HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents

Michael McMahon, Kathryn H. Campbell, A. Kenneth MacLeod, Lesley A. McLaughlin, Colin J. Henderson, C. Roland Wolf (Lead / Corresponding author)

    Research output: Contribution to journalArticle

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    Abstract

    The NRF2 signalling cascade provides a primary response against electrophilic chemicals and oxidative stress. The activation of NRF2-signaling is anticipated to have adverse clinical consequences; NRF2 is activated in a number of cancers, additionally, its pharmacological activation by one compound can reduce the toxicity or efficiency of a second agent administered concomitantly. In this work, we have analysed systematically the ability of 152 research, pre-clinical or clinically used drugs to induce an NRF2 response using the MCF7-AREc32 NRF2 reporter. Ten percent of the tested drugs induced an NRF2 response. The NRF2 activators were not restricted to classical cytotoxic alkylating agents but also included a number of emerging anticancer drugs, including an IGF1-R inhibitor (NVPAEW541), a PIM-1 kinase inhibitor (Pim1 inhibitor 2), a PLK1 inhibitor (BI 2536) and most strikingly seven of nine tested HDAC inhibitors. These findings were further confirmed by demonstrating NRF2-dependent induction of endogenous AKR genes, biomarkers of NRF2 activity. The ability of HDAC inhibitors to stimulate NRF2-signalling did not diminish their own potency as antitumour agents. However, when used to pre-treat cells, they did reduce the efficacy of acrolein. Taken together, our data suggest that the ability of drugs to stimulate NRF2 activity is common and should be investigated as part of the drug-development process.

    Original languageEnglish
    Article numbere114055
    JournalPLoS ONE
    Volume9
    Issue number11
    DOIs
    Publication statusPublished - 26 Nov 2014

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    Histone Deacetylase Inhibitors
    Cytotoxins
    Tumors
    Cells
    drugs
    antineoplastic agents
    Pharmaceutical Preparations
    Neoplasms
    acrolein
    Chemical activation
    Acrolein
    Oxidative stress
    Alkylating Agents
    Biomarkers
    biomarkers
    phosphotransferases (kinases)
    oxidative stress
    Antineoplastic Agents
    Toxicity
    toxicity

    Cite this

    McMahon, Michael ; Campbell, Kathryn H. ; MacLeod, A. Kenneth ; McLaughlin, Lesley A. ; Henderson, Colin J. ; Wolf, C. Roland. / HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents. In: PLoS ONE. 2014 ; Vol. 9, No. 11.
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    HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents. / McMahon, Michael; Campbell, Kathryn H.; MacLeod, A. Kenneth; McLaughlin, Lesley A.; Henderson, Colin J.; Wolf, C. Roland (Lead / Corresponding author).

    In: PLoS ONE, Vol. 9, No. 11, e114055, 26.11.2014.

    Research output: Contribution to journalArticle

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