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1
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McMurry HS, Rivero JD, Chen EY, Kardosh A, Lopez CD, Pegna GJ. Gastroenteropancreatic neuroendocrine tumors: Epigenetic landscape and clinical implications. Curr Probl Cancer 2024; 52:101131. [PMID: 39173542 DOI: 10.1016/j.currproblcancer.2024.101131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 05/22/2024] [Indexed: 08/24/2024]
Abstract
Neuroendocrine tumors (NETs) are a rare, heterogenous group of neoplasms arising from cells of the neuroendocrine system. Amongst solid tumor malignancies, NETs are notable for overall genetic stability and recent data supports the notion that epigenetic changes may drive NET pathogenesis. In this review, major epigenetic mechanisms of NET pathogenesis are reviewed, including changes in DNA methylation, histone modification, chromatin remodeling, and microRNA. Prognostic implications of the above are discussed, as well as the expanding diagnostic utility of epigenetic markers in NETs. Lastly, preclinical and clinical evaluations of epigenetically targeted therapies in NETs and are reviewed, with a focus on future directions in therapeutic advancement.
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Affiliation(s)
- Hannah S McMurry
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, United States
| | - Jaydira Del Rivero
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Emerson Y Chen
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, United States
| | - Adel Kardosh
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, United States
| | - Charles D Lopez
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, United States
| | - Guillaume J Pegna
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, United States.
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2
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Tanaka A, Ogawa M, Zhou Y, Otani Y, Hendrickson RC, Miele MM, Li Z, Klimstra DS, Wang JY, Roehrl MH. Proteogenomic characterization of pancreatic neuroendocrine tumors uncovers hypoxia and immune signatures in clinically aggressive subtypes. iScience 2024; 27:110544. [PMID: 39206147 PMCID: PMC11350455 DOI: 10.1016/j.isci.2024.110544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 04/15/2024] [Accepted: 07/16/2024] [Indexed: 09/04/2024] Open
Abstract
Pancreatic neuroendocrine tumors (PanNETs) represent well-differentiated endocrine neoplasms with variable clinical outcomes. Predicting patient outcomes using the current tumor grading system is challenging. In addition, traditional systemic treatment options for PanNETs, such as somatostatin analogs or cytotoxic chemotherapies, are very limited. To address these issues, we characterized PanNETs using integrated proteogenomics and identified four subtypes. Two proteomic subtypes showed high recurrence rates, suggesting clinical aggressiveness that was missed by current classification. Hypoxia and inflammatory pathways were significantly enriched in the clinically aggressive subtypes. Detailed analyses revealed metabolic adaptation via glycolysis upregulation and oxidative phosphorylation downregulation under hypoxic conditions. Inflammatory signature analysis revealed that immunosuppressive molecules were enriched in immune hot tumors and might be immunotherapy targets. In this study, we characterized clinically aggressive proteomic subtypes of well-differentiated PanNETs and identified candidate therapeutic targets.
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Affiliation(s)
- Atsushi Tanaka
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Makiko Ogawa
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yihua Zhou
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- ICU Department, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yusuke Otani
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Ronald C. Hendrickson
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Matthew M. Miele
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zhuoning Li
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David S. Klimstra
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Michael H. Roehrl
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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3
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Zhang Y, Tang N, Zhou H, Zhu Y. The role of microbial metabolites in endocrine tumorigenesis: From the mechanistic insights to potential therapeutic biomarkers. Biomed Pharmacother 2024; 172:116218. [PMID: 38308969 DOI: 10.1016/j.biopha.2024.116218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/28/2023] [Accepted: 01/22/2024] [Indexed: 02/05/2024] Open
Abstract
Microbial metabolites have been indicated to communicate with the host's endocrine system, regulating hormone production, immune-endocrine communications, and interactions along the gut-brain axis, eventually affecting the occurrence of endocrine cancer. Furthermore, microbiota metabolites such as short-chain fatty acids (SCFAs) have been found to affect the tumor microenvironment and boost immunity against tumors. SCFAs, including butyrate and acetate, have been demonstrated to exert anti-proliferative and anti-protective activity on pancreatic cancer cells. The employing of microbial metabolic products in conjunction with radiation and chemotherapy has shown promising outcomes in terms of reducing treatment side effects and boosting effectiveness. Certain metabolites, such as valerate and butyrate, have been made known to improve the efficiency of CAR T-cell treatment, whilst others, such as indole-derived tryptophan metabolites, have been shown to inhibit tumor immunity. This review explores the intricate interplay between microbial metabolites and endocrine tumorigenesis, spanning mechanistic insights to the discovery of potential therapeutic biomarkers.
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Affiliation(s)
- Yiyi Zhang
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
| | - Nie Tang
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
| | - Hui Zhou
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
| | - Ying Zhu
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
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Saleh Z, Moccia MC, Ladd Z, Joneja U, Li Y, Spitz F, Hong YK, Gao T. Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation. Int J Mol Sci 2024; 25:1331. [PMID: 38279330 PMCID: PMC10816436 DOI: 10.3390/ijms25021331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/12/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are characterized by dysregulated signaling pathways that are crucial for tumor formation and progression. The efficacy of traditional therapies is limited, particularly in the treatment of PNETs at an advanced stage. Epigenetic alterations profoundly impact the activity of signaling pathways in cancer development, offering potential opportunities for drug development. There is currently a lack of extensive research on epigenetic regulation in PNETs. To fill this gap, we first summarize major signaling events that are involved in PNET development. Then, we discuss the epigenetic regulation of these signaling pathways in the context of both PNETs and commonly occurring-and therefore more extensively studied-malignancies. Finally, we will offer a perspective on the future research direction of the PNET epigenome and its potential applications in patient care.
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Affiliation(s)
- Zena Saleh
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Z.S.); (Z.L.)
| | - Matthew C. Moccia
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Z.S.); (Z.L.)
| | - Zachary Ladd
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Z.S.); (Z.L.)
| | - Upasana Joneja
- Department of Pathology, Cooper University Health Care, Camden, NJ 08103, USA
| | - Yahui Li
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Z.S.); (Z.L.)
| | - Francis Spitz
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Z.S.); (Z.L.)
| | - Young Ki Hong
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Z.S.); (Z.L.)
| | - Tao Gao
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA; (Z.S.); (Z.L.)
- Camden Cancer Research Center, Camden, NJ 08103, USA
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5
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Role of Somatostatin Signalling in Neuroendocrine Tumours. Int J Mol Sci 2022; 23:ijms23031447. [PMID: 35163374 PMCID: PMC8836266 DOI: 10.3390/ijms23031447] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.
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Sharma R, Lythgoe MP, Slaich B, Patel N. Exploring the Epigenome in Gastroenteropancreatic Neuroendocrine Neoplasias. Cancers (Basel) 2021; 13:4181. [PMID: 34439335 PMCID: PMC8394968 DOI: 10.3390/cancers13164181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/06/2021] [Accepted: 08/17/2021] [Indexed: 11/17/2022] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasias are a diverse group of neoplasms with different characteristics in terms of site, biological behaviour and metastatic potential. In comparison to other cancers, they are genetically quiet, harbouring relatively few somatic mutations. It is increasingly becoming evident that epigenetic changes are as relevant, if not more so, as somatic mutations in promoting oncogenesis. Despite significant tumour heterogeneity, it is obvious that DNA methylation, histone and chromatin modifications and microRNA expression profiles are distinctive for GEP-NEN subtypes and may correlate with clinical outcome. This review summarises existing knowledge on epigenetic changes, identifying potential contributions to pathogenesis and oncogenesis. In particular, we focus on epigenetic changes pertaining to well-differentiated neuroendocrine tumours, which make up the bulk of NENs. We also highlight both similarities and differences within the subtypes of GEP-NETs and how these relate and compare to other types of cancers. We relate epigenetic understanding to existing treatments and explore how this knowledge may be exploited in the development of novel treatment approaches, such as in theranostics and combining conventional treatment modalities. We consider potential barriers to epigenetic research in GEP-NENs and discuss strategies to optimise research and development of new therapies.
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Affiliation(s)
- Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, London W12 ONN, UK;
| | - Mark P. Lythgoe
- Department of Surgery and Cancer, Imperial College London, London W12 ONN, UK;
| | - Bhavandeep Slaich
- Department of Medicine, University of Leicester, Leicester LE1 7RH, UK; (B.S.); (N.P.)
| | - Nishil Patel
- Department of Medicine, University of Leicester, Leicester LE1 7RH, UK; (B.S.); (N.P.)
