cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
CCAAT-Enhancer-Binding Protein-beta / biosynthesis
Cell Differentiation / drug effects*
Cysteine / chemistry
Diterpenes / chemistry
Diterpenes / pharmacology*
Diterpenes, Kaurane / chemistry
Diterpenes, Kaurane / pharmacology*
Extracellular Signal-Regulated MAP Kinases / metabolism
Humans
Hydrogen Peroxide / analysis
Leukemia, Promyelocytic, Acute / drug therapy*
Mice
Peroxiredoxins / antagonists & inhibitors*
Peroxiredoxins / chemistry
Tretinoin / pharmacology
Tumor Cells, Cultured

Substances

Antineoplastic Agents
CCAAT-Enhancer-Binding Protein-beta
Diterpenes
Diterpenes, Kaurane
adenanthin
adenanthin F
Tretinoin
Hydrogen Peroxide
Peroxiredoxins
Extracellular Signal-Regulated MAP Kinases
Cysteine

Associated data

PubChem-Substance/134970389
PubChem-Substance/134970390
PubChem-Substance/134970391
PubChem-Substance/134970392
PubChem-Substance/134970393
PubChem-Substance/134970394
PubChem-Substance/134970395
PubChem-Substance/134970396
PubChem-Substance/134970397