Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect

Oncogene volume 28, pages 781–791 (2009)Cite this article

A Corrigendum to this article was published on 26 February 2009

Abstract

Sirtuin 1 (Sirt1) and Sirtuin 2 (Sirt2) belong to the family of NAD+ (nicotinamide adenine dinucleotide-positive)-dependent class III histone deacetylases and are involved in regulating lifespan. As cancer is a disease of ageing, targeting Sirtuins is emerging as a promising antitumour strategy. Here we present Salermide (N-{3-[(2-hydroxy-naphthalen-1-ylmethylene)-amino]-phenyl}-2-phenyl-propionamide), a reverse amide with a strong in vitro inhibitory effect on Sirt1 and Sirt2. Salermide was well tolerated by mice at concentrations up to 100 μM and prompted tumour-specific cell death in a wide range of human cancer cell lines. The antitumour activity of Salermide was primarily because of a massive induction of apoptosis. This was independent of global tubulin and K16H4 acetylation, which ruled out a putative Sirt2-mediated apoptotic pathway and suggested an in vivo mechanism of action through Sirt1. Consistently with this, RNA interference-mediated knockdown of Sirt1, but not Sirt2, induced apoptosis in cancer cells. Although p53 has been reported to be a target of Sirt1, genetic p53 knockdowns showed that the Sirt1-dependent proapoptotic effect of Salermide is p53-independent. We were finally able to ascribe the apoptotic effect of Salermide to the reactivation of proapoptotic genes epigenetically repressed exclusively in cancer cells by Sirt1. Taken together, our results underline Salermide's promise as an anticancer drug and provide evidence for the molecular mechanism through which Sirt1 is involved in human tumorigenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Avalos JL, Bever KM, Wolberger C . (2005). Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Mol Cell 17: 855–868.

    Article  CAS  PubMed  Google Scholar 

  • Bedalov A, Gatbonton T, Irvine WP, Gottschling DE, Simon JA . (2001). Identification of a small molecule inhibitor of Sir2p. Proc Natl Acad Sci USA 98: 15113–15118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA . (2002). Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 277: 45099–45107.

    Article  CAS  PubMed  Google Scholar 

  • Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB . (2005). Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123: 437–448.

    Article  CAS  PubMed  Google Scholar 

  • Clark AM, Labute P, Santavy M . (2006). 2D structure depiction. J Chem Inf Model 46: 1107–1123.

    Article  CAS  PubMed  Google Scholar 

  • Finnin MS, Donigian JR, Pavletich NP . (2001). Structure of the histone deacetylase SIRT2. Nat Struct Biol 8: 621–625.

    Article  CAS  PubMed  Google Scholar 

  • Ford J, Jiang M, Milner J . (2005). Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res 65: 10457–10463.

    Article  CAS  PubMed  Google Scholar 

  • Fraga MF, Agrelo R, Esteller M . (2007). Cross-talk between aging and cancer: the epigenetic language. Ann N Y Acad Sci 1100: 60–74.

    Article  CAS  PubMed  Google Scholar 

  • Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G et al. (2005). Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37: 391–400.

    Article  CAS  PubMed  Google Scholar 

  • Fraga MF, Esteller M . (2007). Epigenetics and aging: the targets and the marks. Trends Genet 23: 413–418.

    Article  CAS  PubMed  Google Scholar 

  • Glozak MA, Seto E . (2007). Histone deacetylases and cancer. Oncogene 26: 5420–5432.

    Article  CAS  PubMed  Google Scholar 

  • Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL . (2001). Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem 276: 38837–38843.

    Article  CAS  PubMed  Google Scholar 

  • Guarente L, Picard F . (2005). Calorie restriction—the SIR2 connection. Cell 120: 473–482.

    Article  CAS  PubMed  Google Scholar 

  • Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S et al. (2006). Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res 66: 4368–4377.

    Article  CAS  PubMed  Google Scholar 

  • Herranz M, Martin-Caballero J, Fraga MF, Ruiz-Cabello J, Flores JM, Desco M et al. (2006). The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma. Blood 107: 1174–1177.