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Phillips-Farfán B, Gómez-Chávez F, Medina-Torres EA, Vargas-Villavicencio JA, Carvajal-Aguilera K, Camacho L. Microbiota Signals during the Neonatal Period Forge Life-Long Immune Responses. Int J Mol Sci 2021; 22:ijms22158162. [PMID: 34360926 PMCID: PMC8348731 DOI: 10.3390/ijms22158162] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 12/27/2022] Open
Abstract
The microbiota regulates immunological development during early human life, with long-term effects on health and disease. Microbial products include short-chain fatty acids (SCFAs), formyl peptides (FPs), polysaccharide A (PSA), polyamines (PAs), sphingolipids (SLPs) and aryl hydrocarbon receptor (AhR) ligands. Anti-inflammatory SCFAs are produced by Actinobacteria, Bacteroidetes, Firmicutes, Spirochaetes and Verrucomicrobia by undigested-carbohydrate fermentation. Thus, fiber amount and type determine their occurrence. FPs bind receptors from the pattern recognition family, those from commensal bacteria induce a different response than those from pathogens. PSA is a capsular polysaccharide from B. fragilis stimulating immunoregulatory protein expression, promoting IL-2, STAT1 and STAT4 gene expression, affecting cytokine production and response modulation. PAs interact with neonatal immunity, contribute to gut maturation, modulate the gut–brain axis and regulate host immunity. SLPs are composed of a sphingoid attached to a fatty acid. Prokaryotic SLPs are mostly found in anaerobes. SLPs are involved in proliferation, apoptosis and immune regulation as signaling molecules. The AhR is a transcription factor regulating development, reproduction and metabolism. AhR binds many ligands due to its promiscuous binding site. It participates in immune tolerance, involving lymphocytes and antigen-presenting cells during early development in exposed humans.
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Affiliation(s)
- Bryan Phillips-Farfán
- Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, México City 04530, Mexico; (B.P.-F.); (K.C.-A.)
| | - Fernando Gómez-Chávez
- Laboratorio de Inmunología Experimental, Instituto Nacional de Pediatría, México City 04530, Mexico; (F.G.-C.); (J.A.V.-V.)
- Cátedras CONACyT-Instituto Nacional de Pediatría, México City 04530, Mexico
- Departamento de Formación Básica Disciplinaria, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, Mexico City 07320, Mexico
| | | | | | - Karla Carvajal-Aguilera
- Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, México City 04530, Mexico; (B.P.-F.); (K.C.-A.)
| | - Luz Camacho
- Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, México City 04530, Mexico; (B.P.-F.); (K.C.-A.)
- Correspondence:
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8
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Asa SL, La Rosa S, Basturk O, Adsay V, Minnetti M, Grossman AB. Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors. Endocr Pathol 2021; 32:169-191. [PMID: 33459926 DOI: 10.1007/s12022-021-09662-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/03/2021] [Indexed: 12/17/2022]
Abstract
Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.
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Affiliation(s)
- Sylvia L Asa
- Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.
| | - Stefano La Rosa
- Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Olca Basturk
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Volkan Adsay
- Department of Pathology and Research Center for Translational Medicine (KUTTAM), Koç University Hospital, Istanbul, Turkey
| | - Marianna Minnetti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Ashley B Grossman
- Green Templeton College, University of Oxford and ENETS Centre of Excellence, Royal Free Hospital, London, UK
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Colao A, de Nigris F, Modica R, Napoli C. Clinical Epigenetics of Neuroendocrine Tumors: The Road Ahead. Front Endocrinol (Lausanne) 2020; 11:604341. [PMID: 33384663 PMCID: PMC7770585 DOI: 10.3389/fendo.2020.604341] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 11/12/2020] [Indexed: 12/16/2022] Open
Abstract
Neuroendocrine tumors, or NETs, are cancer originating in neuroendocrine cells. They are mostly found in the gastrointestinal tract or lungs. Functional NETs are characterized by signs and symptoms caused by the oversecretion of hormones and other substances, but most NETs are non-functioning and diagnosis in advanced stages is common. Thus, novel diagnostic and therapeutic strategies are warranted. Epigenetics may contribute to refining the diagnosis, as well as to identify targeted therapy interfering with epigenetic-sensitive pathways. The goal of this review was to discuss the recent advancement in the epigenetic characterization of NETs highlighting their role in clinical findings.
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Affiliation(s)
- Annamaria Colao
- Department of Clinical Medicine and Surgery, Unesco Chair Health Education and Sustainable Development, Federico II University of Naples, Naples, Italy
| | - Filomena de Nigris
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Roberta Modica
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
- *Correspondence: Roberta Modica,
| | - Claudio Napoli
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
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10
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Phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung. Anticancer Drugs 2019; 29:457-465. [PMID: 29420340 DOI: 10.1097/cad.0000000000000596] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The standard-of-care for advanced small cell lung cancer (SCLC) is chemotherapy with cisplatin+etoposide (C+E). Most patients have chemosensitive disease at the outset, but disease frequently relapses and limits survival. Efforts to improve therapeutic outcomes in SCLC and other neuroendocrine cancers have focused on epigenetic agents, including the histone deacetylase inhibitor belinostat. The primary objective was to determine the maximum tolerated dose of the combination of belinostat (B) with C+E. Belinostat was administered as a 48-h continuous intravenous infusion on days 1-2; cisplatin was administered as a 1-h intravenous infusion on day 2; and etoposide was administered as a 1-h intravenous infusion on days 2, 3, and 4. Twenty-eight patients were recruited in this single-center study. The maximum tolerated dose was belinostat 500 mg/m/24 h, cisplatin 60 mg/m, and etoposide 80 mg/m. The combination was safe, although some patients were more susceptible to adverse events. Hematologic toxicities were most commonly observed. Objective responses were observed in 11 (39%) of 28 patients and seven (47%) of 15 patients with neuroendocrine tumors (including SCLC). Patients carrying more than three copies of variant UGT1A1 (*28 and *60) had higher serum levels of belinostat because of slower clearance. DNA damage peaked at 36 h after the initiation of belinostat, as did global lysine acetylation, but returned to baseline 12 h after the end of infusion. The combination of B+C+E is safe and active in SCLC and other neuroendocrine cancers. Future phase II studies should consider genotyping patients for UGT1A1*28 and UGT1A1*60 and to identify patients at an increased risk of adverse events.
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11
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Wanek J, Gaisberger M, Beyreis M, Mayr C, Helm K, Primavesi F, Jäger T, Di Fazio P, Jakab M, Wagner A, Neureiter D, Kiesslich T. Pharmacological Inhibition of Class IIA HDACs by LMK-235 in Pancreatic Neuroendocrine Tumor Cells. Int J Mol Sci 2018; 19:3128. [PMID: 30321986 PMCID: PMC6213165 DOI: 10.3390/ijms19103128] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 09/18/2018] [Accepted: 09/29/2018] [Indexed: 02/07/2023] Open
Abstract
Histone deacetylases (HDACs) play a key role in epigenetic mechanisms in health and disease and their dysfunction is implied in several cancer entities. Analysis of expression patterns in pancreatic neuroendocrine tumors (pNETs) indicated HDAC5 to be a potential target for future therapies. As a first step towards a possible treatment, the aim of this study was to evaluate the in vitro cellular and molecular effects of HDAC5 inhibition in pNET cells. Two pNET cell lines, BON-1 and QGP-1, were incubated with different concentrations of the selective class IIA HDAC inhibitor, LMK-235. Effects on cell viability were determined using the resazurin-assay, the caspase-assay, and Annexin-V staining. Western Blot and immunofluorescence microscopy were performed to assess the effects on HDAC5 functionality. LMK-235 lowered overall cell viability by inducing apoptosis in a dose- and time-dependent manner. Furthermore, acetylation of histone-H3 increased with higher LMK-235 concentrations, indicating functional inhibition of HDAC4/5. Immunocytochemical analysis showed that proliferative activity (phosphohistone H3 and Ki-67) decreased at highest concentrations of LMK-235 while chromogranin and somatostatin receptor 2 (SSTR2) expression increased in a dose-dependent manner. HDAC5 expression was found to be largely unaffected by LMK-235. These findings indicate LMK-235 to be a potential therapeutic approach for the development of an effective and selective pNET treatment.
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Affiliation(s)
- Julia Wanek
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Biomedical Sciences, Salzburg University of Applied Sciences, 5412 Puch/Salzburg, Austria.
- Department of Biosciences, Research Division of Regeneration, Stem Cell Biology and Gerontology, University of Salzburg, 5020 Salzburg, Austria.
| | - Martin Gaisberger
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria.
- Department for Radon Therapy Research, Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria.
- Gastein Research Institute, Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria.
| | - Marlena Beyreis
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria.
| | - Christian Mayr
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria.
| | - Katharina Helm
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Florian Primavesi
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria.
- Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Tarkan Jäger
- Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Pietro Di Fazio
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, 35033 Marburg, Germany.
| | - Martin Jakab
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria.
| | - Andrej Wagner
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Tobias Kiesslich
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria.
