Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs
Autor: | Fabio Bassi, Aurora Paola Borroni, Daniela Crescenti, Andrea Pinto, Nicoletta Rizzi, Camilla Recordati, Chiara Parravicini, Mariangela Garofalo, Cristina Vantaggiato, Eugenio Scanziani, Paolo Ciana, Giulia Dell'Omo, Paola Conti, Adriana Maggi, Ivano Eberini, Giancarlo Pruneri |
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Rok vydání: | 2019 |
Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Models Molecular Cancer Research Mechanism of action Pharmacology Article Cancer prevention Mice 03 medical and health sciences chemistry.chemical_compound Breast cancer Sulindac 0302 clinical medicine Sirtuin 1 Exisulind In vivo Target identification Cell Line Tumor medicine Animals Anticarcinogenic Agents Humans Computer Simulation Cyclooxygenase Inhibitors biology business.industry Anti-Inflammatory Agents Non-Steroidal 3. Good health Oncology chemistry 030220 oncology & carcinogenesis biology.protein Structure-based drug design Cyclooxygenase Tumor Suppressor Protein p53 business Ketorolac medicine.drug Deacetylase activity Nimesulide |
Zdroj: | British Journal of Cancer |
ISSN: | 1532-1827 0007-0920 |
Popis: | 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. |
Databáze: | OpenAIRE |
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