Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs: British Journal of Cancer

G. Dell’Omo, D. Crescenti, C. Vantaggiato, C. Parravicini, A.P. Borroni, N. Rizzi, M. Garofalo, A. Pinto, C. Recordati, E. Scanziani, F.D. Bassi, G. Pruneri, P. Conti, I. Eberini, A. Maggi, P. Ciana

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as chemopreventive agents for many tumours; however, the mechanism responsible for their anti-neoplastic activity remains elusive and the side effects due to cyclooxygenase (COX) inhibition prevent this clinical application. Methods: Molecular biology, in silico, cellular and in vivo tools, including innovative in vivo imaging and classical biochemical assays, were applied to identify and characterise the COX-independent anti-cancer mechanism of NSAIDs. Results: Here, we show that tumour-protective functions of NSAIDs and exisulind (a sulindac metabolite lacking anti-inflammatory activity) occur through a COX-independent mechanism. We demonstrate these NSAIDs counteract carcinogen-induced proliferation by inhibiting the sirtuin 1 (SIRT1) deacetylase activity, augmenting acetylation and activity of the tumour suppressor p53 and increasing the expression of the antiproliferative gene p21. These properties are shared by all NSAIDs except for ketoprofen lacking anti-cancer properties. The clinical interest of the mechanism identified is underlined by our finding that p53 is activated in mastectomy patients undergoing intraoperative ketorolac, a treatment associated with decreased relapse risk and increased survival. Conclusion: Our study, for the first-time, links NSAID chemopreventive activity with direct SIRT1 inhibition and activation of the p53/p21 anti-oncogenic pathway, suggesting a novel strategy for the design of tumour-protective drugs. © 2019, The Author(s).
Original languageEnglish
Pages (from-to)537-546
Number of pages10
JournalEur. J. Cancer
Volume120
Issue number5
DOIs
Publication statusPublished - 2019

Keywords

  • diclofenac
  • ketoprofen
  • ketorolac
  • nicotinamide
  • nimesulide
  • prostaglandin synthase inhibitor
  • protein p53
  • sirtuin 1
  • small interfering RNA
  • sulindac sulfone
  • antineoplastic agent
  • cyclin dependent kinase inhibitor 1A
  • nonsteroid antiinflammatory agent
  • sulindac
  • acetylation
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • antineoplastic activity
  • Article
  • bioluminescence
  • breast cancer
  • cancer incidence
  • cancer inhibition
  • cancer survival
  • chemoprophylaxis
  • computer model
  • controlled study
  • densitometry
  • drug mechanism
  • enantiomer
  • ex vivo study
  • female
  • gene expression
  • in vivo study
  • molecular biology
  • molecular docking
  • molecular model
  • mouse
  • nonhuman
  • priority journal
  • protein expression
  • real time polymerase chain reaction
  • stable transfection
  • Western blotting
  • animal
  • computer simulation
  • drug effect
  • human
  • metabolism
  • tumor cell line
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Anticarcinogenic Agents
  • Cell Line, Tumor
  • Computer Simulation
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclooxygenase Inhibitors
  • Humans
  • Ketorolac
  • Mice
  • Models, Molecular
  • Sirtuin 1
  • Sulindac
  • Tumor Suppressor Protein p53

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