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12
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Gurunathan S, Kang MH, Kim JH. Combination Effect of Silver Nanoparticles and Histone Deacetylases Inhibitor in Human Alveolar Basal Epithelial Cells. Molecules 2018; 23:molecules23082046. [PMID: 30111752 PMCID: PMC6222610 DOI: 10.3390/molecules23082046] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 08/09/2018] [Accepted: 08/10/2018] [Indexed: 01/15/2023] Open
Abstract
Although many treatment strategies have been reported for lung disease, the mechanism of combination therapy using silver nanoparticles (AgNPs) and histone deacetylases inhibitors (HDACi) remains unclear. Therefore, innovative treatment strategies are essential for addressing the therapeutic challenges of this highly aggressive lung cancer. AgNPs and HDACi seem to be the best candidates for anticancer therapy because of their anti-proliferative effect in a variety of cancer cells. First, we synthesized AgNPs using wogonin as a reducing and stabilizing agent, following which the synthesized AgNPs were characterized by various analytical techniques. The synthesized AgNPs exhibited dose- and size-dependent toxicity towards A549 cells. Interestingly, the combination of AgNPs and MS-275 significantly induces apoptosis, which was accompanied by an increased level of reactive oxygen species (ROS); leakage of lactate dehydrogenase (LDH); secretion of TNFα; dysfunction of mitochondria; accumulation autophagosomes; caspase 9/3 activation; up and down regulation of pro-apoptotic genes and anti-apoptotic genes, respectively; and eventually, induced DNA-fragmentation. Our findings suggest that AgNPs and MS-275 induce cell death in A549 lung cells via the mitochondrial-mediated intrinsic apoptotic pathway. Finally, our data show that the combination of AgNPs and MS-275 is a promising new approach for the treatment of lung cancer and our findings contribute to understanding the potential roles of AgNPs and MS-275 in pulmonary disease. However, further study is warranted to potentiate the use of this combination therapy in cancer therapy trials.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
| | - Min-Hee Kang
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
| | - Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
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Iyer S, Agarwal SK. Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types. J Mol Endocrinol 2018; 61:R13-R24. [PMID: 29615472 PMCID: PMC5966343 DOI: 10.1530/jme-18-0050] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 04/03/2018] [Indexed: 12/15/2022]
Abstract
Epigenetic regulation is emerging as a key feature in the molecular characteristics of various human diseases. Epigenetic aberrations can occur from mutations in genes associated with epigenetic regulation, improper deposition, removal or reading of histone modifications, DNA methylation/demethylation and impaired non-coding RNA interactions in chromatin. Menin, the protein product of the gene causative for the multiple endocrine neoplasia type 1 (MEN1) syndrome, interacts with chromatin-associated protein complexes and also regulates some non-coding RNAs, thus participating in epigenetic control mechanisms. Germline inactivating mutations in the MEN1 gene that encodes menin predispose patients to develop endocrine tumors of the parathyroids, anterior pituitary and the duodenopancreatic neuroendocrine tissues. Therefore, functional loss of menin in the various MEN1-associated endocrine cell types can result in epigenetic changes that promote tumorigenesis. Because epigenetic changes are reversible, they can be targeted to develop therapeutics for restoring the tumor epigenome to the normal state. Irrespective of whether epigenetic alterations are the cause or consequence of the tumorigenesis process, targeting the endocrine tumor-associated epigenome offers opportunities for exploring therapeutic options. This review presents epigenetic control mechanisms relevant to the interactions and targets of menin, and the contribution of epigenetics in the tumorigenesis of endocrine cell types from menin loss.
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Affiliation(s)
- Sucharitha Iyer
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Sunita K Agarwal
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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Hofving T, Arvidsson Y, Almobarak B, Inge L, Pfragner R, Persson M, Stenman G, Kristiansson E, Johanson V, Nilsson O. The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines. Endocr Relat Cancer 2018; 25. [PMID: 29540494 PMCID: PMC8133373 DOI: 10.1530/erc-17-0445e] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Tobias Hofving
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Correspondence should be addressed to T Hofving:
| | - Yvonne Arvidsson
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Bilal Almobarak
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Linda Inge
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Roswitha Pfragner
- Institute of Pathophysiology and Immunology, Center for Molecular Medicine, Medical University of Graz, Graz, Austria
| | - Marta Persson
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Göran Stenman
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Erik Kristiansson
- Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
| | - Viktor Johanson
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Ola Nilsson
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
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15
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Hofving T, Arvidsson Y, Almobarak B, Inge L, Pfragner R, Persson M, Stenman G, Kristiansson E, Johanson V, Nilsson O. The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines. Endocr Relat Cancer 2018; 25:367-380. [PMID: 29444910 PMCID: PMC5827037 DOI: 10.1530/erc-17-0445] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 01/15/2018] [Indexed: 12/23/2022]
Abstract
Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2 Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.
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Affiliation(s)
- Tobias Hofving
- Sahlgrenska Cancer CenterDepartment of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Yvonne Arvidsson
- Sahlgrenska Cancer CenterDepartment of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Bilal Almobarak
- Sahlgrenska Cancer CenterDepartment of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Linda Inge
- Sahlgrenska Cancer CenterDepartment of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Roswitha Pfragner
- Institute of Pathophysiology and ImmunologyCenter for Molecular Medicine, Medical University of Graz, Graz, Austria
| | - Marta Persson
- Sahlgrenska Cancer CenterDepartment of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Göran Stenman
- Sahlgrenska Cancer CenterDepartment of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Erik Kristiansson
- Department of Mathematical SciencesChalmers University of Technology, Gothenburg, Sweden
| | - Viktor Johanson
- Department of SurgeryInstitute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Ola Nilsson
- Sahlgrenska Cancer CenterDepartment of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
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16
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Aristizabal Prada ET, Auernhammer CJ. Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets. Endocr Connect 2018; 7:R1-R25. [PMID: 29146887 PMCID: PMC5754510 DOI: 10.1530/ec-17-0286] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 11/16/2017] [Indexed: 12/12/2022]
Abstract
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression-free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras-Raf-MEK-ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors.
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Affiliation(s)
- E T Aristizabal Prada
- Department of Internal Medicine IVCampus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - C J Auernhammer
- Department of Internal Medicine IVCampus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany
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17
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Androutsopoulos VP, Spandidos DA. Antiproliferative effects of TSA, PXD‑101 and MS‑275 in A2780 and MCF7 cells: Acetylated histone H4 and acetylated tubulin as markers for HDACi potency and selectivity. Oncol Rep 2017; 38:3412-3418. [PMID: 29039546 PMCID: PMC5783587 DOI: 10.3892/or.2017.6015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 10/03/2017] [Indexed: 12/26/2022] Open
Abstract
Inhibition of histone deacetylase enzymes (HDACs) has been well documented as an attractive target for the development of chemotherapeutic drugs. The present study investigated the effects of two prototype hydroxamic acid HDAC inhibitors, namely Trichostatin A (TSA) and Belinostat (PXD-101) and the benzamide Entinostat (MS-275) in A2780 ovarian carcinoma and MCF7 breast adenocarcinoma cells. The three HDACi inhibited the proliferation of A2780 and MCF7 cells at comparable levels, below the µM range. Enzyme inhibition assays in a cell-free system showed that TSA was the most potent inhibitor of total HDAC enzyme activity followed by PXD-101 and MS-275. Incubation of A2780 and MCF7 cells with the hydroxamates TSA and PXD-101 for 24 h resulted in a dramatic increase of acetylated tubulin induction (up to 30-fold for TSA). In contrast to acetylated tubulin, western blot analysis and flow cytometry indicated that the induction of acetylated histone H4 was considerably smaller. The benzamide MS-275 exhibited nearly a 2-fold induction of acetylated histone H4 and an even smaller induction of acetylated tubulin in A2780 and MCF7 cells. Taken together, these data suggest that although the three HDACi were equipotent in inhibiting proliferation of MCF7 and A2780 cells, only the benzamide MS-275 did not induce acetylated tubulin expression, a marker of class IIb HDACs.
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Affiliation(s)
- Vasilis P Androutsopoulos
- Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, Voutes 71003, Greece
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, Voutes 71003, Greece
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18
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Finnerty BM, Gray KD, Moore MD, Zarnegar R, Fahey III TJ. Epigenetics of gastroenteropancreatic neuroendocrine tumors: A clinicopathologic perspective. World J Gastrointest Oncol 2017; 9:341-353. [PMID: 28979716 PMCID: PMC5605334 DOI: 10.4251/wjgo.v9.i9.341] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 06/27/2017] [Accepted: 08/04/2017] [Indexed: 02/05/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEP-NET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microRNA and long non-coding RNA (lncRNA) differential expression profiles that are distinctive of GEP-NETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.
