IDENTIFICATION AND CHARACTERIZATION OF SIRT1 AS A NOVEL TARGET OF NSAIDS CHEMOPREVENTION
Tesi di Dottorato
Data di Pubblicazione:
2018
Citazione:
IDENTIFICATION AND CHARACTERIZATION OF SIRT1 AS A NOVEL TARGET OF NSAIDS CHEMOPREVENTION / G. Dell'omo ; tutor: P. Ciana ; coordinatore: A. L. Catapano. DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2018 Dec 17. 31. ciclo, Anno Accademico 2018. [10.13130/dell-omo-giulia_phd2018-12-17].
Abstract:
Several epidemiological, clinical and experimental studies proposed non-steroidal
antiinflammatory drugs (NSAIDs) as promising chemopreventive agents for many types of
cancer. However, their use in chronic treatment is hampered by gastrointestinal, renal and
cardiovascular side effects mainly due to the inhibition of cyclooxygenase (COX) isoenzymes.
The development of NSAIDs as chemopreventive agents is prevented by the limited
knowledge of the mechanism underlying the anti-cancer properties of these drugs. Inhibition
of COX has been proposed as the mechanism underlying their anti-neoplastic activity;
however, several lines of evidence challenged this simple view, among them the antitumor
activity of non-COX inhibitory metabolites, enantiomers and derivatives are perhaps the most
convincing.
The aim of the present project was to investigate a novel direct target of NSAIDs, which may
provide a biochemical explanation of the multiplicity of the COX-independent effects. For that
reason, molecular biology, cellular and in vivo tools, including innovative in vivo imaging and
classical biochemical assays were applied.
Here we identify, for the first time sirtuin 1 (SIRT1) as a direct target of NSAIDs, showing that
inhibition of this histone deacetylase may be responsible of their COX-independent
antineoplastic activity. In particular, we demonstrated that many NSAIDs through SIRT1
inhibition: increased acetylation and activation of tumour suppressor p53 and increase the
expression of antiproliferative gene p21 through SIRT1 inhibition. We showed that the
mechanism occurs selectively in tumour tissue in cells, animal models and also in clinical
setting. Activation of the p53 signaling produces an anti-proliferative effect, which prevents
the early transformation steps of the mammary gland in an animal model of early breast
cancer transformation. Increased local proliferation is not the only hallmark of cancer
modulated by NSAIDs, interestingly our results indicate that the local immunosuppression
promoted in the mammary gland by the exposure to a genotoxic agent can be efficiently
counteracted by NSAIDs.
In conclusion, this thesis presents the discovery and characterization of the new target SIRT1
as effector of NSAIDs mediated chemopreventive activity. Our data disjoin the NSAIDs COXdependent
anti-inflammatory activity from the SIRT1-dependent anti-tumor activity,
therefore suggesting a novel strategy to design molecules displaying anti-neoplastic
chemoprevetinve activity without the COX-dependent side effects.
Tipologia IRIS:
Tesi di dottorato
Keywords:
NSAIDs; SIRT1; p53; chemoprevention; drug discovery
Elenco autori:
G. Dell'Omo
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