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Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs
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Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs
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Journal Article
Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs
2019
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Anti-Inflammatory Agents, Non-Steroidal - adverse effects
/ Anti-Inflammatory Agents, Non-Steroidal - pharmacology
/ Anticarcinogenic Agents - adverse effects
/ Anticarcinogenic Agents - pharmacology
/ Biomedical and Life Sciences
/ Cancer
/ Cyclin-dependent kinase inhibitor p21
/ Cyclin-Dependent Kinase Inhibitor p21 - drug effects
/ Cyclin-Dependent Kinase Inhibitor p21 - metabolism
/ Cyclooxygenase Inhibitors - adverse effects
/ Cyclooxygenase Inhibitors - pharmacology
/ Humans
/ Mice
/ Nonsteroidal anti-inflammatory drugs
/ Oncology
/ Prostaglandin endoperoxide synthase
/ Sulindac
/ Sulindac - analogs & derivatives
/ Tumor Suppressor Protein p53 - drug effects
/ Tumor Suppressor Protein p53 - metabolism
/ Tumors