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Affiliation(s)
- Brendan M Finnerty
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Katherine D Gray
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Maureen D Moore
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Rasa Zarnegar
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
| | - Thomas J Fahey III
- Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
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19
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Jang S, Jin H, Roy M, Ma AL, Gong S, Jaskula‐Sztul R, Chen H. Antineoplastic effects of histone deacetylase inhibitors in neuroendocrine cancer cells are mediated through transcriptional regulation of Notch1 by activator protein 1. Cancer Med 2017; 6:2142-2152. [PMID: 28776955 PMCID: PMC5603840 DOI: 10.1002/cam4.1151] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 06/23/2017] [Accepted: 07/03/2017] [Indexed: 01/19/2023] Open
Abstract
Notch signaling is minimally active in neuroendocrine (NE) cancer cells. While histone deacetylase inhibitors (HDACi) suppress NE cancer growth by inducing Notch, the molecular mechanism underlying this interplay has not yet been defined. NE cancer cell lines BON, H727, and MZ-CRC-1 were treated with known HDACi Thailadepsin-A (TDP-A) and valproic acid (VPA), and Notch1 mRNA expression was measured with RT-PCR. Truncated genomic fragments of the Notch1 promotor region fused with luciferase reporter were used to identify the potential transcription factor (TF) binding site. The key regulatory TF was identified with the electrophoretic mobility shift assay (EMSA). The effect of HDACi on Notch1 level was determined before and after silencing the TF. TDP-A and VPA induced Notch1 mRNA in a dose-dependent manner. A functional DNA motif at -80 to -52 from the Notch1 start codon responsible for the HDACi-dependent Notch1 induction was identified. Mutation of this core sequence failed to induce luciferase activity despite HDACi treatment. EMSA showed the greatest gel shift with AP-1 in nuclear extracts. Knockdown of AP-1 significantly attenuated the effect of HDACi on Notch1 induction. Interestingly, AP-1 transfection did not alter Notch1 level, suggesting that AP-1 is necessary but insufficient for HDACi activation of Notch1. Therefore, AP-1 is the TF that binds to a specific transcription-binding site within the Notch1 promotor region to trigger Notch1 transcription. Elucidating the HDACi activation mechanism may lead to the development of novel therapeutic options against NE cancers and facilitate the identification of clinical responders and prevent adverse effects.
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Affiliation(s)
- Samuel Jang
- Howard Hughes Medical InstituteBirminghamAlabama35233
- Department of SurgeryUniversity of Alabama at BirminghamBirminghamAlabama35233
| | - Haining Jin
- Department of SurgeryUniversity of Alabama at BirminghamBirminghamAlabama35233
| | - Madhuchhanda Roy
- Department of SurgeryUniversity of Alabama at BirminghamBirminghamAlabama35233
| | - Alice L. Ma
- Department of SurgeryUniversity of Alabama at BirminghamBirminghamAlabama35233
| | - Shaoqin Gong
- Department of Biomedical EngineeringUniversity of Wisconsin‐MadisonMadisonWI53715
| | | | - Herbert Chen
- Department of SurgeryUniversity of Alabama at BirminghamBirminghamAlabama35233
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20
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Di Domenico A, Wiedmer T, Marinoni I, Perren A. Genetic and epigenetic drivers of neuroendocrine tumours (NET). Endocr Relat Cancer 2017; 24:R315-R334. [PMID: 28710117 DOI: 10.1530/erc-17-0012] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 07/14/2017] [Indexed: 12/13/2022]
Abstract
Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.
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Affiliation(s)
- Annunziata Di Domenico
- Institute of PathologyUniversity of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of Bern, Bern, Switzerland
| | - Tabea Wiedmer
- Institute of PathologyUniversity of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of Bern, Bern, Switzerland
| | | | - Aurel Perren
- Institute of PathologyUniversity of Bern, Bern, Switzerland
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21
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Kumar N, Tomar R, Pandey A, Tomar V, Singh VK, Chandra R. Preclinical evaluation and molecular docking of 1,3-benzodioxole propargyl ether derivatives as novel inhibitor for combating the histone deacetylase enzyme in cancer. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2017; 46:1288-1299. [PMID: 28847179 DOI: 10.1080/21691401.2017.1369423] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Even after huge strides in medicine, cancer continues to be a formidable disease, which is slated to become the leading cause of death worldwide. The present study investigates the 1,3-benzodioxole and its propargyl ether derivatives as a novel histone deacetylase enzyme inhibitor in order to cure cancer, as aberrant expression of histone deacetylases (HDACs) is associated with carcinogenesis. Bioinformatics approaches were employed to carry out preclinical and pharmacological evaluations of designed benzodioxole derivatives. Furthermore, their interaction with HDAC-1 enzyme was studied through computational methods for their specific inhibitory effects and evaluated for their LD50 (oral rat acute toxicity) value. In addition to this work, three-dimensional (3D) structure of HDAC-1 enzyme was extracted and evaluated using various parameters including Ramachandran plot and molecular docking stimulation. In our study, we found that compound 7 and compound 9 have higher binding score than approved drugs (SAHA, TSA and VPA). Importantly, these compounds were found to possess good pharmacological and pharmacokinetic properties and can be considered as potent novel compound to combat the HDAC-1 enzyme to cure cancer. Compounds were also analyzed and validated with parameters like absorption, metabolism, excretion, toxicity and synthetic accessibility during the preclinical evaluation. This study paves way to search for novel and potent small chemical compounds for inhibiting HDAC-1 enzyme and in particular to combat the cancer progression by interrupting the cell cycle.
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Affiliation(s)
- Neeraj Kumar
- a Department of Chemistry, Drug Discovery and Development Laboratory , University of Delhi , Delhi , India.,b Department of Biotechnology, Stem Cell Research Laboratory , Delhi Technological University , Delhi , India
| | - Ravi Tomar
- a Department of Chemistry, Drug Discovery and Development Laboratory , University of Delhi , Delhi , India
| | - Apurva Pandey
- a Department of Chemistry, Drug Discovery and Development Laboratory , University of Delhi , Delhi , India
| | - Vartika Tomar
- a Department of Chemistry, Drug Discovery and Development Laboratory , University of Delhi , Delhi , India
| | - Vimal Kishor Singh
- c Dr. B. R. Ambedkar Centre for Biomedical Research , University of Delhi , Delhi , India
| | - Ramesh Chandra
- a Department of Chemistry, Drug Discovery and Development Laboratory , University of Delhi , Delhi , India.,c Dr. B. R. Ambedkar Centre for Biomedical Research , University of Delhi , Delhi , India
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HDAC Inhibitor-Induced Mitotic Arrest Is Mediated by Eg5/KIF11 Acetylation. Cell Chem Biol 2017; 24:481-492.e5. [PMID: 28392145 DOI: 10.1016/j.chembiol.2017.03.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 11/08/2016] [Accepted: 03/10/2017] [Indexed: 11/24/2022]
Abstract
Histone deacetylase 1 (HDAC1) is an epigenetic enzyme that regulates key cellular processes, such as cell proliferation, apoptosis, and cell survival, by deacetylating histone substrates. Aberrant expression of HDAC1 is implicated in multiple diseases, including cancer. As a consequence, HDAC inhibitors have emerged as effective anti-cancer drugs. HDAC inhibitor-induced G0/G1 cell-cycle arrest has been attributed to epigenetic transcriptional changes mediated by histone acetylation. However, the mechanism of G2/M arrest remains poorly understood. Here, we identified mitosis-related protein Eg5 (KIF11) as an HDAC1 substrate using a trapping mutant strategy. HDAC1 colocalized with Eg5 during mitosis and influenced the ATPase activity of Eg5. Importantly, an HDAC1- and HDAC2-selective inhibitor caused mitotic arrest and monopolar spindle formation, consistent with a model in which Eg5 deacetylation by HDAC1 is critical for mitotic progression. These findings revealed a previously unknown mechanism of action of HDAC inhibitors involving Eg5 acetylation, and provide a compelling mechanistic hypothesis for HDAC inhibitor-mediated G2/M arrest.
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23
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Cives M, Simone V, Rizzo FM, Silvestris F. NETs: organ-related epigenetic derangements and potential clinical applications. Oncotarget 2016; 7:57414-57429. [PMID: 27418145 PMCID: PMC5302998 DOI: 10.18632/oncotarget.10598] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 06/30/2016] [Indexed: 12/15/2022] Open
Abstract
High-throughput next-generation sequencing methods have recently provided a detailed picture of the genetic landscape of neuroendocrine tumors (NETs), revealing recurrent mutations of chromatin-remodeling genes and little-to-no pathogenetic role for oncogenes commonly mutated in cancer. Concurrently, multiple epigenetic modifications have been described across the whole spectrum of NETs, and their putative function as tumorigenic drivers has been envisaged. As result, it is still unclear whether or not NETs are epigenetically-driven, rather than genetically-induced malignancies. Although the NET epigenome profiling has led to the identification of molecularly-distinct tumor subsets, validation studies in larger cohorts of patients are needed to translate the use of NET epitypes in clinical practice. In the precision medicine era, recognition of subpopulations of patients more likely to respond to therapeutic agents is critical, and future studies testing epigenetic biomarkers are therefore awaited. Restoration of the aberrant chromatin remodeling machinery is an attractive approach for future treatment of cancer and in several hematological malignancies a few epigenetic agents have been already approved. Although clinical outcomes of epigenetic therapies in NETs have been disappointing so far, further clinical trials are required to investigate the efficacy of these drugs. In this context, given the immune-stimulating effects of epidrugs, combination therapies with immune checkpoint inhibitors should be tested. In this review, we provide an overview of the epigenetic changes in both hereditary and sporadic NETs of the gastroenteropancreatic and bronchial tract, focusing on their diagnostic, prognostic and therapeutic implications.
