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1
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Fiorentino F, Fabbrizi E, Mai A, Rotili D. Activation and inhibition of sirtuins: From bench to bedside. Med Res Rev 2025; 45:484-560. [PMID: 39215785 PMCID: PMC11796339 DOI: 10.1002/med.22076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/27/2024] [Accepted: 08/04/2024] [Indexed: 09/04/2024]
Abstract
The sirtuin family comprises seven NAD+-dependent enzymes which catalyze protein lysine deacylation and mono ADP-ribosylation. Sirtuins act as central regulators of genomic stability and gene expression and control key processes, including energetic metabolism, cell cycle, differentiation, apoptosis, and aging. As a result, all sirtuins play critical roles in cellular homeostasis and organism wellness, and their dysregulation has been linked to metabolic, cardiovascular, and neurological diseases. Furthermore, sirtuins have shown dichotomous roles in cancer, acting as context-dependent tumor suppressors or promoters. Given their central role in different cellular processes, sirtuins have attracted increasing research interest aimed at developing both activators and inhibitors. Indeed, sirtuin modulation may have therapeutic effects in many age-related diseases, including diabetes, cardiovascular and neurodegenerative disorders, and cancer. Moreover, isoform selective modulators may increase our knowledge of sirtuin biology and aid to develop better therapies. Through this review, we provide critical insights into sirtuin pharmacology and illustrate their enzymatic activities and biological functions. Furthermore, we outline the most relevant sirtuin modulators in terms of their modes of action, structure-activity relationships, pharmacological effects, and clinical applications.
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Affiliation(s)
- Francesco Fiorentino
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
| | - Emanuele Fabbrizi
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
| | - Antonello Mai
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
- Pasteur Institute, Cenci‐Bolognetti FoundationSapienza University of RomeRomeItaly
| | - Dante Rotili
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
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2
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Wang Y, Tang T, Yuan Y, Li N, Wang X, Guan J. Copper and Copper Complexes in Tumor Therapy. ChemMedChem 2024; 19:e202400060. [PMID: 38443744 DOI: 10.1002/cmdc.202400060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/01/2024] [Accepted: 03/05/2024] [Indexed: 03/07/2024]
Abstract
Copper (Cu), a crucial trace element in physiological processes, has garnered significant interest for its involvement in cancer progression and potential therapeutic applications. The regulation of cellular copper levels is essential for maintaining copper homeostasis, as imbalances can lead to toxicity and cell death. The development of drugs that target copper homeostasis has emerged as a promising strategy for anticancer treatment, with a particular focus on copper chelators, copper ionophores, and novel copper complexes. Recent research has also investigated the potential of copper complexes in cancer therapy.
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Affiliation(s)
- Yingqiao Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Tingxi Tang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yi Yuan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Nan Li
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoqing Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Guan
- Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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3
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Telesca M, Donniacuo M, Bellocchio G, Riemma MA, Mele E, Dell’Aversana C, Sgueglia G, Cianflone E, Cappetta D, Torella D, Altucci L, Castaldo G, Rossi F, Berrino L, Urbanek K, De Angelis A. Initial Phase of Anthracycline Cardiotoxicity Involves Cardiac Fibroblasts Activation and Metabolic Switch. Cancers (Basel) 2023; 16:53. [PMID: 38201480 PMCID: PMC10778158 DOI: 10.3390/cancers16010053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 12/12/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
The application of doxorubicin (DOX) is hampered by cardiotoxicity, with diastolic dysfunction as the earliest manifestation. Fibrosis leads to impaired relaxation, but the mechanisms that operate shortly after DOX exposure are not clear. We asked whether the activation of cardiac fibroblasts (CFs) anticipates myocardial dysfunction and evaluated the effects of DOX on CF metabolism. CFs were isolated from the hearts of rats after the first injection of DOX. In another experiment, CFs were exposed to DOX in vitro. Cell phenotype and metabolism were determined. Early effects of DOX consisted of diastolic dysfunction and unchanged ejection fraction. Markers of pro-fibrotic remodeling and evidence of CF transformation were present immediately after treatment completion. Oxygen consumption rate and extracellular acidification revealed an increased metabolic activity of CFs and a switch to glycolytic energy production. These effects were consistent in CFs isolated from the hearts of DOX-treated animals and in naïve CFs exposed to DOX in vitro. The metabolic switch was paralleled with the phenotype change of CFs that upregulated markers of myofibroblast differentiation and the activation of pro-fibrotic signaling. In conclusion, the metabolic switch and activation of CFs anticipate DOX-induced damage and represent a novel target in the early phase of anthracycline cardiomyopathy.
