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1
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Rauf A, Olatunde A, Islam MR, Ahmad Z, Hafeez N, Hemeg HA, Imran M, Mubarak MS, Ribaudo G. Acetylsalicylic acid and cancer: updates on the new potential of a nature-inspired drug. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03959-6. [PMID: 40021514 DOI: 10.1007/s00210-025-03959-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 02/19/2025] [Indexed: 03/03/2025]
Abstract
Acetylsalicylic acid (ASA), commonly known as aspirin, is an organic compound with the formula C9H8O4 obtained from the natural compound salicylic acid, recognized for its analgesic, anti-inflammatory, antipyretic, and anticancer properties. Its role in medicine and plant biology is well-established, but its emerging potential in cancer treatment has garnered increased attention. This review aims to provide a comprehensive overview of the therapeutic applications of ASA as an anticancer agent, focusing on its mechanisms, effectiveness, and role as an adjuvant therapy, preventive compound, and radioprotective agent. Recent research papers, including mechanistic studies, preclinical investigations, and clinical trials related to the effects of ASA on various cancer types, were reviewed. The review places particular emphasis on the enhancement of traditional chemotherapy drugs by ASA and considers toxicological aspects. The analysis of recent studies highlights the potential of ASA to improve the effectiveness of chemotherapy and its role in cancer inhibition through specific molecular pathways. Mechanistic insights suggest that ASA may influence cellular processes that contribute to cancer growth suppression and increased sensitivity to conventional treatments. ASA exhibits promising potential as an adjunct therapy in cancer treatment, with evidence supporting its benefits in improving therapeutic outcomes when used alongside conventional chemotherapy. Further studies are needed to clarify its mechanisms and ensure its safe and effective application in clinical settings.
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Affiliation(s)
- Abdur Rauf
- Department of Chemistry, University of Swabi, Swabi, Pakistan.
| | - Ahmed Olatunde
- Department of Medical Biochemistry, Abubakar Tafawa Balewa University, Bauchi, 740272, Nigeria
| | - Md Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Zubair Ahmad
- Department of Chemistry, University of Swabi, Swabi, Pakistan
| | - Nabia Hafeez
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, KPK, KPK-25120, Pakistan
| | - Hassan A Hemeg
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Al-Madinah Al-Monawra, 41411, Saudi Arabia
| | - Muhammad Imran
- Chemistry Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha, 61413, Saudi Arabia
| | - Mohammad S Mubarak
- Department of Chemistry, The University of Jordan, Amman, 11942, Jordan.
| | - Giovanni Ribaudo
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, 25123, Italy.
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2
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Al Khzem AH, Gomaa MS, Alturki MS, Tawfeeq N, Sarafroz M, Alonaizi SM, Al Faran A, Alrumaihi LA, Alansari FA, Alghamdi AA. Drug Repurposing for Cancer Treatment: A Comprehensive Review. Int J Mol Sci 2024; 25:12441. [PMID: 39596504 PMCID: PMC11595001 DOI: 10.3390/ijms252212441] [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: 10/28/2024] [Revised: 11/12/2024] [Accepted: 11/17/2024] [Indexed: 11/28/2024] Open
Abstract
Cancer ranks among the primary contributors to global mortality. In 2022, the global incidence of new cancer cases reached about 20 million, while the number of cancer-related fatalities reached 9.7 million. In Saudi Arabia, there were 13,399 deaths caused by cancer and 28,113 newly diagnosed cases of cancer. Drug repurposing is a drug discovery strategy that has gained special attention and implementation to enhance the process of drug development due to its time- and money-saving effect. It involves repositioning existing medications to new clinical applications. Cancer treatment is a therapeutic area where drug repurposing has shown the most prominent impact. This review presents a compilation of medications that have been repurposed for the treatment of various types of cancers. It describes the initial therapeutic and pharmacological classes of the repurposed drugs and their new applications and mechanisms of action in cancer treatment. The review reports on drugs from various pharmacological classes that have been successfully repurposed for cancer treatment, including approved ones and those in clinical trials and preclinical development. It stratifies drugs based on their anticancer repurpose as multi-type, type-specific, and mechanism-directed, and according to their pharmacological classes. The review also reflects on the future potential that drug repurposing has in the clinical development of novel anticancer therapies.
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Affiliation(s)
- Abdulaziz H. Al Khzem
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (M.S.A.); (N.T.); (M.S.)
| | - Mohamed S. Gomaa
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (M.S.A.); (N.T.); (M.S.)
| | - Mansour S. Alturki
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (M.S.A.); (N.T.); (M.S.)
| | - Nada Tawfeeq
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (M.S.A.); (N.T.); (M.S.)
| | - Mohammad Sarafroz
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (M.S.A.); (N.T.); (M.S.)
| | - Shareefa M. Alonaizi
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (S.M.A.); (A.A.F.); (L.A.A.); (F.A.A.); (A.A.A.)
| | - Alhassan Al Faran
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (S.M.A.); (A.A.F.); (L.A.A.); (F.A.A.); (A.A.A.)
| | - Laela Ahmed Alrumaihi
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (S.M.A.); (A.A.F.); (L.A.A.); (F.A.A.); (A.A.A.)
| | - Fatimah Ahmed Alansari
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (S.M.A.); (A.A.F.); (L.A.A.); (F.A.A.); (A.A.A.)
| | - Abdullah Abbas Alghamdi
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (S.M.A.); (A.A.F.); (L.A.A.); (F.A.A.); (A.A.A.)
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3
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Barros S, Coimbra AM, Herath LA, Alves N, Pinheiro M, Ribeiro M, Morais H, Branco R, Martinez O, Santos HG, Montes R, Rodil R, Quintana JB, Santos MM, Neuparth T. Are Environmental Levels of Nonsteroidal Anti-Inflammatory Drugs a Reason for Concern? Chronic Life-Cycle Effects of Naproxen in Zebrafish. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:19627-19638. [PMID: 39445516 DOI: 10.1021/acs.est.4c05599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
The nonsteroidal anti-inflammatory drug naproxen (NPX) is among the most consumed pharmaceuticals worldwide, being detected in surface waters within the ng to μg/L range. Considering the limited chronic ecotoxicity data available for NPX in aquatic ecosystems, the present study aimed at evaluating its impact in the model organism Danio rerio, following a full life-cycle exposure to environmentally relevant concentrations (0.1 to 5.0 μg/L). An integration of apical endpoints, i.e., survival, growth, and reproduction, with gonad histopathology and gene transcription (RNA-seq) was performed to provide additional insights into the mode of action (MoA) of NPX. NPX decreased zebrafish growth and reproduction and led to histopathological alterations in gonads at concentrations as low as 0.1 μg/L. At the molecular level, 0.7 μg/L of NPX led to a disruption in gonads transcription of genes involved in several biological processes associated with reproduction, mainly involving steroid hormone biosynthesis and epigenetic/epitranscriptomic machineries. Collectively, these results show that environmentally realistic concentrations of NPX affect zebrafish reproduction and associated signaling pathways, indicating that current hazard and risk assessment data for NPX underestimate the environmental risk of this pharmaceutical.