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Affiliation(s)
- Mauro Cives
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Valeria Simone
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Francesca Maria Rizzo
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Franco Silvestris
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
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Kuzyniak W, Ermilov EA, Atilla D, Gürek AG, Nitzsche B, Derkow K, Hoffmann B, Steinemann G, Ahsen V, Höpfner M. Tetra-triethyleneoxysulfonyl substituted zinc phthalocyanine for photodynamic cancer therapy. Photodiagnosis Photodyn Ther 2016; 13:148-157. [PMID: 26162500 DOI: 10.1016/j.pdpdt.2015.07.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 06/19/2015] [Accepted: 07/02/2015] [Indexed: 12/29/2022]
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Arvidsson Y, Johanson V, Pfragner R, Wängberg B, Nilsson O. Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells. Neuroendocrinology 2016; 103:578-91. [PMID: 26505883 DOI: 10.1159/000441849] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 10/15/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS Histone deacetylases (HDACs) modulate lysine acetylation on histones and are frequently deregulated in cancer. HDAC inhibitors with potent anti-tumour effects have been developed and are now being tested in clinical trials. The aim of this study was to investigate the effects of valproic acid (VPA), an inhibitor of class I and class IIa HDACs, on neuroendocrine tumour (NET) cell growth. METHODS Three NET cell lines, GOT1 (small intestinal), KRJ-I (small intestinal), and BON (pancreatic), were treated with VPA and examined with respect to cell viability, cell cycle arrest, apoptosis, and global transcriptional response. RESULTS We found that VPA induced a dose-dependent growth inhibition of NET cells in vitro, which was mainly due to activation of extrinsic and intrinsic apoptotic pathways. VPA induced a major transcriptional response by altering the expression of 16-19% of the protein-coding genes in NET cell lines. Pathway analysis allowed the prediction of alterations in key regulatory pathways, e.g. activation of TGF-β1, FOXO3, p53 signalling, and inhibition of MYC signalling. Analysis of GOT1 xenografts showed reduced growth and reduced Ki-67 index, as well as an increase in apoptosis and necrosis after VPA treatment. CONCLUSIONS We found that VPA treatment has a cytotoxic effect on NET cells of intestinal and pancreatic origin. There are several mechanisms by which VPA kills NET cells, which suggests the possibility of combination therapy. We propose that epigenetic therapy with HDAC inhibitors should be evaluated further in patients with NET disease.
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Noor Z, Afzal N, Rashid S. Exploration of Novel Inhibitors for Class I Histone Deacetylase Isoforms by QSAR Modeling and Molecular Dynamics Simulation Assays. PLoS One 2015; 10:e0139588. [PMID: 26431201 PMCID: PMC4592208 DOI: 10.1371/journal.pone.0139588] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 09/15/2015] [Indexed: 12/20/2022] Open
Abstract
Histone deacetylases (HDAC) are metal-dependent enzymes and considered as important targets for cell functioning. Particularly, higher expression of class I HDACs is common in the onset of multiple malignancies which results in deregulation of many target genes involved in cell growth, differentiation and survival. Although substantial attempts have been made to control the irregular functioning of HDACs by employing various inhibitors with high sensitivity towards transformed cells, limited success has been achieved in epigenetic cancer therapy. Here in this study, we used ligand-based pharmacophore and 2-dimensional quantitative structure activity relationship (QSAR) modeling approaches for targeting class I HDAC isoforms. Pharmacophore models were generated by taking into account the known IC50 values and experimental energy scores with extensive validations. The QSAR model having an external R2 value of 0.93 was employed for virtual screening of compound libraries. 10 potential lead compounds (C1-C10) were short-listed having strong binding affinities for HDACs, out of which 2 compounds (C8 and C9) were able to interact with all members of class I HDACs. The potential binding modes of HDAC2 and HDAC8 to C8 were explored through molecular dynamics simulations. Overall, bioactivity and ligand efficiency (binding energy/non-hydrogen atoms) profiles suggested that proposed hits may be more effective inhibitors for cancer therapy.
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Affiliation(s)
- Zainab Noor
- National Center for Bioinformatics, Quaid I Azam University, Islamabad, Pakistan
| | - Noreen Afzal
- National Center for Bioinformatics, Quaid I Azam University, Islamabad, Pakistan
| | - Sajid Rashid
- National Center for Bioinformatics, Quaid I Azam University, Islamabad, Pakistan
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Mapelli P, Aboagye EO, Stebbing J, Sharma R. Epigenetic changes in gastroenteropancreatic neuroendocrine tumours. Oncogene 2015; 34:4439-47. [PMID: 25435371 DOI: 10.1038/onc.2014.379] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 09/25/2014] [Accepted: 10/10/2014] [Indexed: 02/07/2023]
Abstract
An understanding of epigenetic drivers of tumorigenesis has developed rapidly during the last years. The identification of these changes including DNA methylation and histone modifications in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is a step forward in trying to define underlying biologic processes in this heterogeneous disease. The reversible nature of these changes represents a potential therapeutic target. We present an overview of the current knowledge of epigenetic alterations related to GEP-NETs, focusing on the influence and impact these changes have on pathogenesis and prognosis. The potential role of demethylating agents in the management of this patient population is discussed.
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Affiliation(s)
- P Mapelli
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - E O Aboagye
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - J Stebbing
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - R Sharma
- Department of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
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Biological evaluation of 4,5-diarylimidazoles with hydroxamic acid appendages as novel dual mode anticancer agents. Cancer Chemother Pharmacol 2015; 75:691-700. [PMID: 25618416 DOI: 10.1007/s00280-015-2685-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 01/16/2015] [Indexed: 01/24/2023]
Abstract
PURPOSE New (4-aryl-1-methylimidazol-5-yl)cinnamoylhydroxamic acids were prepared as potential dual mode anticancer agents combining the antivascular effect of the 4,5-diarylimidazole moiety and the histone deacetylases (HDAC) inhibition by the cinnamoyl hydroxamate. METHODS Their antiproliferative activity against a panel of primary cells and cancer cell lines was determined by MTT assays and their apoptosis induction by caspase-3 activation. Their ability to reduce the activity of HDAC was measured by enzymatic assays and Western blot analyses of cellular HDAC substrates. Additional effects on cancer cell migration were ascertained via immunofluorescence staining of cytoskeleton components and three-dimensional migration assays. The chorioallantoic membrane assay was used as an in vivo model to assess their antiangiogenic properties. RESULTS The 4-phenyl- and 4-(p-methoxyphenyl)-imidazole derivatives had a greater antiproliferative and apoptosis inducing effect in a variety of cancer cell lines when compared with the approved HDAC inhibitor SAHA, and most distinctly so in non-malignant human umbilical vein endothelial cells. Like SAHA, both compounds acted as pan-HDAC inhibitors. In 518A2 melanoma cells, they led to hyperacetylation of histones and of the cytoplasmic HDAC6 substrate alpha-tubulin. As a consequence, they inhibited the migration and invasion of these cells in transwell invasion assays. In keeping with its pronounced impact on endothelial cells, the 4-phenyl-imidazole derivative also inhibited the growth and sprouting of blood vessels in the chorioallantoic membrane of fertilized hen eggs. CONCLUSIONS The 4-phenyl- and 4-(p-methoxyphenyl)-imidazole compounds combine the antivascular effects of 4,5-diarylimidazoles with HDAC inhibition by cinnamoyl hydroxamates and show additional antimetastatic activity. They are promising candidates for pleiotropic HDAC inhibitors.
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Yuan H, Li AJ, Ma SL, Cui LJ, Wu B, Yin L, Wu MC. Inhibition of autophagy significantly enhances combination therapy with sorafenib and HDAC inhibitors for human hepatoma cells. World J Gastroenterol 2014; 20:4953-4962. [PMID: 24833845 PMCID: PMC4009527 DOI: 10.3748/wjg.v20.i17.4953] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Revised: 11/13/2013] [Accepted: 01/02/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To clarify whether histone deacetylase inhibitors histone deacetylase inhibitors (HDACIs) can sensitize hepatocellular carcinoma (HCC) cells to sorafenib treatment.
METHODS: Bax, Bcl-2, ATG5-ATG12, p21, and p27 protein levels in Hep3B, HepG2, and PLC/PRF/5 cells were examined by Western blot. CCK8 and a fluorometric caspase-3 assay were used to examine cellular viability and apoptosis levels. The effect of Beclin-1 on sensitization of HCC cells to sorafenib was examined by transfecting Beclin-1 siRNA into Hep3B, HepG2, and PLC/PRF/5 cells.
RESULTS: Autophagy inhibition enhances the inhibitory effects of vorinostat and sorafenib alone or in combination on HCC cell growth. Vorinostat and sorafenib synergistically induced apoptosis and cell cycle alterations. Western blot data indicated that HDACIs and Beclin-1 knockdown increased the p53 acetylation level. The knockdown of Beclin-1 enhanced the synergistic effect of the combination of vorinostat with sorafenib.
CONCLUSION: HDACIs can sensitize HCC cells to sorafenib treatment by regulating the acetylation level of Beclin-1.
