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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 H2O2 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.

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Figure 1: Differentiation induction of ATRA-sensitive NB4 cells by adenanthin.
Figure 2: Adenanthin directly targets Prx I and Prx II.
Figure 3: Adenanthin targets the CR of Prx I and inhibits its catalytic activity.
Figure 4: Differentiation induction by silencing of Prx I or Prx II expression in NB4 cells.
Figure 5: The ERK-C/EBPβ axis in adenanthin-induced differentiation.
Figure 6: Effects of adenanthin on ATRA-sensitive and resistant APL mouse models.

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Acknowledgements

We thank S.C. Kogan at the University of California–San Francisco for providing us with leukemic blasts from transgenic mice and F. Besancon at Hôpital St. Louis–Paris for providing NB4-MAD and NB4-GFP cells. We are also grateful to L. Zheng of the Department of Pathology in Shanghai Jiao Tong University School of Medicine for her technological assistance in pathologic examinations. This work was supported, in part, by grants from the National Basic Research Program of China (NO2009CB918404 to G.-Q.C.), the National Natural Science Foundation of China (NSFC; 90813034 to G.-Q.C. and 81070433 to Y.-L.W.), key projects for basic research of Shanghai Science and Technology Commission (11IC1406800 to G.-Q.C. and 11JC1406500 to Y.-L.W.), the NSFC joint Foundation of Yunnan Province (U0832602 to H.-D.S.) and grants from the Shanghai Committee of Education (to G.-Q.C). C.-X.L. and Q.-Q.Y. are PhD candidates at Shanghai Jiao Tong University and the Shanghai Institutes for Biological Sciences of the Chinese Academy of Sciences, respectively, and this work was submitted in partial fulfillment of the requirement for their PhD degrees.

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C.-X.L. and Q.-Q.Y. performed most of the cellular, biochemical and animal experiments. H.-C.Z. led the team for synthesis of biotin-adenanthin and analyzed chemistry and structure-related results, and M.-X.W. and Y.-X.Z. synthesized biotin-adenanthin. Y.-L.W. partially designed and performed cellular experiments. J.-X.P., W.-L.X. and H.-D.S. isolated adenanthin, which was provided from H.-D.S.'s group. L.X. and L.-S.W. contributed to MS analysis. W.L. partially contributed to animal experiments. L.-C.H. performed the ERK assay. T.-J., X.-L.W. and H.-Z.C. contributed to pharmacokinetic analysis. X.H. and A.-W.Z. performed the kinetic analysis. Q.Z. partially designed the experimental plans. G.-Q.C. initiated the project, led the project team, designed experiments, analyzed results and wrote the paper with input from all authors.

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Correspondence to Guo-Qiang Chen.

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Liu, CX., Yin, QQ., Zhou, HC. et al. Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells. Nat Chem Biol 8, 486–493 (2012). https://doi.org/10.1038/nchembio.935

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