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Affiliation(s)
- Susana Barros
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
- CITAB - Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, Pavilhão 2, Vila Real 5000-801, Portugal
| | - Ana M Coimbra
- CITAB - Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, Pavilhão 2, Vila Real 5000-801, Portugal
- Inov4Agro - Institute for Innovation, Capacity Building and Sustainability of Agri-food Production, Vila Real 5000-801,Portugal
| | - Lihini Athapaththu Herath
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
| | - Nélson Alves
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
- FCUP - Department of Biology, Faculty of Sciences, University of Porto (U. Porto), Rua do Campo Alegre s/n, Porto 4169-007, Portugal
| | - Marlene Pinheiro
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
- FCUP - Department of Biology, Faculty of Sciences, University of Porto (U. Porto), Rua do Campo Alegre s/n, Porto 4169-007, Portugal
| | - Marta Ribeiro
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
- FCUP - Department of Biology, Faculty of Sciences, University of Porto (U. Porto), Rua do Campo Alegre s/n, Porto 4169-007, Portugal
| | - Hugo Morais
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
- FCUP - Department of Biology, Faculty of Sciences, University of Porto (U. Porto), Rua do Campo Alegre s/n, Porto 4169-007, Portugal
| | - Ricardo Branco
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
| | - Olga Martinez
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
| | - Hugo G Santos
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
| | - Rosa Montes
- Aquatic One Health Research Center (ARCUS) & Department of Analytical Chemistry, Nutrition and Food Sciences, Universidade de Santiago de Compostela, Constantino Candeira S/N, IIAA building, Santiago de Compostela 15782, Spain
| | - Rosario Rodil
- Aquatic One Health Research Center (ARCUS) & Department of Analytical Chemistry, Nutrition and Food Sciences, Universidade de Santiago de Compostela, Constantino Candeira S/N, IIAA building, Santiago de Compostela 15782, Spain
| | - José Benito Quintana
- Aquatic One Health Research Center (ARCUS) & Department of Analytical Chemistry, Nutrition and Food Sciences, Universidade de Santiago de Compostela, Constantino Candeira S/N, IIAA building, Santiago de Compostela 15782, Spain
| | - Miguel M Santos
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
- FCUP - Department of Biology, Faculty of Sciences, University of Porto (U. Porto), Rua do Campo Alegre s/n, Porto 4169-007, Portugal
| | - Teresa Neuparth
- CIIMAR─Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos, S/N, Matosinhos 4450-208, Portugal
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Simoni OD, Scarpa M, Castagliuolo I, Stepanyan A, Angriman I, Kotsafti A, Nacci C, Scognamiglio F, Negro S, D'Angelo A, Chiminazzo V, Businello G, Ruffolo C, Salmaso R, Franzato B, Gruppo M, Pilati P, Scapinello A, Pozza A, Stecca T, Massani M, Cataldo I, Brignola S, Dei Tos AP, Ceccon C, Guzzardo V, Vignotto C, Facci L, Maretto I, Agostini M, Marchegiani F, Becherucci G, Zizzo M, Bordignon G, Merenda R, Pirozzolo G, Recordare A, Pozza G, Godina M, Mondi I, Verdi D, Lio CD, Laurino L, Saadeh L, Rivella G, Guerriero S, Romiti C, Portale G, Cipollari C, Spolverato YC, Noaro G, Cola R, Candioli S, Gavagna L, Ricagna F, Ortenzi M, Guerrieri M, Tagliente G, Tomassi M, Tedeschi U, Salmaso B, Buzzi G, Parini D, Prando D, Zuin M, Bergamo F, Zagonel V, Porzionato A, Cavallin F, Camillo BD, Cristoforo LD, Bao QR, Pucciarelli S, Bardini R, Spolverato G, Fassan M, Scarpa M. IMMUNOREACT 7: Regular aspirin use is associated with immune surveillance activation in colorectal cancer. Cancer 2024; 130:2272-2286. [PMID: 38644692 DOI: 10.1002/cncr.35297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 01/19/2024] [Accepted: 02/13/2024] [Indexed: 04/23/2024]
Abstract
BACKGROUND Long-term daily use of aspirin reduces incidence and mortality due to colorectal cancer (CRC). This study aimed to analyze the effect of aspirin on the tumor microenvironment, systemic immunity, and on the healthy mucosa surrounding cancer. METHODS Patients with a diagnosis of CRC operated on from 2015 to 2019 were retrospectively analyzed (METACCRE cohort). Expression of mRNA of immune surveillance-related genes (PD-L1, CD80, CD86, HLA I, and HLA II) in CRC primary cells treated with aspirin were extracted from Gene Expression Omnibus-deposited public database (GSE76583). The experiment was replicated in cell lines. The mucosal immune microenvironment of a subgroup of patients participating in the IMMUNOREACT1 (ClinicalTrials.gov NCT04915326) project was analyzed with immunohistochemistry and flow cytometry. RESULTS In the METACCRE Cohort, 12% of 238 patients analyzed were aspirin users. Nodal metastasis was significantly less frequent (p = .008) and tumor-infiltrating lymphocyte infiltration was higher (p = .02) among aspirin users. In the CRC primary cells and selected cell lines, CD80 mRNA expression was increased following aspirin treatment (p = .001). In the healthy mucosa surrounding rectal cancer, the ratio of CD8/CD3 and epithelial cells expressing CD80 was higher in aspirin users (p = .027 and p = .034, respectively). CONCLUSIONS These data suggested that regular aspirin use may have an active role in enhancing immunosurveillance against CRC.
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Affiliation(s)
| | | | | | | | | | | | - Camilla Nacci
- Azienda Ospedale Università di Padova, Padova, Italy
| | | | - Silvia Negro
- Azienda Ospedale Università di Padova, Padova, Italy
| | | | | | | | | | | | | | - Mario Gruppo
- Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | | | | | - Anna Pozza
- Azienda Unità Socio-Sanitaria Locale 2 Marca Trevigiana, Treviso, Italy
| | - Tommaso Stecca
- Azienda Unità Socio-Sanitaria Locale 2 Marca Trevigiana, Treviso, Italy
| | - Marco Massani
- Azienda Unità Socio-Sanitaria Locale 2 Marca Trevigiana, Treviso, Italy
| | - Ivana Cataldo
- Azienda Unità Socio-Sanitaria Locale 2 Marca Trevigiana, Treviso, Italy
| | - Stefano Brignola
- Azienda Unità Socio-Sanitaria Locale 2 Marca Trevigiana, Treviso, Italy
| | | | | | | | | | - Luca Facci
- Azienda Ospedale Università di Padova, Padova, Italy
| | | | | | | | | | - Maurizio Zizzo
- Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | | | - Roberto Merenda
- Azienda Unità Socio-Sanitaria Locale 3 Serenissima, Venezia, Italy
| | | | | | - Giulia Pozza
- Azienda Ospedale Università di Padova, Padova, Italy
| | - Mario Godina
- Azienda Unità Socio-Sanitaria Locale 3 Serenissima, Venezia, Italy
| | - Isabella Mondi
- Azienda Unità Socio-Sanitaria Locale 3 Serenissima, Venezia, Italy
| | - Daunia Verdi
- Azienda Unità Socio-Sanitaria Locale 3 Serenissima, Venezia, Italy
| | - Corrado Da Lio
- Azienda Unità Socio-Sanitaria Locale 3 Serenissima, Venezia, Italy
| | - Licia Laurino
- Azienda Unità Socio-Sanitaria Locale 3 Serenissima, Venezia, Italy
| | - Luca Saadeh
- Azienda Ospedale Università di Padova, Padova, Italy
| | | | | | | | | | | | | | - Giulia Noaro
- Azienda Unità Socio-Sanitaria Locale 6 Euganea, Padova, Italy
| | - Roberto Cola
- Azienda Unità Socio-Sanitaria Locale 6 Euganea, Padova, Italy
| | | | - Laura Gavagna
- Azienda Unità Socio-Sanitaria Locale 1 Dolomiti, Belluno, Italy
| | - Fabio Ricagna
- Azienda Unità Socio-Sanitaria Locale 1 Dolomiti, Belluno, Italy
| | - Monica Ortenzi
- Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy
| | - Mario Guerrieri
- Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy
| | | | | | | | | | - Gianluca Buzzi
- Azienda Unità Socio-Sanitaria Locale 5 Polesana, Rovigo, Italy
| | - Dario Parini
- Azienda Unità Socio-Sanitaria Locale 5 Polesana, Rovigo, Italy
| | - Daniela Prando
- Azienda Unità Socio-Sanitaria Locale 5 Polesana, Rovigo, Italy
| | - Matteo Zuin
- Azienda Unità Socio-Sanitaria Locale 3 Serenissima, Venezia, Italy
| | | | | | | | | | | | | | | | | | - Romeo Bardini
- Azienda Ospedale Università di Padova, Padova, Italy
| | | | - Matteo Fassan
- Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
- Azienda Ospedale Università di Padova, Padova, Italy
| | - Marco Scarpa
- Azienda Ospedale Università di Padova, Padova, Italy