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Affiliation(s)
- Marialucia Telesca
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (M.T.); (M.D.); (G.B.); (M.A.R.); (E.M.); (F.R.); (L.B.); (A.D.A.)
| | - Maria Donniacuo
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (M.T.); (M.D.); (G.B.); (M.A.R.); (E.M.); (F.R.); (L.B.); (A.D.A.)
| | - Gabriella Bellocchio
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (M.T.); (M.D.); (G.B.); (M.A.R.); (E.M.); (F.R.); (L.B.); (A.D.A.)
| | - Maria Antonietta Riemma
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (M.T.); (M.D.); (G.B.); (M.A.R.); (E.M.); (F.R.); (L.B.); (A.D.A.)
| | - Elena Mele
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (M.T.); (M.D.); (G.B.); (M.A.R.); (E.M.); (F.R.); (L.B.); (A.D.A.)
| | - Carmela Dell’Aversana
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (C.D.); (G.S.); (L.A.)
- BIOGEM, Via Camporeale, 83031 Ariano Irpino, Italy
| | - Giulia Sgueglia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (C.D.); (G.S.); (L.A.)
| | - Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, Viale Europa, 88100 Catanzaro, Italy;
| | - Donato Cappetta
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Lecce-Monteroni, 73047 Lecce, Italy;
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy;
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (C.D.); (G.S.); (L.A.)
- BIOGEM, Via Camporeale, 83031 Ariano Irpino, Italy
- Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS)-National Research Council (CNR), 80131 Naples, Italy
| | - Giuseppe Castaldo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Via A. Pansini 5, 80131 Naples, Italy;
- CEINGE-Advanced Biotechnologies “Franco Salvatore”, Via G. Salvatore 486, 80131 Naples, Italy
| | - Francesco Rossi
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (M.T.); (M.D.); (G.B.); (M.A.R.); (E.M.); (F.R.); (L.B.); (A.D.A.)
| | - Liberato Berrino
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (M.T.); (M.D.); (G.B.); (M.A.R.); (E.M.); (F.R.); (L.B.); (A.D.A.)
| | - Konrad Urbanek
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Via A. Pansini 5, 80131 Naples, Italy;
- CEINGE-Advanced Biotechnologies “Franco Salvatore”, Via G. Salvatore 486, 80131 Naples, Italy
| | - Antonella De Angelis
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Costantinopoli 16, 80138 Naples, Italy; (M.T.); (M.D.); (G.B.); (M.A.R.); (E.M.); (F.R.); (L.B.); (A.D.A.)
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Lee YT, Tan YJ, Oon CE. BZD9L1 Differentially Regulates Sirtuins in Liver-Derived Cells by Inducing Reactive Oxygen Species. Biomedicines 2023; 11:3059. [PMID: 38002059 PMCID: PMC10669747 DOI: 10.3390/biomedicines11113059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 11/04/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
Growing evidence has highlighted that mitochondrial dysfunction contributes to drug-induced toxicities and leads to drug attrition and post-market withdrawals. The acetylation or deacetylation of mitochondrial proteins can affect mitochondrial functions as the cells adapt to various cellular stresses and other metabolic challenges. SIRTs act as critical deacetylases in modulating mitochondrial function in response to drug toxicity, oxidative stress, reactive oxygen species (ROS), and energy metabolism. We previously showed that a recently characterised SIRT inhibitor (BZD9L1) is non-toxic in rodents in a short-term toxicity evaluation. However, the impact of BZD9L1 on mitochondrial function is unknown. This work aims to determine the effects of BZD9L1 on mitochondrial function in human normal liver and kidney-derived cell lines using the Agilent Seahorse Cell Mito Stress Test to complement our short-term toxicity evaluations in vivo. The Mito Stress assay revealed that BZD9L1 could potentially trigger oxidative stress by inducing ROS, which promotes proton leak and reduces coupling efficiency in liver-derived THLE cells. However, the same was not observed in human kidney-derived HEK293 cells. Interestingly, BZD9L1 had no impact on SIRT3 protein expression in both cell lines but affected SOD2 and its acetylated form at 72 h in THLE cells, indicating that BZD9L1 exerted its effect through SIRT3 activity rather than protein expression. In contrast, BZD9L1 reduced SIRT1 protein expression and impacted the p53 protein differently in both cell lines. Although BZD9L1 did not affect the spare respiratory capacity in vitro, these findings call for further validation of mitochondrial function through assessment of other mitochondrial parameters to evaluate the safety of BZD9L1.
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Affiliation(s)
| | | | - Chern Ein Oon
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia; (Y.T.L.); (Y.J.T.)