    Article  CAS  PubMed  Google Scholar 

  • Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG et al. (2003). Small molecule activators of Sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425: 191–196.

    Article  CAS  PubMed  Google Scholar 

  • Huhtiniemi T, Wittekindt C, Laitinen T, Leppanen J, Salminen A, Poso A et al. (2006). Comparative and pharmacophore model for deacetylase SIRT1. J Comput Aided Mol Des 20: 589–599.

    Article  CAS  PubMed  Google Scholar 

  • Jones G, Willett P, Glen RC, Leach AR, Taylor R . (1997). Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267: 727–748.

    Article  CAS  PubMed  Google Scholar 

  • Kamel C, Abrol M, Jardine K, He X, McBurney MW . (2006). SirT1 fails to affect p53-mediated biological functions. Aging Cell 5: 81–88.

    Article  CAS  PubMed  Google Scholar 

  • Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M et al. (2008). Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13: 454–463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Longo VD, Kennedy BK . (2006). Sirtuins in aging and age-related disease. Cell 126: 257–268.

    Article  CAS  PubMed  Google Scholar 

  • Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A et al. (2001). Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107: 137–148.

    Article  CAS  PubMed  Google Scholar 

  • Mai A, Massa S, Lavu S, Pezzi R, Simeoni S, Ragno R et al. (2005). Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. J Med Chem 48: 7789–7795.

    Article  CAS  PubMed  Google Scholar 

  • Mariadason JM . (2008). HDACs and HDAC inhibitors in colon cancer. Epigenetics 3: 28–37.

    Article  PubMed  Google Scholar 

  • Marks PA . (2007). Discovery and development of SAHA as an anticancer agent. Oncogene 26: 1351–1356.

    Article  CAS  PubMed  Google Scholar 

  • Marks PA, Breslow R . (2007). Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol 25: 84–90.

    Article  CAS  PubMed  Google Scholar 

  • Min J, Landry J, Sternglanz R, Xu RM . (2001). Crystal structure of a SIR2 homolog–NAD complex. Cell 105: 269–279.

    Article  CAS  PubMed  Google Scholar 

  • Minucci S, Pelicci PG . (2006). Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6: 38–51.

    Article  CAS  PubMed  Google Scholar 

  • Napper AD, Hixon J, McDonagh T, Keavey K, Pons JF, Barker J et al. (2005). Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem 48: 8045–8054.

    Article  CAS  PubMed  Google Scholar 

  • North BJ, Marshall BL, Borra MT, Denu JM, Verdin E . (2003). The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 11: 437–444.

    Article  CAS  PubMed  Google Scholar 

  • Olaharski AJ, Rine J, Marshall BL, Babiarz J, Zhang L, Verdin E et al. (2005). The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases. PLoS Genet 1: e77.

    Article  PubMed  PubMed Central  Google Scholar 

  • Onufriev A, Bashford D, Case DA . (2004). Exploring protein native states and large-scale conformational changes with a modified generalized born model. Proteins 55: 383–394.

    Article  CAS  PubMed  Google Scholar 

  • Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M et al. (2006). Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene 25: 176–185.

    Article  CAS  PubMed  Google Scholar 

  • Parks BA, Jiang L, Thomas PM, Wenger CD, Roth MJ, Boyne II MT et al. (2007). Top-down proteomics on a chromatographic time scale using linear ion trap Fourier transform hybrid mass spectrometers. Anal Chem 79: 7984–7991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ponder JW, Case DA . (2003). Force fields for protein simulations. Adv Protein Chem 66: 27–85.

    Article  CAS  PubMed  Google Scholar 

  • Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN et al. (2006). Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet 2: e40.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rodrigues NR, Rowan A, Smith ME, Kerr IB, Bodmer WF, Gannon JV et al. (1990). p53 mutations in colorectal cancer. Proc Natl Acad Sci USA 87: 7555–7559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ropero S, Menendez JA, Vazquez-Martin A, Montero S, Cortes-Funes H, Colomer R . (2004). Trastuzumab plus tamoxifen: anti-proliferative and molecular interactions in breast carcinoma. Breast Cancer Res Treat 86: 125–137.

