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

doi:10.1038/s41416-018-0372-7

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 journal › Article › peer-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 language	English
Pages (from-to)	537-546
Number of pages	10
Journal	Eur. J. Cancer
Volume	120
Issue number	5
DOIs	https://doi.org/10.1038/s41416-018-0372-7
Publication status	Published - 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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Dell’Omo, G., Crescenti, D., Vantaggiato, C., Parravicini, C., Borroni, A. P., Rizzi, N., Garofalo, M., Pinto, A., Recordati, C., Scanziani, E., Bassi, F. D., Pruneri, G., Conti, P., Eberini, I., Maggi, A., & Ciana, P. (2019). Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs: British Journal of Cancer. Eur. J. Cancer, 120(5), 537-546. https://doi.org/10.1038/s41416-018-0372-7

Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs : British Journal of Cancer. / Dell’Omo, G.; Crescenti, D.; Vantaggiato, C.; Parravicini, C.; Borroni, A.P.; Rizzi, N.; Garofalo, M.; Pinto, A.; Recordati, C.; Scanziani, E.; Bassi, F.D.; Pruneri, G.; Conti, P.; Eberini, I.; Maggi, A.; Ciana, P.

In: Eur. J. Cancer, Vol. 120, No. 5, 2019, p. 537-546.

Research output: Contribution to journal › Article › peer-review

Dell’Omo, G, Crescenti, D, Vantaggiato, C, Parravicini, C, Borroni, AP, Rizzi, N, Garofalo, M , Pinto, A, Recordati, C, Scanziani, E, Bassi, FD , Pruneri, G, Conti, P, Eberini, I, Maggi, A & Ciana, P 2019, 'Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs: British Journal of Cancer', Eur. J. Cancer, vol. 120, no. 5, pp. 537-546. https://doi.org/10.1038/s41416-018-0372-7

Dell’Omo, G. ; Crescenti, D. ; Vantaggiato, C. ; Parravicini, C. ; Borroni, A.P. ; Rizzi, N. ; Garofalo, M. ; Pinto, A. ; Recordati, C. ; Scanziani, E. ; Bassi, F.D. ; Pruneri, G. ; Conti, P. ; Eberini, I. ; Maggi, A. ; Ciana, P. / Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs : British Journal of Cancer. In: Eur. J. Cancer. 2019 ; Vol. 120, No. 5. pp. 537-546.

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

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. {\textcopyright} 2019, The Author(s).",

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",

author = "G. Dell{\textquoteright}Omo and D. Crescenti and C. Vantaggiato and C. Parravicini and A.P. Borroni and N. Rizzi and M. Garofalo and A. Pinto and C. Recordati and E. Scanziani and F.D. Bassi and G. Pruneri and P. Conti and I. Eberini and A. Maggi and P. Ciana",

note = "Cited By :4 Export Date: 26 February 2020 CODEN: BJCAA Correspondence Address: Ciana, P.; Department of Oncology and Hemato-Oncology, University of MilanItaly; email: paolo.ciana@unimi.it Chemicals/CAS: diclofenac, 15307-79-6, 15307-86-5; ketoprofen, 22071-15-4, 57495-14-4; ketorolac, 74103-06-3; nicotinamide, 11032-50-1, 98-92-0; nimesulide, 51803-78-2; sulindac sulfone, 59973-80-7; sulindac, 38194-50-2; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Cyclin-Dependent Kinase Inhibitor p21; Cyclooxygenase Inhibitors; Ketorolac; Sirtuin 1; Sulindac; sulindac sulfone; Tumor Suppressor Protein p53 Funding details: Ministero dell{\textquoteright}Istruzione, dell{\textquoteright}Universit{\`a} e della Ricerca Funding details: 11903 Funding details: 2009–2439 Funding text 1: Ethical approval animal experimentation All animal experimentation was carried out in accordance with the Guide for the Care and Use of Laboratory Animals in accordance with the European Guidelines for Animal Care and Use of Experimental Animals, approved by the Italian Ministry of the Research and University (MIUR) and controlled by the panel of experts of the Department of Pharmacological and Biomolecular Sciences (University of Milan, 20133 Milan, Italy). For the experiments before 2014 the MIUR authorisation was DM 295/ 2012-A dated 20.12.2012 n. 10/2012, afterward experiments were done under MIUR authorisation n. 611/2015 PR. All animal experimentation was carried out in the full observation of the Directive 2010/63/UE. Funding text 2: We thank L. Maravigna, M. Pandini, F. Cicala, M. Rebecchi, and C. Meda for technical assistance. This work was supported by Italian Association for Cancer Research IG Grants 11903 (to P.C.), CARIPLO Foundation Project 2009–2439 (to P.C.) and Frame Program 7 of European Union: INMiND-278850 (to A.M. and P.C.). References: Torre, L.A., Global cancer statistics, 2012 (2015) CA a Cancer J. 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year = "2019",

doi = "10.1038/s41416-018-0372-7",

language = "English",

volume = "120",

pages = "537--546",

journal = "Eur. J. Cancer",

issn = "0959-8049",

publisher = "Elsevier Ltd",

number = "5",

}

TY - JOUR

T1 - Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs

T2 - British Journal of Cancer

AU - Dell’Omo, G.