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Lewis A, Humphreys DT, Pan-Castillo B, Berti G, Felice C, Gordon H, Gadhok R, Nijhuis A, Mehta S S, Eleid L, Iqbal S, Armuzzi A, Minicozzi A, Giannoulatou E, ChinAleong J, Feakins R, Sagi-Kiss V, Barisic D, Koufaki MI, Bundy JG, Lindsay JO, Silver A. Epigenetic and Metabolic Reprogramming of Fibroblasts in Crohn's Disease Strictures Reveals Histone Deacetylases as Therapeutic Targets. J Crohns Colitis 2024; 18:895-907. [PMID: 38069679 PMCID: PMC11147807 DOI: 10.1093/ecco-jcc/jjad209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/26/2023] [Accepted: 12/05/2023] [Indexed: 06/05/2024]
Abstract
BACKGROUND AND AIMS No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterized fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. METHODS We undertook immunohistochemistry, metabolic, signalling pathway and epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/NSCD fibroblasts were cultured with TGFβ and valproic acid [VPA]. RESULTS Stricturing CD was characterized by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1, HDAC2, and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFβ stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appeared 'metabolically primed' and responded more strongly to both TGFβ and VPA. Treatment with VPA revealed TGFβ-dependent and TGFβ-independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. CONCLUSIONS Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype and metabolic priming characterize SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFβ-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis.
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Affiliation(s)
- Amy Lewis
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
| | - David T Humphreys
- Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia
- St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia
| | - Belen Pan-Castillo
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
| | - Giulio Berti
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
| | - Carla Felice
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
- Department of Internal Medicine University of Padua, Internal Medicine 1 Unit, Ca' Foncello Hospital, Treviso, Italy
| | - Hannah Gordon
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
| | - Radha Gadhok
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
| | - Anke Nijhuis
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
| | - Shameer Mehta S
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
| | - Liliane Eleid
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
| | - Sidra Iqbal
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
| | | | - Annamaria Minicozzi
- Department of Colorectal Surgery, Division of Surgery & Perioperative Care, The Royal London Hospital, Whitechapel, London E1 1BB, UK
| | - Eleni Giannoulatou
- Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia
- St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia
| | - Joanne ChinAleong
- Department of Histopathology, The Royal London Hospital, London E1 1BB, UK
| | - Roger Feakins
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Virag Sagi-Kiss
- Department of Metabolism, Digestion and Reproduction, Imperial College London, Burlington Danes Building, Du Cane Road, London W12 0NN, UK
| | - Dora Barisic
- Department of Metabolism, Digestion and Reproduction, Imperial College London, Burlington Danes Building, Du Cane Road, London W12 0NN, UK
| | - Margarita-Ioanna Koufaki
- Department of Metabolism, Digestion and Reproduction, Imperial College London, Burlington Danes Building, Du Cane Road, London W12 0NN, UK
| | - Jacob G Bundy
- Department of Metabolism, Digestion and Reproduction, Imperial College London, Burlington Danes Building, Du Cane Road, London W12 0NN, UK
| | - James O Lindsay
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
| | - Andrew Silver
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK
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6
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Elwood P, Morgan G, Watkins J, Protty M, Mason M, Adams R, Dolwani S, Pickering J, Delon C, Longley M. Aspirin and cancer treatment: systematic reviews and meta-analyses of evidence: for and against. Br J Cancer 2024; 130:3-8. [PMID: 38030748 PMCID: PMC10782022 DOI: 10.1038/s41416-023-02506-5] [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: 06/02/2023] [Revised: 10/25/2023] [Accepted: 11/13/2023] [Indexed: 12/01/2023] Open
Abstract
Aspirin as a possible treatment of cancer has been of increasing interest for over 50 years, but the balance of the risks and benefits remains a point of contention. We summarise the valid published evidence 'for' and 'against' the use of aspirin as a cancer treatment and we present what we believe are relevant ethical implications. Reasons for aspirin include the benefits of aspirin taken by patients with cancer upon relevant biological cancer mechanisms. These explain the observed reductions in metastatic cancer and vascular complications in cancer patients. Meta-analyses of 118 observational studies of mortality in cancer patients give evidence consistent with reductions of about 20% in mortality associated with aspirin use. Reasons against aspirin use include increased risk of a gastrointestinal bleed though there appears to be no valid evidence that aspirin is responsible for fatal gastrointestinal bleeding. Few trials have been reported and there are inconsistencies in the results. In conclusion, given the relative safety and the favourable effects of aspirin, its use in cancer seems justified, and ethical implications of this imply that cancer patients should be informed of the present evidence and encouraged to raise the topic with their healthcare team.
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Affiliation(s)
- Peter Elwood
- Population Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Gareth Morgan
- Population Medicine, Cardiff University, Cardiff, CF14 4XN, UK.
| | - John Watkins
- Population Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Majd Protty
- Systems Immunity Research Institute, Cardiff University, Cardiff, CF14 4XN, UK
| | - Malcolm Mason
- School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Richard Adams
- Population Medicine, Cardiff University, Cardiff, CF14 4XN, UK
- Wales Cancer Bank, University Hospital of Wales, Cardiff, CF14 4XN, UK
| | - Sunil Dolwani
- School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Janet Pickering
- Population Medicine, Cardiff University, Cardiff, CF14 4XN, UK
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Holt AK, Najumudeen AK, Collard TJ, Li H, Millett LM, Hoskin AJ, Legge DN, Mortensson EMH, Flanagan DJ, Jones N, Kollareddy M, Timms P, Hitchings MD, Cronin J, Sansom OJ, Williams AC, Vincent EE. Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer Metab 2023; 11:18. [PMID: 37858256 PMCID: PMC10588174 DOI: 10.1186/s40170-023-00318-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 10/07/2023] [Indexed: 10/21/2023] Open
Abstract
BACKGROUND To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood. METHODS We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo. RESULTS We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor-CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo. CONCLUSIONS Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.
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Affiliation(s)
- Amy K Holt
- School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TW, UK
| | - Arafath K Najumudeen
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Tracey J Collard
- School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TW, UK
| | - Hao Li
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | | | - Ashley J Hoskin
- School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TW, UK
| | - Danny N Legge
- School of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK
| | - Eleanor M H Mortensson
- School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TW, UK
| | | | - Nicholas Jones
- Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - Madhu Kollareddy
- School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TW, UK
| | - Penny Timms
- School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TW, UK
| | - Matthew D Hitchings
- Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - James Cronin
- Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Ann C Williams
- School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TW, UK
| | - Emma E Vincent
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
- MRC Integrative Epidemiology Unit, Oakfield House, University of Bristol, Bristol, BS8 2BN, UK.
