Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics

Giovanna Sociali; Lauretta Galeno; Marco Daniele Parenti; Alessia Grozio; Inga Bauer; Mario Passalacqua; Silvia Boero; Alessandra Donadini; Enrico Millo; Marta Bellotti; Laura Sturla; Patrizia Damonte; Alessandra Puddu; Claudia Ferroni; Greta Varchi; Claudio Franceschi; Alberto Ballestrero; Alessandro Poggi; Santina Bruzzone; Alessio Nencioni; Alberto Del Rio

doi:10.1016/j.ejmech.2015.08.024

Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics

Giovanna Sociali, Lauretta Galeno, Marco Daniele Parenti, Alessia Grozio, Inga Bauer, Mario Passalacqua, Silvia Boero, Alessandra Donadini, Enrico Millo, Marta Bellotti, Laura Sturla, Patrizia Damonte, Alessandra Puddu, Claudia Ferroni, Greta Varchi, Claudio Franceschi, Alberto Ballestrero, Alessandro Poggi, Santina Bruzzone, Alessio NencioniAlberto Del Rio

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

60 Scopus citations

Abstract

The NAD⁺-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6. As predicted based on SIRT6's biological functions, the identified new SIRT6 inhibitors increase histone H3 lysine 9 acetylation, reduce TNF-α production and increase glucose uptake in cultured cells. In addition, these compounds exacerbate DNA damage and cell death in response to the PARP inhibitor olaparib in BRCA2-deficient Capan-1 cells and cooperate with gemcitabine to the killing of pancreatic cancer cells. In conclusion, new SIRT6 inhibitors with a quinazolinedione-based structure have been identified which are active in cells and could potentially find applications in cancer treatment.

Original language	English (US)
Pages (from-to)	530-539
Number of pages	10
Journal	European Journal of Medicinal Chemistry
Volume	102
DOIs	https://doi.org/10.1016/j.ejmech.2015.08.024
State	Published - Aug 24 2015

Keywords

Anticancer drugs
Chemotherapy
Molecular design
NAD-dependent deacetylases
Quinazolinedione
Sirtuins
Small molecule inhibitors

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2015.08.024

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Sociali, G., Galeno, L., Parenti, M. D., Grozio, A., Bauer, I., Passalacqua, M., Boero, S., Donadini, A., Millo, E., Bellotti, M., Sturla, L., Damonte, P., Puddu, A., Ferroni, C., Varchi, G., Franceschi, C., Ballestrero, A., Poggi, A., Bruzzone, S., ... Del Rio, A. (2015). Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics. European Journal of Medicinal Chemistry, 102, 530-539. https://doi.org/10.1016/j.ejmech.2015.08.024

Sociali, G, Galeno, L, Parenti, MD, Grozio, A, Bauer, I, Passalacqua, M, Boero, S, Donadini, A, Millo, E, Bellotti, M, Sturla, L, Damonte, P, Puddu, A, Ferroni, C, Varchi, G, Franceschi, C, Ballestrero, A, Poggi, A, Bruzzone, S, Nencioni, A & Del Rio, A 2015, 'Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics', European Journal of Medicinal Chemistry, vol. 102, pp. 530-539. https://doi.org/10.1016/j.ejmech.2015.08.024

@article{433d152495814f108048b96866e2a6bc,

title = "Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics",

abstract = "The NAD+-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6. As predicted based on SIRT6's biological functions, the identified new SIRT6 inhibitors increase histone H3 lysine 9 acetylation, reduce TNF-α production and increase glucose uptake in cultured cells. In addition, these compounds exacerbate DNA damage and cell death in response to the PARP inhibitor olaparib in BRCA2-deficient Capan-1 cells and cooperate with gemcitabine to the killing of pancreatic cancer cells. In conclusion, new SIRT6 inhibitors with a quinazolinedione-based structure have been identified which are active in cells and could potentially find applications in cancer treatment.",

keywords = "Anticancer drugs, Chemotherapy, Molecular design, NAD-dependent deacetylases, Quinazolinedione, Sirtuins, Small molecule inhibitors",

author = "Giovanna Sociali and Lauretta Galeno and Parenti, {Marco Daniele} and Alessia Grozio and Inga Bauer and Mario Passalacqua and Silvia Boero and Alessandra Donadini and Enrico Millo and Marta Bellotti and Laura Sturla and Patrizia Damonte and Alessandra Puddu and Claudia Ferroni and Greta Varchi and Claudio Franceschi and Alberto Ballestrero and Alessandro Poggi and Santina Bruzzone and Alessio Nencioni and {Del Rio}, Alberto",