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Abstract
The field of epigenetics has evolved rapidly over recent years providing insight into the tumorigenesis of many solid and haematological malignancies. Determination of epigenetic modifications in neuroendocrine tumour (NET) development is imperative if we are to improve our understanding of the biology of this heterogenous group of tumours. Epigenetic marks such as DNA methylation at RASSF1A are frequent findings in NETs of all origins and may be associated with worse prognosis. MicroRNA signatures and histone modifications have been identified which can differentiate subtypes of NET and distinguish NET from adenocarcinoma in cases of diagnostic uncertainty. Historically, candidate gene-driven approaches have yielded limited insight into the epigenetics of NET. Recent progress has been facilitated by development of high-throughput tools including second-generation sequencing and arrays for analysis of the 'epigenome' of tumour and normal tissue, permitting unbiased approaches such as exome sequencing that identified mutations of chromatin-remodelling genes ATRX/DAXX in 44% of pancreatic NETs. Epigenetic changes are reversible and therefore represent an attractive therapeutic target; to date, clinical outcomes of epigenetic therapies in solid tumours have been disappointing; however, in vitro studies on NETs are promising and further clinical trials are required to determine utility of this class of novel agents. In this review, we perform a comprehensive evaluation of epigenetic changes found in NETs to date, including rare NETs such as phaeochromocytoma and adrenocortical tumours. We suggest priorities for future research and discuss potential clinical applications and novel therapies.
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Affiliation(s)
- A Karpathakis
- University College London Cancer Institute, 72 Huntley Street, London WC1E 6BT, UK
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Koutsounas I, Giaginis C, Patsouris E, Theocharis S. Current evidence for histone deacetylase inhibitors in pancreatic cancer. World J Gastroenterol 2013; 19:813-28. [PMID: 23430136 PMCID: PMC3574878 DOI: 10.3748/wjg.v19.i6.813] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 10/18/2011] [Accepted: 01/05/2013] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive human cancers, with more than 200 000 deaths worldwide every year. Despite recent efforts, conventional treatment approaches, such as surgery and classic chemotherapy, have only slightly improved patient outcomes. More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm. Among new agents, histone deacetylase inhibitors (HDACIs) are now being tested. HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression, apoptosis, cell cycle progression and angiogenesis. HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines. In the present review, the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro, as well as their antiproliferative effects in animal models are presented. HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor effects, at well-tolerated doses.
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Larsson C. Epigenetic aspects on therapy development for gastroenteropancreatic neuroendocrine tumors. Neuroendocrinology 2013; 97:19-25. [PMID: 22456267 DOI: 10.1159/000336087] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Accepted: 12/10/2011] [Indexed: 01/16/2023]
Abstract
The understanding of epigenetic modifications in gastroenteropancreatic neuroendocrine tumors is a novel and still small field. Activation of the insulin-like growth factor 2 gene locus by loss of imprinting is a classical epigenetic alteration frequently observed in insulinoma. Inactivation of the MEN1 gene, commonly involved in endocrine pancreatic tumors, impairs the association with mixed lineage leukemia involved in histone H3K4me3 methylation. In addition, promising effects on tumor phenotypes such as growth, apoptosis, cell cycle arrest, and expression of neuroendocrine markers have been obtained in vitro for inhibitors of DNA methyltransferase (azacytidine) and histone deacetylation (butyrate, valproic acid, trichostatin A and MS-275). The frequent need for complementary treatments in addition to surgery in this tumor entity supports further efforts in the development and application of drugs acting at general as well as more specific epigenetic alterations.
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Affiliation(s)
- Catharina Larsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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Abstract
Epigenetic modifications constitute the next frontier in tumor biology research. Post-translation modification of histones dynamically influences gene expression independent of alterations to the DNA sequence. These mechanisms are often mediated by histone linkers or by proteins associated with the recruitment of DNA-binding proteins, HDAC I and II interacting proteins and transcriptional activators, coactivators or corepressors. Early evidence suggested that histones and their modifiers are involved in sophisticated processes that modulate tumor behavior and cellular phenotype. In this review, we discuss how recent discoveries about chromatin modifications, particularly histone acetylation, are shaping our knowledge of cell biology and our understanding of the molecular circuitry governing tumor progression and consider whether recent insights may extend to novel therapeutic approaches. Furthermore, we discuss the latest oncogenomic findings in Head and Neck Squamous Cell Carcinoma (HNSCC) from studies using Next Generation Sequencing (NGS) technology and highlight the impact of mutations identified in histones and their modifiers.
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Affiliation(s)
- Manoela D Martins
- Department of Oral Pathology, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Rogerio M Castilho
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
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Wong C, Vosburgh E, Levine AJ, Cong L, Xu EY. Human neuroendocrine tumor cell lines as a three-dimensional model for the study of human neuroendocrine tumor therapy. J Vis Exp 2012:e4218. [PMID: 22929519 PMCID: PMC3486771 DOI: 10.3791/4218] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Neuroendocrine tumors (NETs) are rare tumors, with an incidence of two per 100, 000 individuals per year, and they account for 0.5% of all human malignancies.1 Other than surgery for the minority of patients who present with localized disease, there is little or no survival benefit of systemic therapy. Therefore, there is a great need to better understand the biology of NETs, and in particular define new therapeutic targets for patients with nonresectable or metastatic neuroendocrine tumors. 3D cell culture is becoming a popular method for drug screening due to its relevance in modeling the in vivo tumor tissue organization and microenvironment.2,3 The 3D multicellular spheroids could provide valuable information in a more timely and less expensive manner than directly proceeding from 2D cell culture experiments to animal (murine) models. To facilitate the discovery of new therapeutics for NET patients, we have developed an in vitro 3D multicellular spheroids model using the human NET cell lines. The NET cells are plated in a non-adhesive agarose-coated 24-well plate and incubated under physiological conditions (5% CO2, 37 °C) with a very slow agitation for 16-24 hr after plating. The cells form multicellular spheroids starting on the 3rd or 4th day. The spheroids become more spherical by the 6th day, at which point the drug treatments are initiated. The efficacy of the drug treatments on the NET spheroids is monitored based on the morphology, shape and size of the spheroids with a phase-contrast light microscope. The size of the spheroids is estimated automatically using a custom-developed MATLAB program based on an active contour algorithm. Further, we demonstrate a simple method to process the HistoGel embedding on these 3D spheroids, allowing the use of standard histological and immunohistochemical techniques. This is the first report on generating 3D spheroids using NET cell lines to examine the effect of therapeutic drugs. We have also performed histology on these 3D spheroids, and displayed an example of a single drug's effect on growth and proliferation of the NET spheroids. Our results support that the NET spheroids are valuable for further studies of NET biology and drug development.
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Wu J, Zhou Z, Hu Y, Dong S. Butyrate-induced GPR41 activation inhibits histone acetylation and cell growth. J Genet Genomics 2012; 39:375-84. [PMID: 22884094 DOI: 10.1016/j.jgg.2012.05.008] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2011] [Revised: 05/06/2012] [Accepted: 05/09/2012] [Indexed: 01/31/2023]
Abstract
Butyrate has been recently identified as a natural ligand of the G-protein-coupled receptor 41 (GPR41). In addition, it is an inhibitor of histone deacetylase (HDAC). Butyrate treatment results in the hyperacetylation of histones, with resultant multiple biological effects including inhibition of proliferation, induction of cell cycle arrest, and apoptosis, in a variety of cultured mammalian cells. However, it is not clear whether GPR41 is actively involved in the above-mentioned processes. In this study, we generated a stable cell line expressing the hGPR41 receptor in order to investigate the involvement of GPR41 on butyrate-induced biochemical and physiologic processes. We found that GPR41 activation may be a compensatory mechanism to counter the increase in histone H3 acetylation levels induced by butyrate treatment. Moreover, GPR41 had an inhibitory effect on the anti-proliferative, pro-apoptotic effects of butyrate. GPR41 expression induced cell cycle arrest at the G1-stage, while its activation by butyrate can cause more cells to pass the G1 checkpoint. These results indicated that GPR41 was associated with histone acetylation and might be involved in the acetylation-related regulation of cell processes including proliferation, apoptosis, and the cell cycle.