AU - Crescenti, D.

AU - Vantaggiato, C.

AU - Parravicini, C.

AU - Borroni, A.P.

AU - Rizzi, N.

AU - Garofalo, M.

AU - Pinto, A.

AU - Recordati, C.

AU - Scanziani, E.

AU - Bassi, F.D.

AU - Pruneri, G.

AU - Conti, P.

AU - Eberini, I.

AU - Maggi, A.

AU - Ciana, P.

N1 - Cited By :4 Export Date: 26 February 2020 CODEN: BJCAA Correspondence Address: Ciana, P.; Department of Oncology and Hemato-Oncology, University of MilanItaly; email: paolo.ciana@unimi.it Chemicals/CAS: diclofenac, 15307-79-6, 15307-86-5; ketoprofen, 22071-15-4, 57495-14-4; ketorolac, 74103-06-3; nicotinamide, 11032-50-1, 98-92-0; nimesulide, 51803-78-2; sulindac sulfone, 59973-80-7; sulindac, 38194-50-2; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Cyclin-Dependent Kinase Inhibitor p21; Cyclooxygenase Inhibitors; Ketorolac; Sirtuin 1; Sulindac; sulindac sulfone; Tumor Suppressor Protein p53 Funding details: Ministero dell’Istruzione, dell’Università e della Ricerca Funding details: 11903 Funding details: 2009–2439 Funding text 1: Ethical approval animal experimentation All animal experimentation was carried out in accordance with the Guide for the Care and Use of Laboratory Animals in accordance with the European Guidelines for Animal Care and Use of Experimental Animals, approved by the Italian Ministry of the Research and University (MIUR) and controlled by the panel of experts of the Department of Pharmacological and Biomolecular Sciences (University of Milan, 20133 Milan, Italy). For the experiments before 2014 the MIUR authorisation was DM 295/ 2012-A dated 20.12.2012 n. 10/2012, afterward experiments were done under MIUR authorisation n. 611/2015 PR. All animal experimentation was carried out in the full observation of the Directive 2010/63/UE. Funding text 2: We thank L. Maravigna, M. Pandini, F. Cicala, M. Rebecchi, and C. Meda for technical assistance. This work was supported by Italian Association for Cancer Research IG Grants 11903 (to P.C.), CARIPLO Foundation Project 2009–2439 (to P.C.) and Frame Program 7 of European Union: INMiND-278850 (to A.M. and P.C.). References: Torre, L.A., Global cancer statistics, 2012 (2015) CA a Cancer J. 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PY - 2019

Y1 - 2019

N2 - 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).

AB - 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).

KW - diclofenac

KW - ketoprofen

KW - ketorolac

KW - nicotinamide

KW - nimesulide

KW - prostaglandin synthase inhibitor

KW - protein p53

KW - sirtuin 1

KW - small interfering RNA

KW - sulindac sulfone

KW - antineoplastic agent

KW - cyclin dependent kinase inhibitor 1A

KW - nonsteroid antiinflammatory agent

KW - sulindac

KW - acetylation

KW - animal cell

KW - animal experiment

KW - animal model

KW - animal tissue

KW - antineoplastic activity

KW - Article

KW - bioluminescence

KW - breast cancer

KW - cancer incidence

KW - cancer inhibition

KW - cancer survival

KW - chemoprophylaxis

KW - computer model

KW - controlled study

KW - densitometry

KW - drug mechanism

KW - enantiomer

KW - ex vivo study

KW - female

KW - gene expression

KW - in vivo study

KW - molecular biology

KW - molecular docking

KW - molecular model

KW - mouse

KW - nonhuman

KW - priority journal

KW - protein expression

KW - real time polymerase chain reaction

KW - stable transfection

KW - Western blotting

KW - animal

KW - computer simulation

KW - drug effect

KW - human

KW - metabolism

KW - tumor cell line

KW - Animals

KW - Anti-Inflammatory Agents, Non-Steroidal

KW - Anticarcinogenic Agents

KW - Cell Line, Tumor

KW - Computer Simulation

KW - Cyclin-Dependent Kinase Inhibitor p21

KW - Cyclooxygenase Inhibitors

KW - Humans

KW - Ketorolac

KW - Mice

KW - Models, Molecular

KW - Sirtuin 1

KW - Sulindac

KW - Tumor Suppressor Protein p53

U2 - 10.1038/s41416-018-0372-7

DO - 10.1038/s41416-018-0372-7

M3 - Article

VL - 120

SP - 537

EP - 546

JO - Eur. J. Cancer

JF - Eur. J. Cancer

SN - 0959-8049

IS - 5

ER -