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8
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Liu KY, Wang Q, Nakatsu CH, Jones-Hall Y, Jiang Q. Combining gamma-tocopherol and aspirin synergistically suppresses colitis-associated colon tumorigenesis and modulates the gut microbiota in mice, and inhibits the growth of human colon cancer cells. Eur J Pharmacol 2023; 946:175656. [PMID: 36921708 DOI: 10.1016/j.ejphar.2023.175656] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 03/11/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
Despite being shown to be effective for chemoprevention of colorectal cancer, aspirin has limitations including adverse effects and inability to block colitis-associated colon cancer (CAC). γ-Tocopherol (γT), a vitamin E form, has been reported to mitigate experimental colitis and CAC, prolong the anti-inflammatory activity of aspirin and alleviate aspirin-induced adverse effect. We therefore hypothesize that combining γT and aspirin is better than either compound singly for suppressing CAC. This hypothesis was tested in the murine azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model and with human HCT116 colon cancer cells. Compared to the control, combining aspirin (250 ppm) and γT (500 ppm) but not either compound alone significantly reduced AOM/DSS-induced tumor area and multiplicity of large-size tumors by 60% and 50%, respectively. Meanwhile, γT mitigated aspirin-promoted inflammation and stomach lesions in mice. Moreover, the combination appeared to cause favorable changes of gut microbiota compared to the control and synergistically suppressed the growth of HCT116 cells. Our study demonstrates that combining aspirin and γT improves anticancer effects and counteracts side effects compared to aspirin and may therefore be a novel combinatory chemopreventive agent against CAC.
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Affiliation(s)
- Kilia Y Liu
- Department of Nutrition Science, Purdue University, West Lafayette, IN, USA
| | - Qianyue Wang
- Department of Nutrition Science, Purdue University, West Lafayette, IN, USA
| | - Cindy H Nakatsu
- Department of Agronomy, Purdue University, West Lafayette, IN, USA
| | - Yava Jones-Hall
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Qing Jiang
- Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
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9
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Zhu X, Luo X, Long X, Jiang S, Xie X, Zhang Q, Wang H. CircAGO2 promotes colorectal cancer progression by inhibiting heat shock protein family B (small) member 8 via miR-1-3p/retinoblastoma binding protein 4 axis. Funct Integr Genomics 2023; 23:78. [PMID: 36881338 DOI: 10.1007/s10142-023-00990-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/08/2023] [Accepted: 02/16/2023] [Indexed: 03/08/2023]
Abstract
This paper was to uncover the mechanism of circular RNA Argonaute 2 (circAGO2) in colorectal cancer (CRC) progression. The expression of circAGO2 was detected in CRC cells and tissues, and the relationship between clinicopathological features of CRC and circAGO2 level was evaluated. The growth and invasion of CRC cells and subcutaneous xenograft of nude mice were measured to evaluate the effect of circAGO2 on CRC development. Bioinformatics databases were applied to analyze levels of retinoblastoma binding protein 4 (RBBP4) and heat shock protein family B 8 (HSPB8) in cancer tissues. The relevance of circAGO2 and RBBP4 expression and the relationship between RBBP4 and HSPB8 during histone acetylation were assessed. The targeting relationship between miR-1-3p and circAGO2 or RBBP4 was predicted and confirmed. The effects of miR-1-3p and RBBP4 on biological functions of CRC cells were also verified. CircAGO2 was upregulated in CRC. CircAGO2 promoted the growth and invasion of CRC cells. CircAGO2 competitively bound to miR-1-3p and regulated RBBP4 expression, thus inhibiting HSPB8 transcription by promoting histone deacetylation. Silencing circAGO2 enhanced miR-1-3p expression and reduced RBBP4 expression, while suppression of miR-1-3p downgraded levels of miR-1-3p, up-regulated RBBP4, and facilitated cell proliferation and invasion in the presence of silencing circAGO2. RBBP4 silencing decreased RBBP4 expression and reduced proliferation and invasion of cells where circAGO2 and miR-1-3p were silenced. CircAGO2 overexpression decoyed miR-1-3p to increase RBBP4 expression, which inhibited HSPB8 transcription via histone deacetylation in HSPB8 promoter region, promoting proliferation and invasion of CRC cells.
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Affiliation(s)
- Xijia Zhu
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Guilin Medical University, No. 212 Renmin Road, Lingui District, Guilin, Guangxi, 541100, People's Republic of China
| | - Xishun Luo
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Guilin Medical University, No. 212 Renmin Road, Lingui District, Guilin, Guangxi, 541100, People's Republic of China
| | - Xiangkai Long
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Guilin Medical University, No. 212 Renmin Road, Lingui District, Guilin, Guangxi, 541100, People's Republic of China
| | - Shiyu Jiang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Guilin Medical University, No. 212 Renmin Road, Lingui District, Guilin, Guangxi, 541100, People's Republic of China
| | - Xinyang Xie
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Guilin Medical University, No. 212 Renmin Road, Lingui District, Guilin, Guangxi, 541100, People's Republic of China
| | - Qiqi Zhang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Guilin Medical University, No. 212 Renmin Road, Lingui District, Guilin, Guangxi, 541100, People's Republic of China
| | - Haipeng Wang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Guilin Medical University, No. 212 Renmin Road, Lingui District, Guilin, Guangxi, 541100, People's Republic of China.
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10
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Babu SSN, Singla S, Jena G. Role of Combination Treatment of Aspirin and Zinc in DMH-DSS-induced Colon Inflammation, Oxidative Stress and Tumour Progression in Male BALB/c Mice. Biol Trace Elem Res 2023; 201:1327-1343. [PMID: 35438409 DOI: 10.1007/s12011-022-03241-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 04/09/2022] [Indexed: 02/07/2023]
Abstract
Colitis-associated colorectal cancer serves as a prototype of inflammation-associated cancers which is linked with repeated cycles of inflammation and DNA repair deficits. Several preclinical and clinical data reported that aspirin has a chemo-preventive effect in colorectal cancer and is associated with dose-dependent side effects. Furthermore, it has been reported that zinc supplementation improves the quality of life in patients undergoing chemotherapy by alteration of colonic cancer cell gene expression. However, explication of the detailed molecular mechanisms involved in the combined administration of aspirin and zinc-mediated protection against colitis-associated colorectal cancer deserves further investigation. For the induction of colitis-associated colorectal cancer, male BALB/c mice were administered 1,2-dimethylhydrazine dihydrochloride (DMH) 20 mg/kg/bw thrice before the initiation of every DSS cycle (3%w/v in drinking water). One week after the initiation of DSS treatment, aspirin (40 mg/kg; p.o.) and zinc in the form of zinc sulphate (3 mg/kg; p.o.) were administered for 8 weeks. Combination of aspirin and zinc as intervention significantly ameliorated DAI score, myeloperoxidase activity, histological score, apoptotic cells and protein expression of various inflammatory markers including nuclear factor kappa light chain enhancer of activated B cells (NFκBp65), cycloxygenase-2 (COX-2) and interleukin-6 (IL-6); proliferation markers such as proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription 3 (STAT3) expression significantly decreased, and antioxidant enzymes nuclear factor erythroid 2-related factor 2 (Nrf-2), metallothionein, catalase and superoxide dismutase (SOD) significantly increased as evaluated by immunohistochemistry and western blot analysis.
