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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References
Hanson, J.R. Diterpenoids. Nat. Prod. Rep. 26, 1156–1171 (2009).
Roberts, S.C. Production and engineering of terpenoids in plant cell culture. Nat. Chem. Biol. 3, 387–395 (2007).
de Olieveira, A.M., Tirapelli, C.R., Ambrosio, S.R. & da Costa, F.B. Diterpenes: a therapeutic promise for cardiovascular diseases. Recent Pat. Cardiovasc. Drug Discov. 3, 1–8 (2008).
Titov, D.V. et al. XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat. Chem. Biol. 7, 182–188 (2011).
Wood, Z.A., Poole, L.B. & Karplus, P.A. Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science 300, 650–653 (2003).
Rhee, S.G. Cell signaling. H2O2, a necessary evil for cell signaling. Science 312, 1882–1883 (2006).
Dickinson, B.C. & Chang, C.J. Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat. Chem. Biol. 7, 504–511 (2011).
Rhee, S.G., Chae, H.Z. & Kim, K. Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic. Biol. Med. 38, 1543–1552 (2005).
Rhee, S.G. & Woo, H.A. Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones. Antioxid. Redox Signal. 15, 781–794 (2011).
Kang, S.W., Rhee, S.G., Chang, T.S., Jeong, W. & Choi, M.H. 2-Cys peroxiredoxin function in intracellular signal transduction: therapeutic implications. Trends Mol. Med. 11, 571–578 (2005).
Jiang, B. et al. Diterpenoids from Isodon adenantha. J. Nat. Prod. 65, 1111–1116 (2002).
Wang, Z.Y. & Chen, Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 111, 2505–2515 (2008).
Zhang, X.W. et al. Arsenic trioxide controls the fate of the PML-RARα oncoprotein by directly binding PML. Science 328, 240–243 (2010).
Raelson, J.V. et al. The PML/RAR α oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood 88, 2826–2832 (1996).
de las Heras, B. & Hortelano, S. Molecular basis of the anti-inflammatory effects of terpenoids. Inflamm. Allergy Drug Targets 8, 28–39 (2009).
Kotake, Y. et al. Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat. Chem. Biol. 3, 570–575 (2007).
Groll, M. et al. A plant pathogen virulence factor inhibits the eukaryotic proteasome by a novel mechanism. Nature 452, 755–758 (2008).
Wood, Z.A., Schroder, E., Robin Harris, J. & Poole, L.B. Structure, mechanism and regulation of peroxiredoxins. Trends Biochem. Sci. 28, 32–40 (2003).
Woo, H.A. et al. Inactivation of peroxiredoxin I by phosphorylation allows localized H2O2 accumulation for cell signaling. Cell 140, 517–528 (2010).
Hirotsu, S. et al. Crystal structure of a multifunctional 2-Cys peroxiredoxin heme-binding protein 23 kDa/proliferation-associated gene product. Proc. Natl. Acad. Sci. USA 96, 12333–12338 (1999).
Singh, J., Petter, R.C., Baillie, T.A. & Whitty, A. The resurgence of covalent drugs. Nat. Rev. Drug Discov. 10, 307–317 (2011).
Ahn, K. et al. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem. Biol. 16, 411–420 (2009).
Gierse, J.K., Koboldt, C.M., Walker, M.C., Seibert, K. & Isakson, P.C. Kinetic basis for selective inhibition of cyclo-oxygenases. Biochem. J. 339, 607–614 (1999).
Nagamura-Inoue, T., Tamura, T. & Ozato, K. Transcription factors that regulate growth and differentiation of myeloid cells. Int. Rev. Immunol. 20, 83–105 (2001).
Miranda, M.B. & Johnson, D.E. Signal transduction pathways that contribute to myeloid differentiation. Leukemia 21, 1363–1377 (2007).
Guerzoni, C., Ferrari-Amorotti, G., Bardini, M., Mariani, S.A. & Calabretta, B. Effects of C/EBPα and C/EBPβ in BCR/ABL-expressing cells: differences and similarities. Cell Cycle 5, 1254–1257 (2006).
Wang, X., Martindale, J.L., Liu, Y. & Holbrook, N.J. The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem. J. 333, 291–300 (1998).
Guyton, K.Z., Liu, Y., Gorospe, M., Xu, Q. & Holbrook, N.J. Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J. Biol. Chem. 271, 4138–4142 (1996).
Hu, X. et al. Prolonged activation of the mitogen-activated protein kinase pathway is required for macrophage-like differentiation of a human myeloid leukemic cell line. Cell Growth Differ. 11, 191–200 (2000).
Cassinat, B. et al. New role for granulocyte colony-stimulating factor-induced extracellular signal-regulated kinase 1/2 in histone modification and retinoic acid receptor α recruitment to gene promoters: relevance to acute promyelocytic leukemia cell differentiation. Mol. Cell Biol. 31, 1409–1418 (2011).
Ji, Y. & Studzinski, G.P. Retinoblastoma protein and CCAAT/enhancer-binding protein β are required for 1,25-dihydroxyvitamin D3-induced monocytic differentiation of HL60 cells. Cancer Res. 64, 370–377 (2004).
Brown, D. et al. A PMLRARα transgene initiates murine acute promyelocytic leukemia. Proc. Natl. Acad. Sci. USA 94, 2551–2556 (1997).
Kogan, S.C., Hong, S.H., Shultz, D.B., Privalsky, M.L. & Bishop, J.M. Leukemia initiated by PMLRARα: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable. Blood 95, 1541–1550 (2000).
Guibal, F.C. et al. Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia. Blood 114, 5415–5425 (2009).
Martens, J.H. et al. PML-RARα/RXR alters the epigenetic landscape in acute promyelocytic leukemia. Cancer Cell 17, 173–185 (2010).
Nowak, D., Stewart, D. & Koeffler, H.P. Differentiation therapy of leukemia: 3 decades of development. Blood 113, 3655–3665 (2009).
Lomenick, B., Olsen, R.W. & Huang, J. Identification of direct protein targets of small molecules. ACS Chem. Biol. 6, 34–46 (2011).
Nasr, R. et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat. Med. 14, 1333–1342 (2008).
de Lera, A.R., Bourguet, W., Altucci, L. & Gronemeyer, H. Design of selective nuclear receptor modulators: RAR and RXR as a case study. Nat. Rev. Drug Discov. 6, 811–820 (2007).
Abdel-Wahab, O. & Levine, R.L. Metabolism and the leukemic stem cell. J. Exp. Med. 207, 677–680 (2010).
Callens, C. et al. Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia. J. Exp. Med. 207, 731–750 (2010).
Duprez, E., Wagner, K., Koch, H. & Tenen, D.G. C/EBPβ: a major PML-RARA-responsive gene in retinoic acid-induced differentiation of APL cells. EMBO J. 22, 5806–5816 (2003).
Duprez, E. A new role for C/EBPβ in acute promyelocytic leukemia. Cell Cycle 3, 389–390 (2004).
López-Pedrera, C. et al. Proteomic analysis of acute myeloid leukemia: Identification of potential early biomarkers and therapeutic targets. Proteomics 6, S293–S299 (2006).
Kim, J.H. et al. Up-regulation of peroxiredoxin 1 in lung cancer and its implication as a prognostic and therapeutic target. Clin. Cancer Res. 14, 2326–2333 (2008).
Raj, L. et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475, 231–234 (2011).
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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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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DOI: https://doi.org/10.1038/nchembio.935