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  • Original Article
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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.

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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.

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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

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  1. E Lara
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Correspondence to M Esteller or M F Fraga.

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

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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

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

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