title: HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents.
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 and, 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 (NVP-AEW541), 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.
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: McMahon
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, United Kingdom.
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Campbell
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, United Kingdom.
authors.forename: A Kenneth
authors.initials: AK
authors.lastname: MacLeod
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, United Kingdom.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: McLaughlin
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Henderson
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, United Kingdom.
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
mesh_terms: D000171:Acrolein / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D061745:Antioxidant Response Elements / Q000187:drug effects; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000008:administration & dosage / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D056572:Histone Deacetylase Inhibitors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D000171:Acrolein; D017526:Receptor, IGF Type 1; D051573:Proto-Oncogene Proteins c-pim-1