title: Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells.
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.
authors.affiliation: 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.
authors.forename: Chuan-Xu
authors.initials: CX
authors.lastname: Liu
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Yin
authors.forename: Hu-Chen
authors.initials: HC
authors.lastname: Zhou
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Wu
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Pu
authors.forename: Li
authors.initials: L
authors.lastname: Xia
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Ming-Xuan
authors.initials: MX
authors.lastname: Wu
authors.forename: Li-Cai
authors.initials: LC
authors.lastname: He
authors.forename: Ya-Xue
authors.initials: YX
authors.lastname: Zhao
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Wang
authors.forename: Wei-Lie
authors.initials: WL
authors.lastname: Xiao
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Ai-Wu
authors.initials: AW
authors.lastname: Zhou
authors.forename: Li-Shun
authors.initials: LS
authors.lastname: Wang
authors.forename: Han-Dong
authors.initials: HD
authors.lastname: Sun
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects*; D003545:Cysteine / Q000737:chemistry; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D045786:Diterpenes, Kaurane / Q000737:chemistry / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000032:analysis; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D051379:Mice; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; D004224:Diterpenes; D045786:Diterpenes, Kaurane; C000600164:adenanthin; C466222:adenanthin F; D014212:Tretinoin; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D048049:Extracellular Signal-Regulated MAP Kinases; D003545:Cysteine