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5
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Wu QJ, Zhang TN, Chen HH, Yu XF, Lv JL, Liu YY, Liu YS, Zheng G, Zhao JQ, Wei YF, Guo JY, Liu FH, Chang Q, Zhang YX, Liu CG, Zhao YH. The sirtuin family in health and disease. Signal Transduct Target Ther 2022; 7:402. [PMID: 36581622 PMCID: PMC9797940 DOI: 10.1038/s41392-022-01257-8] [Citation(s) in RCA: 352] [Impact Index Per Article: 117.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/10/2022] [Accepted: 11/18/2022] [Indexed: 12/30/2022] Open
Abstract
Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.
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Affiliation(s)
- Qi-Jun Wu
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tie-Ning Zhang
- grid.412467.20000 0004 1806 3501Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Huan-Huan Chen
- grid.412467.20000 0004 1806 3501Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xue-Fei Yu
- grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jia-Le Lv
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu-Yang Liu
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ya-Shu Liu
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Gang Zheng
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jun-Qi Zhao
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yi-Fan Wei
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jing-Yi Guo
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Fang-Hua Liu
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qing Chang
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yi-Xiao Zhang
- grid.412467.20000 0004 1806 3501Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Cai-Gang Liu
- grid.412467.20000 0004 1806 3501Department of Cancer, Breast Cancer Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu-Hong Zhao
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
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Abstract
Sirtuins are NAD+-dependent protein lysine deacylase and mono-ADP ribosylases present in both prokaryotes and eukaryotes. The sirtuin family comprises seven isoforms in mammals, each possessing different subcellular localization and biological functions. Sirtuins have received increasing attention in the past two decades given their pivotal functions in a variety of biological contexts, including cytodifferentiation, transcriptional regulation, cell cycle progression, apoptosis, inflammation, metabolism, neurological and cardiovascular physiology and cancer. Consequently, modulation of sirtuin activity has been regarded as a promising therapeutic option for many pathologies. In this review, we provide an up-to-date overview of sirtuin biology and pharmacology. We examine the main features of the most relevant inhibitors and activators, analyzing their structure-activity relationships, applications in biology, and therapeutic potential.
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Cuomo F, Dell'Aversana C, Chioccarelli T, Porreca V, Manfrevola F, Papulino C, Carafa V, Benedetti R, Altucci L, Cobellis G, Cobellis G. HIF3A Inhibition Triggers Browning of White Adipocytes via Metabolic Rewiring. Front Cell Dev Biol 2022; 9:740203. [PMID: 35096807 PMCID: PMC8790297 DOI: 10.3389/fcell.2021.740203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 12/13/2021] [Indexed: 12/15/2022] Open
Abstract
Maintenance of energy balance between intake and expenditure is a prerequisite of human health, disrupted in severe metabolic diseases, such as obesity and type 2 diabetes (T2D), mainly due to accumulation of white adipose tissue (WAT). WAT undergoes a morphological and energetic remodelling toward brown adipose tissue (BAT) and the BAT activation has anti-obesity potential. The mechanisms or the regulatory factors able to activate BAT thermogenesis have been only partially deciphered. Identifying novel regulators of BAT induction is a question of great importance for fighting obesity and T2D. Here, we evaluated the role of Hif3α in murine pre-adipocyte 3T3-L1 cell line, a versatile and well characterized biological model of adipogenesis, by gain- and loss-of function approaches and in thermogenesis-induced model in vivo. HIF3A is regulated by inflammation, it modulates lypolysis in adipose tissue of obese adults, but its role in energy metabolism has not previously been investigated. We characterized gene and protein expression patterns of adipogenesis and metabolic activity in vitro and mechanistically in vivo. Overexpression of Hif3α in differentiating adipocytes increases white fat cells, whereas silencing of Hif3α promotes “browning” of white cells, activating thermogenesis through upregulation of Ucp1, Elovl3, Prdm16, Dio2 and Ppargc1a genes. Investigating cell metabolism, Seahorse Real-Time Cell Metabolism Analysis showed that silencing of Hif3α resulted in a significant increase of mitochondrial uncoupling with a concomitant increase in acetyl-CoA metabolism and Sirt1 and Sirt3 expression. The causal Hif3α/Ucp1 inverse relation has been validated in Cannabinoid receptor 1 (CB1) knockout, a thermogenesis-induced model in vivo. Our data indicate that Hif3α inhibition triggers “browning” of white adipocytes activating the beneficial thermogenesis rewiring energy metabolism in vitro and in vivo. HIF3A is a novel player that controls the energy metabolism with potential applications in developing therapy to fight metabolic disorders, as obesity, T2D and ultimately cancer.
