Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner

Anna R. McCarthy, Marijke C. C. Sachweh, Maureen Higgins, Johanna Campbell, Catherine J. Drummond, Ingeborg M. M. van Leeuwen, Lisa Pirrie, Marcus J. G. W. Ladds, Nicholas J. Westwood, Sonia Lain

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    Abstract

    While small-molecule inhibitors of class I/II histone deacetylases (HDAC) have been approved for cancer treatment, inhibitors of the sirtuins (a family of class III HDACs) still require further validation and optimization to enter clinical trials. Recent studies show that tenovin-6, a small-molecule inhibitor of sirtuins SirT1 and SirT2, reduces tumor growth in vivo and eliminates leukemic stem cells in a murine model for chronic myelogenous leukemia. Here, we describe a tenovin analogue, tenovin-D3, that preferentially inhibits sirtuin SirT2 and induces predicted phenotypes for SirT2 inhibition. Unlike tenovin-6 and in agreement with its weak effect on SirT1 (a p53 deacetylase), tenovin-D3 fails to increase p53 levels or transcription factor activity. However, tenovin-D3 promotes expression of the cell-cycle regulator and p53 target p21(WAF1/CIP1) (CDKN1A) in a p53-independent manner. Structure-activity relationship studies strongly support that the ability of tenovin-D3 to inhibit SirT2 contributes to this p53-independent induction of p21. The ability of tenovin-D3 to increase p21mRNA and protein levels is shared with class I/II HDAC inhibitors currently used in the clinic and therefore suggests that SirT2 inhibition and class I/II HDAC inhibitors have similar effects on cell-cycle progression. Mol Cancer Ther; 12(4);352-60. (C) 2013 AACR.

    Original languageEnglish
    Pages (from-to)352-360
    Number of pages9
    JournalMolecular Cancer Therapeutics
    Volume12
    Issue number4
    DOIs
    Publication statusPublished - Apr 2013

    Keywords

    • ACETYLATION
    • ACTIVATION
    • HISTONE DEACETYLASE INHIBITORS
    • ENZYME
    • RESVERATROL
    • STRESS
    • MECHANISM
    • P53
    • DISEASE
    • PLURIPOTENT STEM-CELLS

    Cite this

    McCarthy, A. R., Sachweh, M. C. C., Higgins, M., Campbell, J., Drummond, C. J., van Leeuwen, I. M. M., ... Lain, S. (2013). Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner. Molecular Cancer Therapeutics, 12(4), 352-360. https://doi.org/10.1158/1535-7163.MCT-12-0900
    McCarthy, Anna R. ; Sachweh, Marijke C. C. ; Higgins, Maureen ; Campbell, Johanna ; Drummond, Catherine J. ; van Leeuwen, Ingeborg M. M. ; Pirrie, Lisa ; Ladds, Marcus J. G. W. ; Westwood, Nicholas J. ; Lain, Sonia. / Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 4. pp. 352-360.
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    abstract = "While small-molecule inhibitors of class I/II histone deacetylases (HDAC) have been approved for cancer treatment, inhibitors of the sirtuins (a family of class III HDACs) still require further validation and optimization to enter clinical trials. Recent studies show that tenovin-6, a small-molecule inhibitor of sirtuins SirT1 and SirT2, reduces tumor growth in vivo and eliminates leukemic stem cells in a murine model for chronic myelogenous leukemia. Here, we describe a tenovin analogue, tenovin-D3, that preferentially inhibits sirtuin SirT2 and induces predicted phenotypes for SirT2 inhibition. Unlike tenovin-6 and in agreement with its weak effect on SirT1 (a p53 deacetylase), tenovin-D3 fails to increase p53 levels or transcription factor activity. However, tenovin-D3 promotes expression of the cell-cycle regulator and p53 target p21(WAF1/CIP1) (CDKN1A) in a p53-independent manner. Structure-activity relationship studies strongly support that the ability of tenovin-D3 to inhibit SirT2 contributes to this p53-independent induction of p21. The ability of tenovin-D3 to increase p21mRNA and protein levels is shared with class I/II HDAC inhibitors currently used in the clinic and therefore suggests that SirT2 inhibition and class I/II HDAC inhibitors have similar effects on cell-cycle progression. Mol Cancer Ther; 12(4);352-60. (C) 2013 AACR.",
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    author = "McCarthy, {Anna R.} and Sachweh, {Marijke C. C.} and Maureen Higgins and Johanna Campbell and Drummond, {Catherine J.} and {van Leeuwen}, {Ingeborg M. M.} and Lisa Pirrie and Ladds, {Marcus J. G. W.} and Westwood, {Nicholas J.} and Sonia Lain",
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    McCarthy, AR, Sachweh, MCC, Higgins, M, Campbell, J, Drummond, CJ, van Leeuwen, IMM, Pirrie, L, Ladds, MJGW, Westwood, NJ & Lain, S 2013, 'Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner', Molecular Cancer Therapeutics, vol. 12, no. 4, pp. 352-360. https://doi.org/10.1158/1535-7163.MCT-12-0900

    Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner. / McCarthy, Anna R.; Sachweh, Marijke C. C.; Higgins, Maureen; Campbell, Johanna; Drummond, Catherine J.; van Leeuwen, Ingeborg M. M.; Pirrie, Lisa; Ladds, Marcus J. G. W.; Westwood, Nicholas J.; Lain, Sonia.

    In: Molecular Cancer Therapeutics, Vol. 12, No. 4, 04.2013, p. 352-360.

    Research output: Contribution to journalArticle

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    T1 - Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner

    AU - McCarthy, Anna R.

    AU - Sachweh, Marijke C. C.

    AU - Higgins, Maureen

    AU - Campbell, Johanna

    AU - Drummond, Catherine J.

    AU - van Leeuwen, Ingeborg M. M.

    AU - Pirrie, Lisa

    AU - Ladds, Marcus J. G. W.

    AU - Westwood, Nicholas J.

    AU - Lain, Sonia

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    AB - While small-molecule inhibitors of class I/II histone deacetylases (HDAC) have been approved for cancer treatment, inhibitors of the sirtuins (a family of class III HDACs) still require further validation and optimization to enter clinical trials. Recent studies show that tenovin-6, a small-molecule inhibitor of sirtuins SirT1 and SirT2, reduces tumor growth in vivo and eliminates leukemic stem cells in a murine model for chronic myelogenous leukemia. Here, we describe a tenovin analogue, tenovin-D3, that preferentially inhibits sirtuin SirT2 and induces predicted phenotypes for SirT2 inhibition. Unlike tenovin-6 and in agreement with its weak effect on SirT1 (a p53 deacetylase), tenovin-D3 fails to increase p53 levels or transcription factor activity. However, tenovin-D3 promotes expression of the cell-cycle regulator and p53 target p21(WAF1/CIP1) (CDKN1A) in a p53-independent manner. Structure-activity relationship studies strongly support that the ability of tenovin-D3 to inhibit SirT2 contributes to this p53-independent induction of p21. The ability of tenovin-D3 to increase p21mRNA and protein levels is shared with class I/II HDAC inhibitors currently used in the clinic and therefore suggests that SirT2 inhibition and class I/II HDAC inhibitors have similar effects on cell-cycle progression. Mol Cancer Ther; 12(4);352-60. (C) 2013 AACR.

    KW - ACETYLATION

    KW - ACTIVATION

    KW - HISTONE DEACETYLASE INHIBITORS

    KW - ENZYME

    KW - RESVERATROL

    KW - STRESS

    KW - MECHANISM

    KW - P53

    KW - DISEASE

    KW - PLURIPOTENT STEM-CELLS

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    DO - 10.1158/1535-7163.MCT-12-0900

    M3 - Article

    VL - 12

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    EP - 360

    JO - Molecular Cancer Therapeutics

    JF - Molecular Cancer Therapeutics

    SN - 1535-7163

    IS - 4

    ER -