    Article  CAS  PubMed  Google Scholar 

  • Stunkel W, Peh BK, Tan YC, Nayagam VM, Wang X, Salto-Tellez M et al. (2007). Function of the SIRT1 protein deacetylase in cancer. Biotechnol J 2: 1360–1368.

    Article  CAS  PubMed  Google Scholar 

  • Sun Y, Sun D, Li F, Tian L, Li C, Li L et al. (2007). Downregulation of Sirt1 by antisense oligonucleotides induces apoptosis and enhances radiation sensitization in A549 lung cancer cells. Lung Cancer 58: 21–29.

    Article  PubMed  Google Scholar 

  • Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D . (2004). Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell 16: 93–105.

    Article  CAS  PubMed  Google Scholar 

  • Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW et al. (2006). SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev 20: 1256–1261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK et al. (2001). hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107: 149–159.

    Article  CAS  PubMed  Google Scholar 

  • Villar-Garea A, Israel L, Imhof A . (2008). Analysis of histone modifications by mass spectrometry. Curr Protoc Prot Sci (Chapter 14, Unit 14 10).

  • Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y et al. (2006). Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol 8: 1025–1031.

    Article  CAS  PubMed  Google Scholar 

  • Xu WS, Parmigiani RB, Marks PA . (2007). Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26: 5541–5552.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was primarily supported by the European Union (LSHG-CT-2006-037415). MFF is funded by the Spanish Ramon & Cajal Programme and the Health Department of the Spanish Government (PI061267). Thanks are due to PRIN2006 (AM) and AICR2007 (AM) for grants. The Cancer Epigenetics group at the CNIO is supported by the Health (FIS01-04) and Education and Science (I+D+I MCYT08-03, FU2004-02073/BMC and Consolider MEC09-05) Departments of the Spanish Government, the European Grant TRANSFOG LSHC-CT-2004-503438, EPITRON LSHC-CT-2005-518417, APO-SYS HEALTH-F4-2007-200767 and the Spanish Association Against Cancer (AECC). EL is a recipient of a fellowship from the FIS Spanish Research Program. VC is a recipient of a Fellowship from the FPU Spanish Research Program.

Author information

Authors and Affiliations

  1. Cancer Epigenetics Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    E Lara, V Calvanese, P Lopez-Nieva, S Ropero & M F Fraga

  2. Dipartimento di Studi Farmaceutici, Istituto Pasteur, Fondazione Cenci Bolognetti, Università degli Studi di Roma ‘La Sapienza’, Roma, Italy

    A Mai & D Rotili

  3. Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Napoli, Italy

    L Altucci & A Nebbioso

  4. CIC bioGUNE, CIBERehd, Bizkaia Technology Park, Bizkaia, Spain

    M L Martinez-Chantar, M Varela-Rey & J M Mato

  5. Macromolecular Crystallography Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    G Montoya

  6. Computational Chemistry Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    J Oyarzabal

  7. Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    S Velasco & M Serrano

  8. Bruker Daltonik GmbH, Bremen, Germany

    M Witt

  9. Histone Modifications Group, Adolf-Butenandt Institut, University of Munich, Munich, Germany

    A Villar-Garea & A Inhof

  10. Cancer Epigenetics and Biology Program (PEBC), Catalan Institute of Oncology (ICO), Barcelona, Spain

    M Esteller

  11. Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Cantoblanco, Madrid, Spain

    M F Fraga

Authors
  1. E Lara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Mai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V Calvanese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Altucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Lopez-Nieva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M L Martinez-Chantar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Varela-Rey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Rotili
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Nebbioso
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Ropero
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G Montoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J Oyarzabal
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S Velasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M Serrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M Witt
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. A Villar-Garea
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. A Inhof
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. J M Mato
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. M Esteller
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. M F Fraga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to M Esteller or M F Fraga.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lara, E., Mai, A., Calvanese, V. et al. Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect. Oncogene 28, 781–791 (2009). https://doi.org/10.1038/onc.2008.436

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.436

Keywords

This article is cited by

Search

Advanced search

Quick links