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Affiliation(s)
- Francesca Cuomo
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Carmela Dell'Aversana
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy.,Institute Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS)-National Research Council (CNR), Napoli, Italy
| | - Teresa Chioccarelli
- Department of Experimental Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Veronica Porreca
- Department of Experimental Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Francesco Manfrevola
- Department of Experimental Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Chiara Papulino
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Vincenzo Carafa
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Rosaria Benedetti
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Lucia Altucci
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy.,Biogem Institute of Molecular and Genetic Biology, Ariano Irpino, Italy
| | - Gilda Cobellis
- Department of Experimental Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Gilda Cobellis
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
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8
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Hong JY, Lin H. Sirtuin Modulators in Cellular and Animal Models of Human Diseases. Front Pharmacol 2021; 12:735044. [PMID: 34650436 PMCID: PMC8505532 DOI: 10.3389/fphar.2021.735044] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/24/2021] [Indexed: 12/22/2022] Open
Abstract
Sirtuins use NAD+ to remove various acyl groups from protein lysine residues. Through working on different substrate proteins, they display many biological functions, including regulation of cell proliferation, genome stability, metabolism, and cell migration. There are seven sirtuins in humans, SIRT1-7, each with unique enzymatic activities, regulatory mechanisms, subcellular localizations, and substrate scopes. They have been indicated in many human diseases, including cancer, neurodegeneration, microbial infection, metabolic and autoimmune diseases. Consequently, interests in development of sirtuin modulators have increased in the past decade. In this brief review, we specifically summarize genetic and pharmacological modulations of sirtuins in cancer, neurological, and cardiovascular diseases. We further anticipate this review will be helpful for scrutinizing the significance of sirtuins in the studied diseases.
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Affiliation(s)
- Jun Young Hong
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, United States
| | - Hening Lin
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, United States.,Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Cornell University, Ithaca, NY, United States
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Wang Y, Xie Q, Tan H, Liao M, Zhu S, Zheng LL, Huang H, Liu B. Targeting cancer epigenetic pathways with small-molecule compounds: Therapeutic efficacy and combination therapies. Pharmacol Res 2021; 173:105702. [PMID: 34102228 DOI: 10.1016/j.phrs.2021.105702] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/07/2021] [Accepted: 05/29/2021] [Indexed: 02/08/2023]
Abstract
Epigenetics mainly refers to covalent modifications to DNA or histones without affecting genomes, which ultimately lead to phenotypic changes in cells or organisms. Given the abundance of regulatory targets in epigenetic pathways and their pivotal roles in tumorigenesis and drug resistance, the development of epigenetic drugs holds a great promise for the current cancer therapy. However, lack of potent, selective, and clinically tractable small-molecule compounds makes the strategy to target cancer epigenetic pathways still challenging. Therefore, this review focuses on epigenetic pathways, small molecule inhibitors targeting DNA methyltransferase (DNMT) and small molecule inhibitors targeting histone modification (the main regulatory targets are histone acetyltransferases (HAT), histone deacetylases (HDACs) and histone methyltransferases (HMTS)), as well as the combination strategies of the existing epigenetic therapeutic drugs and more new therapies to improve the efficacy, which will shed light on a new clue on discovery of more small-molecule drugs targeting cancer epigenetic pathways as promising strategies in the future.
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Affiliation(s)
- Yi Wang
- Health Management Center, Sichuan Provincial People' Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, PR China
| | - Qiang Xie
- Department of Stomatology, Sichuan Provincial People' Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Huidan Tan
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Minru Liao
- Department of Stomatology, Sichuan Provincial People' Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Shiou Zhu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Ling-Li Zheng
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, No. 278, Baoguang Rd, Xindu Region, Chengdu 610500, PR China.
| | - Haixia Huang
- Oral & Maxillofacial Reconstruction and Regeneration Laboratory, Southwest Medical University, Luzhou, 646000, PR China; Department of Prosthodontics, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, 646000, PR China.
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China.
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Gao X, Dong QZ. Advance in metabolism and target therapy in breast cancer stem cells. World J Stem Cells 2020; 12:1295-1306. [PMID: 33312399 PMCID: PMC7705469 DOI: 10.4252/wjsc.v12.i11.1295] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/06/2020] [Accepted: 09/27/2020] [Indexed: 02/06/2023] Open
Abstract
Breast cancer, like many other cancers, is believed to be driven by a population of cells that display stem cell properties. Recent studies suggest that cancer stem cells (CSCs) are essential for tumor progression, and tumor relapse is thought to be caused by the presence of these cells. CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies. Additionally, the metabolic properties of cancer cells differ markedly from those of normal cells. The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells. Metabolic targeting of breast CSCs (BCSCs) may be a very effective strategy for anti-cancer treatment of breast cancer cells. Thus, in this review, we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.
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Affiliation(s)
- Xu Gao
- Department of Breast Surgery, Yiwu Maternity and Children Hospital, Yiwu 322000, Zhejiang Province, China.
| | - Qiong-Zhu Dong
- Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai 200032, China
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