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Affiliation(s)
- Singothu Siva Nagendra Babu
- Facility for Risk Assessment and Intervention Studies, Dept. of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, India, 160062
| | - Shivani Singla
- Facility for Risk Assessment and Intervention Studies, Dept. of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, India, 160062
| | - Gopabandhu Jena
- Facility for Risk Assessment and Intervention Studies, Dept. of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, India, 160062.
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11
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Szabó B, Németh K, Mészáros K, Krokker L, Likó I, Saskői É, Németh K, Szabó PT, Szücs N, Czirják S, Szalóki G, Patócs A, Butz H. Aspirin Mediates Its Antitumoral Effect Through Inhibiting PTTG1 in Pituitary Adenoma. J Clin Endocrinol Metab 2022; 107:3066-3079. [PMID: 36059148 PMCID: PMC9681612 DOI: 10.1210/clinem/dgac496] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Indexed: 11/19/2022]
Abstract
CONTEXT DNA demethylation and inhibitory effects of aspirin on pituitary cell proliferation have been demonstrated. OBJECTIVE Our aim was to clarify the molecular mechanisms behind the aspirin-related effects in pituitary cells. METHODS DNA methylome and whole transcriptome profile were investigated in RC-4B/C and GH3 pituitary cell lines upon aspirin treatment. Effects of aspirin and a demethylation agent, decitabine, were further tested in vitro. PTTG1 expression in 41 human PitNET samples and whole genome gene and protein expression data of 76 PitNET and 34 control samples (available in Gene Expression Omnibus) were evaluated. RESULTS Aspirin induced global DNA demethylation and consequential transcriptome changes. Overexpression of Tet enzymes and their cofactor Uhrf2 were identified behind the increase of 5-hydroxymethylcytosine (5hmC). Besides cell cycle, proliferation, and migration effects that were validated by functional experiments, aspirin increased Tp53 activity through p53 acetylation and decreased E2f1 activity. Among the p53 controlled genes, Pttg1 and its interacting partners were downregulated upon aspirin treatment by inhibiting Pttg1 promoter activity. 5hmC positively correlated with Tet1-3 and Tp53 expression, and negatively correlated with Pttg1 expression, which was reinforced by the effect of decitabine. Additionally, high overlap (20.15%) was found between aspirin-regulated genes and dysregulated genes in PitNET tissue samples. CONCLUSION A novel regulatory network has been revealed, in which aspirin regulated global demethylation, Tp53 activity, and Pttg1 expression along with decreased cell proliferation and migration. 5hmC, a novel tissue biomarker in PitNET, indicated aspirin antitumoral effect in vitro as well. Our findings suggest the potential beneficial effect of aspirin in PitNET.
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Affiliation(s)
- Borbála Szabó
- Department of Laboratory Medicine, Semmelweis University, H-1089 Budapest, Hungary
- Hereditary Tumours Research Group, Hungarian Academy of Sciences—Semmelweis University, H-1089 Budapest, Hungary
| | - Kinga Németh
- Hereditary Tumours Research Group, Hungarian Academy of Sciences—Semmelweis University, H-1089 Budapest, Hungary
| | - Katalin Mészáros
- Hereditary Tumours Research Group, Hungarian Academy of Sciences—Semmelweis University, H-1089 Budapest, Hungary
| | - Lilla Krokker
- Department of Laboratory Medicine, Semmelweis University, H-1089 Budapest, Hungary
- Hereditary Tumours Research Group, Hungarian Academy of Sciences—Semmelweis University, H-1089 Budapest, Hungary
| | - István Likó
- Hereditary Tumours Research Group, Hungarian Academy of Sciences—Semmelweis University, H-1089 Budapest, Hungary
| | - Éva Saskői
- Department of Molecular Genetics and the National Tumor Biology Laboratory, National Institute of Oncology, H-1122 Budapest, Hungary
| | - Krisztina Németh
- MS Metabolomics Research Group, Centre for Structural Study, Research Centre for Natural Sciences, Eötvös Loránd Research Network, H-1117 Budapest, Hungary
| | - Pál Tamás Szabó
- MS Metabolomics Research Group, Centre for Structural Study, Research Centre for Natural Sciences, Eötvös Loránd Research Network, H-1117 Budapest, Hungary
| | - Nikolette Szücs
- Department of Endocrinology, Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, H-1083 Budapest, Hungary
| | - Sándor Czirják
- National Institute of Clinical Neurosciences, H-1145 Budapest, Hungary
| | - Gábor Szalóki
- Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, H-1085 Budapest, Hungary
| | - Attila Patócs
- Department of Laboratory Medicine, Semmelweis University, H-1089 Budapest, Hungary
- Hereditary Tumours Research Group, Hungarian Academy of Sciences—Semmelweis University, H-1089 Budapest, Hungary
- Department of Molecular Genetics and the National Tumor Biology Laboratory, National Institute of Oncology, H-1122 Budapest, Hungary
| | - Henriett Butz
- Correspondence: Henriett Butz MD, PhD, Hereditary Endocrine Tumours Research Group, Department of Laboratory Medicine, Semmelweis University, 4. Nagyvárad tér, H-1089, Budapest, Hungary.
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12
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Liu R, Zhou F, Yu J, Wei X, Liu X, Yuan X, Yu C. Abrusamide H Impairs the Secretion of the Cytokines in RAW264.7 Cells and the Inflammatory Infiltration in Tail Transection-Induced Zebrafish. Chem Biodivers 2022; 19:e202200474. [PMID: 36190475 DOI: 10.1002/cbdv.202200474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 09/28/2022] [Indexed: 11/09/2022]
Abstract
Abrus mollis Hance (Leguminosae) has a variety of biological activities, including anti-inflammatory, antioxidant, antibacterial, antiviral, and antitumor activities. However, the specific substances responsible for the anti-inflammatory effects are unknown. Abrusamide H (BJBS) is a truxillic acid derivative obtained from the leaves of Abrus mollis Hance and has potential anti-inflammatory effects. In this study, we aimed to estimate the potential effect and mechanism of BJBS in inflammation by establishing lipopolysaccharide (LPS)-stimulated RAW264.7 cells in vitro and an injured zebrafish tail fin in vivo. The RAW264.7 cells were treated with different concentrations of BJBS after LPS stimulation. The production of nitric oxide (NO) was detected by Griess reaction, and reactive oxygen species (ROS) were detected by an ROS assay kit. The levels of proinflammatory cytokines, including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 18 (IL-18) were measured by ELISA. Results showed that BJBS at all concentrations inhibited the proliferation of RAW264.7 macrophages after LPS stimulation by cell counting kit-8 and the production of NO and ROS. In the BJBS treatment group, the levels of IL-6, TNF-α, IL-1β, and IL-18 decreased in a concentration-dependent manner. The results in vivo showed that no significant difference in the survival of zebrafish between the BJBS and blank groups and BJBS inhibited the migration and aggregation of zebrafish neutrophils in a dose-dependent manner in inflammation induced by tail transection-induced inflammation. In conclusion, BJBS inhibited the production of NO and ROS, decreased the levels of secreted IL-6, TNF-α, IL-1β, and IL-18, and reduced the migration and aggregation of zebrafish neutrophils.