note = "Funding Information: This work was supported by the Emilia Romagna Start-Up grant of the Italian Association for Cancer Research (AIRC) grant # 6266 to A.D.R.; by the FP7 grant PANACREAS, # 256986 , to A.N.; by the AIRC Start-Up grant # 6108 to A.N.; by the Italian Ministry of Health grants GR-2008-1135635 and GR-2011-02347192 , to A.N.; by the Compagnia di San Paolo grant R.O.L. 689 , to A.N.; by the Fondazione CARIGE , to A.N.; by the Fondazione Umberto Veronesi (to A.N.); and by the University of Genova (A.N., and S.B.). The authors also wish to thank Dr. Kathrin F. Chua (Department of Medicine, Stanford University, Stanford, CA) for providing valuable reagents for this study; Dr. Filippo Ansaldi and Dr. Giancarlo Icardi (Department of Health Sciences, University of Genoa, Genoa, Italy) for the use of the BSL2+ Facility; Dr. Maximilien Murone and Dr. Maria Von Holtey (Debiopharm Group, Lausanne, Switzerland) for the helpful discussion. Publisher Copyright: {\textcopyright} 2015 Elsevier Masson SAS. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2015",

month = aug,

day = "24",

doi = "10.1016/j.ejmech.2015.08.024",

language = "English (US)",

volume = "102",

pages = "530--539",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics

AU - Sociali, Giovanna

AU - Galeno, Lauretta

AU - Parenti, Marco Daniele

AU - Grozio, Alessia

AU - Bauer, Inga

AU - Passalacqua, Mario

AU - Boero, Silvia

AU - Donadini, Alessandra

AU - Millo, Enrico

AU - Bellotti, Marta

AU - Sturla, Laura

AU - Damonte, Patrizia

AU - Puddu, Alessandra

AU - Ferroni, Claudia

AU - Varchi, Greta

AU - Franceschi, Claudio

AU - Ballestrero, Alberto

AU - Poggi, Alessandro

AU - Bruzzone, Santina

AU - Nencioni, Alessio

AU - Del Rio, Alberto

N1 - Funding Information: This work was supported by the Emilia Romagna Start-Up grant of the Italian Association for Cancer Research (AIRC) grant # 6266 to A.D.R.; by the FP7 grant PANACREAS, # 256986 , to A.N.; by the AIRC Start-Up grant # 6108 to A.N.; by the Italian Ministry of Health grants GR-2008-1135635 and GR-2011-02347192 , to A.N.; by the Compagnia di San Paolo grant R.O.L. 689 , to A.N.; by the Fondazione CARIGE , to A.N.; by the Fondazione Umberto Veronesi (to A.N.); and by the University of Genova (A.N., and S.B.). The authors also wish to thank Dr. Kathrin F. Chua (Department of Medicine, Stanford University, Stanford, CA) for providing valuable reagents for this study; Dr. Filippo Ansaldi and Dr. Giancarlo Icardi (Department of Health Sciences, University of Genoa, Genoa, Italy) for the use of the BSL2+ Facility; Dr. Maximilien Murone and Dr. Maria Von Holtey (Debiopharm Group, Lausanne, Switzerland) for the helpful discussion. Publisher Copyright: © 2015 Elsevier Masson SAS. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2015/8/24

Y1 - 2015/8/24

N2 - The NAD+-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6. As predicted based on SIRT6's biological functions, the identified new SIRT6 inhibitors increase histone H3 lysine 9 acetylation, reduce TNF-α production and increase glucose uptake in cultured cells. In addition, these compounds exacerbate DNA damage and cell death in response to the PARP inhibitor olaparib in BRCA2-deficient Capan-1 cells and cooperate with gemcitabine to the killing of pancreatic cancer cells. In conclusion, new SIRT6 inhibitors with a quinazolinedione-based structure have been identified which are active in cells and could potentially find applications in cancer treatment.

AB - The NAD+-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6. As predicted based on SIRT6's biological functions, the identified new SIRT6 inhibitors increase histone H3 lysine 9 acetylation, reduce TNF-α production and increase glucose uptake in cultured cells. In addition, these compounds exacerbate DNA damage and cell death in response to the PARP inhibitor olaparib in BRCA2-deficient Capan-1 cells and cooperate with gemcitabine to the killing of pancreatic cancer cells. In conclusion, new SIRT6 inhibitors with a quinazolinedione-based structure have been identified which are active in cells and could potentially find applications in cancer treatment.

KW - Anticancer drugs

KW - Chemotherapy

KW - Molecular design

KW - NAD-dependent deacetylases

KW - Quinazolinedione

KW - Sirtuins

KW - Small molecule inhibitors

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U2 - 10.1016/j.ejmech.2015.08.024

DO - 10.1016/j.ejmech.2015.08.024

M3 - Article

C2 - 26310895

AN - SCOPUS:84940179025

VL - 102

SP - 530

EP - 539

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -

Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics

Abstract

Keywords

ASJC Scopus subject areas

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