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Affiliation(s)
- Jin Wu
- Institute of Chemical and Translational Genomics, East China Normal University, Shanghai 200062, China
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36
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Knipstein J, Gore L. Entinostat for treatment of solid tumors and hematologic malignancies. Expert Opin Investig Drugs 2011; 20:1455-67. [DOI: 10.1517/13543784.2011.613822] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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37
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Sun JY, Xu L, Tseng H, Ciccarelli B, Fulciniti M, Hunter ZR, Maghsoudi K, Hatjiharissi E, Zhou Y, Yang G, Zhu B, Liu X, Gong P, Ioakimidis L, Sheehy P, Patterson CJ, Munshi NC, O'Connor OA, Treon SP. Histone deacetylase inhibitors demonstrate significant preclinical activity as single agents, and in combination with bortezomib in Waldenström's macroglobulinemia. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2011; 11:152-6. [PMID: 21454220 DOI: 10.3816/clml.2011.n.036] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
We studied the role of histone deacetylase inhibitors in Waldenstrom's macroglobulinemia (WM). Gene expression profiling of bone marrow CD19+ cells from 30 patients and 10 healthy donors showed overexpression of HDAC4, HDAC9, and Sirt5, with validation of HDAC9 overexpression by q-PCR in primary and BCWM.1 cells. Suberoylanilide hydroxamic acid, trichostatin A, panobinostat, and sirtinol demonstrated dose-dependent killing of BCWM.1 cells. TSA showed the greatest potency with IC50 of 70 nM. Importantly, HDAC9 activity was decreased following TSA treatment suggesting an essential role for this HDAC in WM therapy. The combination of bortezomib plus HDAC inhibitors resulted in at least additive tumor cell killing in BCWM.1 cells. TSA and bortezomib-induced apoptosis depended on a similar set of caspase activation, whereas their effect on cell cycle regulators was distinctly different. These results provided a framework for examining HDAC inhibitors as monotherapy, as well as combination therapy with bortezomib in WM.
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Affiliation(s)
- Jenny Y Sun
- Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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Gupta S, Engstrom PF, Cohen SJ. Emerging therapies for advanced gastroenteropancreatic neuroendocrine tumors. Clin Colorectal Cancer 2011; 10:298-309. [PMID: 21813338 DOI: 10.1016/j.clcc.2011.06.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 12/21/2010] [Accepted: 01/24/2011] [Indexed: 01/17/2023]
Abstract
Neuroendocrine tumors comprise a heterogeneous group of neoplasms derived from peptide- and amine-producing cells of the neuroendocrine system. Gastroenteropancreatic NET are differentiated into tumors and carcinomas based on their malignant potential and subdivided into those arising from the pancreas (islet cell tumors or pancreatic NET) and the more classical gut "carcinoids". Moderate to well differentiated NET have historically been considered rare tumors but recent epidemiological statistics suggest that their frequency has increased substantially over the past three decades. While the incidence of NET is increasing, data from both the US and UK demonstrate no improvement in outcomes over a similar time period. Due to the generally indolent biology of NET, most patients present with advanced disease before symptoms become apparent. In patients with localized NET, the 5-year survival rates after resection range from 60 to 90%, while regional lymph node involvement decreases the 5-year survival rates after surgery to 50-75%. Patients with distant metastases have a 5 year survival rate of approximately 25-40%. Conventional cytotoxic chemotherapy is of unclear benefit in patients with these generally slow growing tumors. Multiple agents have been tested in Phase 2 and Phase 3 trials. In general, the lack of major objective responses with significant toxicities has limited routine use of traditional chemotherapy agents and has emphasized the need to develop new agents in these diseases. This review will focus on emerging molecularly-targeted treatments with an emphasis on their underlying biologic and preclinical rationale.
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Affiliation(s)
- Sameer Gupta
- Fox Chase Cancer Center, Philadelphia, PA 19111, USA
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Noaman E, Fahmy N, Yousri R, Shawi OE, Ghazy M. Evaluation of the Antitumor and Radiosynthetizing Activity of a Novel Quinoline Sulfonamide Derivative (PIQSA) as a Histone Deacetylase Inhibitor. ACTA ACUST UNITED AC 2011. [DOI: 10.4236/jct.2011.24077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Wiedenmann B, Pavel M, Kos-Kudla B. From targets to treatments: a review of molecular targets in pancreatic neuroendocrine tumors. Neuroendocrinology 2011; 94:177-90. [PMID: 21893937 DOI: 10.1159/000329386] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 05/15/2011] [Indexed: 12/30/2022]
Abstract
Pancreatic neuroendocrine tumors (pancreatic NET) are relatively rare, slowly growing tumors, although their incidence is increasing, and patients may survive for several years with metastatic disease. Apart from symptomatic relief, there have been few treatment options for these tumors in the past. More recently, investigators have explored the potential of molecularly targeted agents in treating pancreatic NET, with some success. In this review, we consider the data supporting exploitation of different targets in pancreatic NET, including peptide receptors, receptor tyrosine kinases (involved in tumor angiogenesis and more directly supporting tumor growth), and intracellular targets, such as the mammalian target of rapamycin (mTOR), which has a central role in regulating cell growth, metabolism, and apoptosis. Probably due to the paucity of pancreatic NET, many clinical trials to date have included heterogeneous NET populations, and there are few randomized studies of this specific patient population. Very recently, promising results have been achieved in placebo-controlled, phase III trials with the multitargeted tyrosine kinase inhibitor, sunitinib, and the mTOR inhibitor, everolimus. These agents have been approved or are currently being reviewed by authorities for use in patients with pancreatic NET. Here we review potential molecular targets in pancreatic NET and summarize the available data for targeted agents from phase II and III trials open to patients with this tumor.
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Affiliation(s)
- Bertram Wiedenmann
- Department of Hepatology, Gastroenterology and Endocrinology, Charité Medical School, Berlin, Germany.
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Susick L, Senanayake T, Veluthakal R, Woster PM, Kowluru A. A novel histone deacetylase inhibitor prevents IL-1beta induced metabolic dysfunction in pancreatic beta-cells. J Cell Mol Med 2010. [PMID: 20141611 DOI: 10.1111/j.1582-4934.2008.00672.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) has recently been shown to inhibit deleterious effects of cytokines on beta-cells, but it is unable to protect beta-cells from death due to its own cytotoxicity. Herein, we investigated novel HDAC inhibitors for their cytoprotective effects against IL-1beta-induced damage to isolated beta-cells. We report that three novel compounds (THS-73-44, THS-72-5 and THS-78-5) significantly inhibited HDAC activity and increased the acetylation of histone H4 in isolated beta-cells. Further, these compounds exerted no toxic effects on metabolic cell viability in these cells. However, among the three compounds tested, only THS-78-5 protected against IL-1beta-mediated loss in beta-cell viability. THS-78-5 was also able to attenuate IL-1beta-induced inducible nitric oxide synthase expression and subsequent NO release. Our data also indicate that the cytoprotective properties of THS-78-5 against IL-1beta-mediated effects may, in part, be due to inhibition of IL-1beta-induced transactivation of nuclear factor kappaB (NF-kappaB) in these cells. Together, we provide evidence for a novel HDAC inhibitor with a significant potential to prevent IL-1beta-mediated effects on isolated beta-cells. Potential implications of these findings in the development of novel therapeutics to prevent deleterious effects of cytokines and the onset of autoimmune diabetes are discussed.
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Affiliation(s)
- Laura Susick
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
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Susick L, Senanayake T, Veluthakal R, Woster PM, Kowluru A. A novel histone deacetylase inhibitor prevents IL-1beta induced metabolic dysfunction in pancreatic beta-cells. J Cell Mol Med 2010; 13:1877-85. [PMID: 20141611 DOI: 10.1111/j.1582-4934.2009.00672.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) has recently been shown to inhibit deleterious effects of cytokines on beta-cells, but it is unable to protect beta-cells from death due to its own cytotoxicity. Herein, we investigated novel HDAC inhibitors for their cytoprotective effects against IL-1beta-induced damage to isolated beta-cells. We report that three novel compounds (THS-73-44, THS-72-5 and THS-78-5) significantly inhibited HDAC activity and increased the acetylation of histone H4 in isolated beta-cells. Further, these compounds exerted no toxic effects on metabolic cell viability in these cells. However, among the three compounds tested, only THS-78-5 protected against IL-1beta-mediated loss in beta-cell viability. THS-78-5 was also able to attenuate IL-1beta-induced inducible nitric oxide synthase expression and subsequent NO release. Our data also indicate that the cytoprotective properties of THS-78-5 against IL-1beta-mediated effects may, in part, be due to inhibition of IL-1beta-induced transactivation of nuclear factor kappaB (NF-kappaB) in these cells. Together, we provide evidence for a novel HDAC inhibitor with a significant potential to prevent IL-1beta-mediated effects on isolated beta-cells. Potential implications of these findings in the development of novel therapeutics to prevent deleterious effects of cytokines and the onset of autoimmune diabetes are discussed.
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Affiliation(s)
- Laura Susick
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
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Stojsic Z, Brasanac D, Bilanovic D, Mitrovic O, Stevanovic R, Boricic I. Large-cell neuroendocrine carcinoma of the ampulla of Vater. Med Oncol 2009; 27:1144-8. [PMID: 19898974 DOI: 10.1007/s12032-009-9350-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2009] [Accepted: 10/22/2009] [Indexed: 10/20/2022]
Abstract
Large-cell neuroendocrine carcinoma is a high-grade neuroendocrine carcinoma, originally described in the lung. The tumor rarely occurs in extrapulmonary sites like the gastrointestinal tract, and only few examples have been described in the ampulla of Vater. A new case of large-cell neuroendocrine carcinoma of the ampulla of Vater in a 60-year-old man is reported. After pancreatoduodenectomy, macroscopic examination revealed ulcerated tumor in the region of the ampulla of Vater. Microscopically, the tumor exhibited organoid, predominantly nested growth pattern, consisting of large, polygonal cells with pleomorphic nuclei. Average number of mitoses was 36 per 10 high-power fields. Small and large areas of necrosis were identified. Immunohistochemically, the tumor cells were positive for synaptophysin, chromogranin A, PGP 9.5, neuron-specific enolase, pancytokeratin, CK8 and somatostatin and negative for CK7, CK20, S-100, TTF-1, HMB-45, CD117, E-cadherin and regulatory peptides. Ki-67 proliferative index was 41%. Histone deacetylase (HDAC) analysis showed almost identical results for HDAC1, HDAC2 and HDAC3--60, 60.3 and 61%, respectively. Two months after surgery, liver metastases occurred, confirming highly aggressive behavior of large-cell neuroendocrine carcinoma.