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Affiliation(s)
- Roujia Liu
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, East Waihuan Road 280, Guangzhou, P. R. China
| | - Feirong Zhou
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, East Waihuan Road 280, Guangzhou, P. R. China
| | - Jiaxian Yu
- Jinan University, Guangzhou, P. R. China
| | - Xinru Wei
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, East Waihuan Road 280, Guangzhou, P. R. China
| | - Xiangying Liu
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, East Waihuan Road 280, Guangzhou, P. R. China
| | - Xujiang Yuan
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, East Waihuan Road 280, Guangzhou, P. R. China
| | - Chuqin Yu
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, East Waihuan Road 280, Guangzhou, P. R. China
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13
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Tan SYX, Zhang J, Tee WW. Epigenetic Regulation of Inflammatory Signaling and Inflammation-Induced Cancer. Front Cell Dev Biol 2022; 10:931493. [PMID: 35757000 PMCID: PMC9213816 DOI: 10.3389/fcell.2022.931493] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 05/23/2022] [Indexed: 01/10/2023] Open
Abstract
Epigenetics comprise a diverse array of reversible and dynamic modifications to the cell’s genome without implicating any DNA sequence alterations. Both the external environment surrounding the organism, as well as the internal microenvironment of cells and tissues, contribute to these epigenetic processes that play critical roles in cell fate specification and organismal development. On the other hand, dysregulation of epigenetic activities can initiate and sustain carcinogenesis, which is often augmented by inflammation. Chronic inflammation, one of the major hallmarks of cancer, stems from proinflammatory cytokines that are secreted by tumor and tumor-associated cells in the tumor microenvironment. At the same time, inflammatory signaling can establish positive and negative feedback circuits with chromatin to modulate changes in the global epigenetic landscape. In this review, we provide an in-depth discussion of the interconnected crosstalk between epigenetics and inflammation, specifically how epigenetic mechanisms at different hierarchical levels of the genome control inflammatory gene transcription, which in turn enact changes within the cell’s epigenomic profile, especially in the context of inflammation-induced cancer.
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Affiliation(s)
- Shawn Ying Xuan Tan
- Chromatin Dynamics and Disease Epigenetics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Jieqiong Zhang
- Chromatin Dynamics and Disease Epigenetics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Wee-Wei Tee
- Chromatin Dynamics and Disease Epigenetics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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14
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Qorri B, Mokhtari RB, Harless WW, Szewczuk MR. Next Generation of Cancer Drug Repurposing: Therapeutic Combination of Aspirin and Oseltamivir Phosphate Potentiates Gemcitabine to Disable Key Survival Pathways Critical for Pancreatic Cancer Progression. Cancers (Basel) 2022; 14:1374. [PMID: 35326525 PMCID: PMC8946854 DOI: 10.3390/cancers14061374] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/26/2022] [Accepted: 03/02/2022] [Indexed: 12/12/2022] Open
Abstract
Resistance to chemotherapeutics and high metastatic rates contribute to the abysmal survival rate in patients with pancreatic cancer. An alternate approach for treating human pancreatic cancer involves repurposing the anti-inflammatory drug, aspirin (ASA), with oseltamivir phosphate (OP) in combination with the standard chemotherapeutic agent, gemcitabine (GEM). The question is whether treatment with ASA and OP can sensitize cancer cells to the cytotoxicity induced by GEM and limit the development of chemoresistance. To assess the key survival pathways critical for pancreatic cancer progression, we used the AlamarBlue cytotoxicity assay to determine the cell viability and combination index for the drug combinations, flow cytometric analysis of annexin V apoptosis assay to detect apoptotic and necrotic cells, fluorometric QCM™ chemotaxis migration assay to assess cellular migration, fluorometric extracellular matrix (ECM) cell adhesion array kit to assess the expression of the ECM proteins, scratch wound assay using the 96-well WoundMaker™, and the methylcellulose clonogenic assay to assess clonogenic potential. The combination of ASA and OP with GEM significantly upended MiaPaCa-2 and PANC-1 pancreatic cancer cell viability, clonogenic potential, expression of critical extracellular matrix proteins, migration, and promoted apoptosis. ASA in combination with OP significantly improves the effectiveness of GEM in the treatment of pancreatic cancer and disables key survival pathways critical to disease progression.
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Affiliation(s)
- Bessi Qorri
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (B.Q.); (R.B.M.)
| | - Reza Bayat Mokhtari
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (B.Q.); (R.B.M.)
| | | | - Myron R. Szewczuk
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (B.Q.); (R.B.M.)
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15
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Epigenetic Regulation: A Link between Inflammation and Carcinogenesis. Cancers (Basel) 2022; 14:cancers14051221. [PMID: 35267528 PMCID: PMC8908969 DOI: 10.3390/cancers14051221] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/17/2022] [Accepted: 02/24/2022] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Epigenetics encompasses all the modifications that occur within cells that are independent of gene mutations. The environment is the main influencer of these alterations. It is well known that a proinflammatory environment can promote and sustain the carcinogenic process and that this environment induces epigenetic alterations. In this review, we will report how a proinflammatory microenvironment that encircles the tumor core can be responsible for the induction of epigenetic drift. Abstract Epigenetics encompasses a group of dynamic, reversible, and heritable modifications that occur within cells that are independent of gene mutations. These alterations are highly influenced by the environment, from the environment that surrounds the human being to the internal microenvironments located within tissues and cells. The ways that pigenetic modifications promote the initiation of the tumorigenic process have been widely demonstrated. Similarly, it is well known that carcinogenesis is supported and prompted by a strong proinflammatory environment. In this review, we introduce our report of a proinflammatory microenvironment that encircles the tumor core but can be responsible for the induction of epigenetic drift. At the same time, cancer cells can alter their epigenetic profile to generate a positive loop in the promotion of the inflammatory process. Therefore, an in-depth understanding of the epigenetic networks between the tumor microenvironment and cancer cells might highlight new targetable mechanisms that could prevent tumor progression.
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Zou Z, Zheng W, Fan H, Deng G, Lu SH, Jiang W, Yu X. Aspirin enhances the therapeutic efficacy of cisplatin in oesophageal squamous cell carcinoma by inhibition of putative cancer stem cells. Br J Cancer 2021; 125:826-838. [PMID: 34316020 PMCID: PMC8438052 DOI: 10.1038/s41416-021-01499-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 06/08/2021] [Accepted: 07/13/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) are related to the patient's prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood. METHODS We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells. RESULTS ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model. CONCLUSIONS ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.
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Affiliation(s)
- Zhigeng Zou
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Zheng
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongjun Fan
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guodong Deng
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shih-Hsin Lu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Jiang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Xiying Yu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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17
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Sehanobish E, Asad M, Barbi M, Porcelli SA, Jerschow E. Aspirin Actions in Treatment of NSAID-Exacerbated Respiratory Disease. Front Immunol 2021; 12:695815. [PMID: 34305932 PMCID: PMC8297972 DOI: 10.3389/fimmu.2021.695815] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/07/2021] [Indexed: 12/21/2022] Open
Abstract
Non-steroidal Anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (N-ERD) is characterized by nasal polyposis, chronic rhinosinusitis, adult-onset asthma and hypersensitive reactions to cyclooxygenase-1 (COX-1) inhibitors. Among the available treatments for this disease, a combination of endoscopic sinus surgery followed by aspirin desensitization and aspirin maintenance therapy has been an effective approach. Studies have shown that long-term aspirin maintenance therapy can reduce the rate of nasal polyp recurrence in patients with N-ERD. However, the exact mechanism by which aspirin can both trigger and suppress airway disease in N-ERD remains poorly understood. In this review, we summarize current knowledge of aspirin effects in N-ERD, cardiovascular disease, and cancer, and consider potential mechanistic pathways accounting for the effects of aspirin in N-ERD.
