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

The diperpenoid adenanthin covalently modifies the resolving cysteine from peroxiredoxins to inhibit the reduction of hydrogen peroxide, a second messenger in cells, and thereby activates pathways that promote the differentiation of leukemia cells. 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.