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Affiliation(s)
- Z Stojsic
- Institute of Pathology, School of Medicine, University of Belgrade, Dr Subotica 1/II, 11000, Belgrade, Serbia.
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Capurso G, Fazio N, Festa S, Panzuto F, De Braud F, Delle Fave G. Molecular target therapy for gastroenteropancreatic endocrine tumours: biological rationale and clinical perspectives. Crit Rev Oncol Hematol 2009; 72:110-124. [PMID: 19249226 DOI: 10.1016/j.critrevonc.2009.01.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2008] [Revised: 01/13/2009] [Accepted: 01/28/2009] [Indexed: 02/08/2023] Open
Abstract
Gastroenteropancreatic endocrine tumours (GEP ETs) represent a relatively rare and heterogeneous group of neoplasms whose therapy can be challenging. The poorly differentiated, fast-growing cases are treated with chemotherapy. In the slow-growing ones, biotherapy is usually performed. Several categories of targeted therapies have been studied for their treatment in vitro and in vivo. A critical review of molecular alterations suggests a rationale for targeting angiogenesis, and the phosphatidylinositol 3 kinase (PI(3)K)/AKT/mammalian target of rapamycin (mTOR) pathway. Accordingly, antiangiogenic agents and mTOR inhibitors are presently the most tested agents in phase II and III studies. Bevacizumab, some multitarget inhibitors, and mTOR inhibitors showed promising results in patients with advanced GEP ETs. A limited activity has been reported for imatinib and epidermal growth factor receptor (EGFR) inhibitors. Combinations of molecular targeted therapies with different sites of action, and somatostatin analogues may be relevant to avoid molecular escape pathways. Future trials should include more homogeneous groups of patients and pay more attention to the subgroup with progressive disease.
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Affiliation(s)
- Gabriele Capurso
- Digestive and Liver Disease Unit, S. Andrea Hospital, II Medical School, University "La Sapienza", Via Di Grottarossa 1035-1039, 00189, Rome, Italy
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Meng F, Han M, Zheng B, Wang C, Zhang R, Zhang XH, Wen JK. All-trans retinoic acid increases KLF4 acetylation by inducing HDAC2 phosphorylation and its dissociation from KLF4 in vascular smooth muscle cells. Biochem Biophys Res Commun 2009; 387:13-8. [PMID: 19486889 DOI: 10.1016/j.bbrc.2009.05.112] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2009] [Accepted: 05/25/2009] [Indexed: 10/20/2022]
Abstract
The zinc finger transcription factor Krüppel-like factor 4 (KLF4) has been implicated in vascular smooth muscle cell differentiation induced by all-trans retinoic acid (ATRA). However, the molecular mechanism whereby ATRA regulates KLF4 activity is still poorly understood. Here, we show that ATRA-induced histone deacetylase 2 (HDAC2) phosphorylation at Ser424 in VSMCs and inhibited the interaction of HDAC2 with KLF4. Inhibiting JNK by JNK inhibitor SP600125 or knockdown of JNK by JNK siRNA abrogated ATRA-induced HDAC2 phosphorylation and reversed ATRA-induced suppression of the interaction of HDAC2 with KLF4. We further demonstrated that HDAC2 directly deacetylated KLF4, and that KLF4 acetylation and binding activity of KLF4 to the SM22alpha promoter were significantly increased in ATRA-treated VSMCs. Collectively, our results indicate that ATRA induces HDAC2 phosphorylation mediated by JNK signaling, and thus causes HDAC2 dissociation from KLF4, subsequently leading to the increase in KLF4 acetylation.
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Affiliation(s)
- Fang Meng
- Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang, PR China
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Di Bernardo G, Squillaro T, Dell'Aversana C, Miceli M, Cipollaro M, Cascino A, Altucci L, Galderisi U. Histone deacetylase inhibitors promote apoptosis and senescence in human mesenchymal stem cells. Stem Cells Dev 2009; 18:573-581. [PMID: 18694296 DOI: 10.1089/scd.2008.0172] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Histone deacetylase inhibitors (HDACi) have received a great amount of attention for their antitumoral properties. Suberoyl anilide hydroxamic acid (SAHA) and MS-275 are among the more promising HDACi for cancer treatments. Although these HDACi compounds exert low toxicity on normal cells, the therapies based on these molecules can cause side effects that can greatly impair the functions of the bone marrow microenvironment. This is a complex system that contains several types of stem cells, such as mesenchymal stem cells (MSCs). We conducted comparative studies on the effects of SAHA and MS-275 on human MSCs in order to ascertain if these compounds can impair the physiology of MSCs. Both SAHA and MS-275 induced an arrest in the cell cycle along with the induction of apoptotic pathways as evidenced by flow cytometry, annexin assay, detection of activated caspase 9, and molecular analysis of Bax/Bcl-2 expression. The MS-275 treatment induced an increase of senescent cells, whereas in cells treated with SAHA, we detected a reduction of senescent cells compared to the control. We hypothesize that SAHA preferentially transactivates apoptotic genes, thereby inducing a great majority of the damaged cells to die by programmed cell death rather than senescence. Following the HDACi treatment, we observed a decrease in the expression of some genes that are involved in the regulation of stem cell properties. This suggests that SAHA and MS-275 could also be involved in the impairment of the stemness characteristics of MSCs. The phenomena that were induced by HDACi treatment were associated with an upregulation of several cyclin kinase inhibitors. By contrast, the p53-p21 pathway is apparently not involved in these processes.
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Affiliation(s)
- Giovanni Di Bernardo
- Department of Experimental Medicine, Section of Biotechnology and Molecular Biology, Excellence Research Center for Cardiovascular Diseases, Second University of Naples, Naples, Italy
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Ahn MY, Na YJ, Lee JW, Lee BM, Kim HS. Apicidin Induces Apoptosis via Cytochrome c-Mediated Intrinsic Pathway in Human Ovarian Cancer Cells. Biomol Ther (Seoul) 2009; 17:17-24. [DOI: 10.4062/biomolther.2009.17.1.17] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
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Takasuna K, Katsuyoshi C, Manabe S. Pre-clinical QT Risk Assessment in Pharmaceutical Companies - Issues of Current QT Risk Assessment -. Biomol Ther (Seoul) 2009. [DOI: 10.4062/biomolther.2009.17.1.1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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Ren G, Zhang G, Dong Z, Liu Z, Li L, Feng Y, Su D, Zhang Y, Huang B, Lu J. Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers. Int J Biochem Cell Biol 2008; 41:1094-101. [PMID: 19013255 DOI: 10.1016/j.biocel.2008.10.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2008] [Revised: 09/04/2008] [Accepted: 10/05/2008] [Indexed: 10/21/2022]
Abstract
HOXB13 is a homeodomain protein implicated to play a role in growth arrest in AR (androgen receptor)-negative prostate cancer cells. Expression of HOXB13 is restricted to the AR-expressing prostate cells. In this report, we demonstrate that the HDAC inhibitor NaB (sodium butyrate) was able to induce cell growth arrest and to increase HOXB13 expression in AR-negative prostate cancer cells. We also show that both HDAC4 and YY1 participated in the repression of HOXB13 expression through an epigenetic mechanism involving histone acetylation modification. Specifically, co-immunoprecipitation assays revealed that HDAC4 and YY1 formed a complex. The chromatin immunoprecipitation (ChIP) assays verified that HDAC4 was recruited to HOXB13 promoter by YY1. Moreover, promoter truncation and point mutation studies determined that the two proximal YY1 binding sites on the HOXB13 promoter were essential for the recruitments of YY1 and HDAC4. Data presented in this report suggest that YY1 and HDAC4 affected cell growth by repressing transcriptional regulation of HOXB13 through an epigenetic modification of histones.
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Affiliation(s)
- Guoling Ren
- Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, PR China
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Höpfner M, Schuppan D, Scherübl H. Treatment of gastrointestinal neuroendocrine tumors with inhibitors of growth factor receptors and their signaling pathways: recent advances and future perspectives. World J Gastroenterol 2008; 14:2461-73. [PMID: 18442192 PMCID: PMC2708356 DOI: 10.3748/wjg.14.2461] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2008] [Revised: 03/15/2008] [Indexed: 02/06/2023] Open
Abstract
The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies, which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors. This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors. In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e. combining growth factor (receptor)-targeting agents with chemo- or biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.
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