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Affiliation(s)
- Esha Sehanobish
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Mohammad Asad
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Mali Barbi
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Steven A. Porcelli
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Elina Jerschow
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
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18
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Nascimento-Gonçalves E, Mendes BA, Silva-Reis R, Faustino-Rocha AI, Gama A, Oliveira PA. Animal Models of Colorectal Cancer: From Spontaneous to Genetically Engineered Models and Their Applications. Vet Sci 2021; 8:vetsci8040059. [PMID: 33916402 PMCID: PMC8067250 DOI: 10.3390/vetsci8040059] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/15/2021] [Accepted: 03/29/2021] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer is one of the most common gastrointestinal malignancies in humans, affecting approximately 1.8 million people worldwide. This disease has a major social impact and high treatment costs. Animal models allow us to understand and follow the colon cancer progression; thus, in vivo studies are essential to improve and discover new ways of prevention and treatment. Dietary natural products have been under investigation for better and natural prevention, envisioning to show their potential. This manuscript intends to provide the readers a review of rodent colorectal cancer models available in the literature, highlighting their advantages and disadvantages, as well as their potential in the evaluation of several drugs and natural compounds’ effects on colorectal cancer.
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Affiliation(s)
- Elisabete Nascimento-Gonçalves
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (E.N.-G.); (B.A.L.M.); (R.S.-R.)
| | - Bruno A.L. Mendes
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (E.N.-G.); (B.A.L.M.); (R.S.-R.)
| | - Rita Silva-Reis
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (E.N.-G.); (B.A.L.M.); (R.S.-R.)
| | - Ana I. Faustino-Rocha
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (E.N.-G.); (B.A.L.M.); (R.S.-R.)
- Department of Zootechnics, School of Sciences and Technology, University of Évora, 7000-812 Évora, Portugal
- Correspondence: (A.I.F.-R.); (P.A.O.)
| | - Adelina Gama
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal;
- Animal and Veterinary Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
| | - Paula A. Oliveira
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (E.N.-G.); (B.A.L.M.); (R.S.-R.)
- Animal and Veterinary Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
- Correspondence: (A.I.F.-R.); (P.A.O.)
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19
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Clapper ML, Chang WCL, Cooper HS. Dysplastic Aberrant Crypt Foci: Biomarkers of Early Colorectal Neoplasia and Response to Preventive Intervention. Cancer Prev Res (Phila) 2021; 13:229-240. [PMID: 32132117 DOI: 10.1158/1940-6207.capr-19-0316] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 10/04/2019] [Accepted: 10/25/2019] [Indexed: 12/15/2022]
Abstract
The discovery of aberrant crypt foci (ACF) more than three decades ago not only enhanced our understanding of how colorectal tumors form, but provided new opportunities to detect lesions prior to adenoma development and intervene in the colorectal carcinogenesis process even earlier. Because not all ACF progress to neoplasia, it is important to stratify these lesions based on the presence of dysplasia and establish early detection methods and interventions that specifically target dysplastic ACF (microadenomas). Significant progress has been made in characterizing the morphology and genetics of dysplastic ACF in both preclinical models and humans. Image-based methods have been established and new techniques that utilize bioactivatable probes and capture histologic abnormalities in vivo are emerging for lesion detection. Successful identification of agents that target dysplastic ACF holds great promise for intervening even earlier in the carcinogenesis process to maximize tumor inhibition. Future preclinical and clinical prevention studies should give significant attention to assessing the utility of dysplastic ACF as the earliest identifiable biomarker of colorectal neoplasia and response to therapy.See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention.
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Affiliation(s)
- Margie L Clapper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
| | - Wen-Chi L Chang
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Harry S Cooper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.,Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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20
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Zhang BY, Zhang L, Chen YM, Qiao X, Zhao SL, Li P, Liu JF, Wen X, Yang J. Corosolic acid inhibits colorectal cancer cells growth as a novel HER2/HER3 heterodimerization inhibitor. Br J Pharmacol 2021; 178:1475-1491. [PMID: 33443775 DOI: 10.1111/bph.15372] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND PURPOSE Colorectal cancer is the third most common cancer worldwide. HER2 and HER3 are two members of human epidermal receptor family of tyrosine kinase receptors (RTKs) and associated with poor survival in colorectal cancer. They have been observed as important therapeutic targets in various types of cancer. Corosolic acid, a natural pentacyclic triterpene, has been demonstrated to have a significant anti-cancer activity. However, the target of corosolic acid has not yet been explored. This study aimed to reveal the direct targets of corosolic acid underlying its anti-cancer activities. EXPERIMENTAL APPROACH The targets of corosolic acid were revealed by the phospho-RTK array, bio-layer interferometry, co-immunoprecipitation, and proximity ligation assay. The inhibitory action of corosolic acid on HER2/HER3 heterodimerization and related downstream signalling were investigated in HCT116 and SW480 cells. In addition, the chemo-preventive effects of corosolic acid were validated in both HCT116 xenograft model and AOM/DSS model. KEY RESULTS Our results demonstrated that corosolic acid could prevent NRG1-induced HER2/HER3 heterodimerization and suppress the phosphorylation of both HER2 and HER3. Furthermore, HER2 and HER3 could regulate the downstream signalling pathways of RalA/RalBP1/CDK1 and PI3K/Akt/PKA, respectively, resulting in the changes in phosphorylation of Drp1 and mitochondrial dynamics. corosolic acid exhibited anti-cancer activity in both HCT116 xenograft model and AOM/DSS model. CONCLUSIONS AND IMPLICATIONS Collectively, our results demonstrated corosolic acid directly targeted HER2 and HER3 heterodimerization and inhibited mitochondrial fission via regulating RalA/RalBP1/CDK1 and PI3K/Akt/PKA pathways, revealing a novel mechanism underlying the beneficial effects of corosolic acid on colorectal cancer.
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Affiliation(s)
- Bi-Ying Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lei Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yi-Meng Chen
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xin Qiao
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shu-Ling Zhao
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ping Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jin-Feng Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaodong Wen
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jie Yang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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21
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Belayneh YM, Amare GG, Meharie BG. Updates on the molecular mechanisms of aspirin in the prevention of colorectal cancer: Review. J Oncol Pharm Pract 2021; 27:954-961. [PMID: 33427041 DOI: 10.1177/1078155220984846] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Colorectal cancer is one of the commonest malignancies worldwide. The estimated lifetime risk of the disease is about 5% with an incidence of one million new cases and 600,000 deaths worldwide every year. It is estimated that in 2019, approximately 134,490 new cases of colorectal cancer will be diagnosed with 49,190 mortalities. Though the disease is regarded as a disorder of the more developed world, the occurrence is steadily increasing in many developing countries. Since chronic inflammation is a known aggravating risk factor for colorectal cancer, anti-inflammatory agents such as aspirin have been used to prevent the development of colorectal cancer and related mortality. The potential mechanisms for the effect of aspirin in the prevention of colorectal cancer have been proposed and broadly classified as cyclooxygenase (COX) dependent and COX-independent. Some of the primary effectors of COX-dependent mechanisms in carcinogenesis are likely to be prostaglandins. In contrast to the reversible action of other nonsteroidal anti-inflammatory drugs, aspirin is known to irreversibly inactivate COX enzymes to suppress production of prostaglandins. COX-independent mechanisms of anticancer effects of aspirin include down-regulation of nuclear factor kappa B activity and Akt activation, modulation of Bcl-2 and Bax family proteins, suppression of vascular endothelial growth factor, induction of apoptosis, disruption of DNA repair mechanisms, and induction of spermidine/spermine N1-acetyltransferase that modulates polyamine catabolism.
