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.
authors: Department of Experimental Medicine, Section of Biochemistry and CEBR, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy.
authors: Giovanna
authors: G
authors: Sociali
authors: Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy.
authors: Lauretta
authors: L
authors: Galeno
authors: Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy; Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy.
authors: Marco Daniele
authors: MD
authors: Parenti
authors: Department of Experimental Medicine, Section of Biochemistry and CEBR, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy.
authors: Alessia
authors: A
authors: Grozio
authors: Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy.
authors: Inga
authors: I
authors: Bauer
authors: Department of Experimental Medicine, Section of Biochemistry and CEBR, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy.
authors: Mario
authors: M
authors: Passalacqua
authors: Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy; IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Istituto Nazionale per la Ricerca Sul Cancro, 16132 Genoa, Italy.
authors: Silvia
authors: S
authors: Boero
authors: Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy.
authors: Alessandra
authors: A
authors: Donadini
authors: Department of Experimental Medicine, Section of Biochemistry and CEBR, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy.
authors: Enrico
authors: E
authors: Millo
authors: Department of Experimental Medicine, Section of Biochemistry and CEBR, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy.
authors: Marta
authors: M
authors: Bellotti
authors: Department of Experimental Medicine, Section of Biochemistry and CEBR, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy.
authors: Laura
authors: L
authors: Sturla
authors: Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy.
authors: Patrizia
authors: P
authors: Damonte
authors: Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy.
authors: Alessandra
authors: A
authors: Puddu
authors: Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Via P. Gobetti 101, 40129 Bologna, Italy.
authors: Claudia
authors: C
authors: Ferroni
authors: Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Via P. Gobetti 101, 40129 Bologna, Italy.
authors: Greta
authors: G
authors: Varchi
authors: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy; Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Via P. Gobetti 101, 40129 Bologna, Italy.
authors: Claudio
authors: C
authors: Franceschi
authors: Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy; IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Istituto Nazionale per la Ricerca Sul Cancro, 16132 Genoa, Italy.
authors: Alberto
authors: A
authors: Ballestrero
authors: IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Istituto Nazionale per la Ricerca Sul Cancro, 16132 Genoa, Italy.
authors: Alessandro
authors: A
authors: Poggi
authors: Department of Experimental Medicine, Section of Biochemistry and CEBR, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy. Electronic address: santina.bruzzone@unige.it.
authors: Santina
authors: S
authors: Bruzzone
authors: Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy; IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Istituto Nazionale per la Ricerca Sul Cancro, 16132 Genoa, Italy. Electronic address: alessio.nencioni@unige.it.
authors: Alessio
authors: A
authors: Nencioni
authors: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy; Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Via P. Gobetti 101, 40129 Bologna, Italy. Electronic address: alberto.delrio@gmail.com.
authors: Alberto
authors: A
authors: Del Rio
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D052999:Quinazolinones; C516592:SIRT6 protein, human; D037761:Sirtuins; C531550:olaparib
keywords: Anticancer drugs; Chemotherapy; Molecular design; NAD(+)-dependent deacetylases; Quinazolinedione; Sirtuins; Small molecule inhibitors