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Affiliation(s)
- Yaschilal Muche Belayneh
- Department of Pharmacy, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
| | - Gedefew Getnet Amare
- Department of Pharmacy, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
| | - Birhanu Geta Meharie
- Department of Pharmacy, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
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22
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Hao J, Dai X, Gao J, Li Y, Hou Z, Chang Z, Wang Y. Curcumin suppresses colorectal tumorigenesis via the Wnt/β-catenin signaling pathway by downregulating Axin2. Oncol Lett 2021; 21:186. [PMID: 33574925 PMCID: PMC7816292 DOI: 10.3892/ol.2021.12447] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, with high incidence and mortality rates. Conventional therapies, including surgery, chemotherapy and radiation, are extensively used for the treatment of CRC. However, patients present with adverse effects, such as toxicity, hepatic injury and drug resistance. Thus, there is an urgent requirement to identify effective and safe therapy for CRC. Curcumin (CUR), a polyphenol substrate extracted from the rhizome of Curcuma longa, has been extensively studied for the treatment of CRC due to its high efficacy and fewer side effects. Previous studies have reported that several signaling pathways, such as NF-κB, Wnt/β-catenin, are involved in the antitumor effects of CUR in vitro. However, the effect and mechanisms in vivo are not yet fully understood. The present study aimed to determine the molecular mechanism of colorectal cancer in vivo. Reverse transcription-quantitative PCR, western blot and immunohistochemistry analyses were performed to determine the underlying molecular mechanism of curcumin's anti-cancer effect in azoxymethane-dextran sodium sulfate induced colorectal cancer. The results of the present study demonstrated that CUR suppressed tumorigenesis in AOM-DSS induced CRC in mice, and anticancer effects were exerted by suppressing the expression of pro-inflammatory cytokines, and downregulating Axin2 in the Wnt/β-catenin signaling pathway. Taken together, these results exhibit the potential in vivo mechanisms of the anticancer effects of CUR, and highlight Axin2 as a potential therapeutic target for CRC.
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Affiliation(s)
- Jiaxue Hao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education/College of Life Science, Northwest University, Xi'an, Shaanxi 710069, P.R. China
| | - Xufen Dai
- Food and Drug Technology Research Center, Shaanxi Province Food and Drug Supervision and Inspection Research, Shaanxi Institute for Food and Drug Control, Xi'an, Shaanxi 710065, P.R. China
| | - Juan Gao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education/College of Life Science, Northwest University, Xi'an, Shaanxi 710069, P.R. China
| | - Yuexuan Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education/College of Life Science, Northwest University, Xi'an, Shaanxi 710069, P.R. China
| | - Zhaoling Hou
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education/College of Life Science, Northwest University, Xi'an, Shaanxi 710069, P.R. China
| | - Zhongman Chang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education/College of Life Science, Northwest University, Xi'an, Shaanxi 710069, P.R. China
| | - Yuxin Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education/College of Life Science, Northwest University, Xi'an, Shaanxi 710069, P.R. China
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23
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Intestinal Inflammation is Linked to Hypoacetylation of Histone 3 Lysine 27 and can be Reversed by Valproic Acid Treatment in Inflammatory Bowel Disease Patients. Cell Mol Gastroenterol Hepatol 2020; 11:889-891.e6. [PMID: 33232823 PMCID: PMC7900835 DOI: 10.1016/j.jcmgh.2020.11.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/16/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022]
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24
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Noreen F, Chaber-Ciopinska A, Regula J, Schär P, Truninger K. Longitudinal analysis of healthy colon establishes aspirin as a suppressor of cancer-related epigenetic aging. Clin Epigenetics 2020; 12:164. [PMID: 33143725 PMCID: PMC7607658 DOI: 10.1186/s13148-020-00956-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/22/2020] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Colon cancer (CC) is the third most common cancer worldwide, highlighting the importance of developing effective prevention strategies. Accumulating evidence supports that aspirin use reduces CC incidence. We reported previously that aspirin suppresses age-associated and CC-relevant DNA methylation (DNAm) in healthy colon. Here we addressed the aspirin's effectiveness in longitudinal cohort. METHODS We measured genome-wide DNAm in 124 healthy normal mucosa samples taken at baseline (time point 1, t1) and after 10-years follow-up (time point 2, t2) from a longitudinal female screening cohort. We investigated the time-dependent methylation drift in aspirin users and nonusers using multivariable regression and related the modulatory effect of aspirin to colonic epigenome-aging and CC. RESULTS Over time, compared to nonusers, long-term (≥ 2 years) aspirin users showed less hypermethylated CpGs (proximal: 17% vs. 87%; distal: 16% vs. 70%) and more hypomethylated CpGs (proximal: 83% vs. 13%; distal: 84% vs. 30%). Overall, users showed 2% (P = 0.02) less mean methylation levels than nonusers in proximal colon and displayed repressed methylation age (mAge). Methylation loss in users occurred at several CC-specific tumor suppressors that gained methylation in nonusers. Methylation loss in users effected genes involved in immune system and inflammation, while methylation gain in nonusers effected genes involved in metabolism. CONCLUSIONS This is the first longitudinal study demonstrating effectiveness of aspirin-use in suppression of age-related and CC-relevant hypermethylation in the normal colon. These findings provide a rationale for future studies to evaluate loci that may serve as markers to identify individuals that will benefit most from aspirin and hence increase its efficiency in CC prevention and therapy.
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Affiliation(s)
- Faiza Noreen
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland. .,Swiss Institute of Bioinformatics, 4053, Basel, Switzerland.
| | - Anna Chaber-Ciopinska
- Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland
| | - Jaroslaw Regula
- Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland
| | - Primo Schär
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland
| | - Kaspar Truninger
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland. .,Gastroenterologie Oberaargau, 4900, Langenthal, Switzerland.
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25
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Zhang X, Du R, Luo N, Xiang R, Shen W. Aspirin mediates histone methylation that inhibits inflammation-related stemness gene expression to diminish cancer stemness via COX-independent manner. Stem Cell Res Ther 2020; 11:370. [PMID: 32854760 PMCID: PMC7450956 DOI: 10.1186/s13287-020-01884-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 07/01/2020] [Accepted: 08/10/2020] [Indexed: 12/21/2022] Open
Abstract
Background The widely recognized anti-cancer potential of aspirin has created a broad interest to explore the clinical benefits of aspirin in cancer therapy. However, the current understanding of the molecular mechanisms involved in the anti-cancer potential of aspirin remains limited. Methods Cancer stemness assays which contained ALDH, side population, chemo-resistance, sphere formation, and tumorigenesis were performed to validate aspirin function in vitro and in vivo. Histone modification assay was performed to check the effect of aspirin on histone methylation as well as the activity of HDAC and KDM6A/B. Inhibitor in vivo assay was performed to evaluate therapeutic effects of various inhibitor combination manners. Results In regards to in vitro studies, aspirin diminishes cancer cell stemness properties which include reducing the ALDH+ subpopulation, side population, chemo-resistance, and sphere formation in three cancer types. In regards to in vivo studies, aspirin decreases tumor growth and metastasis and prolongs survival. In addition, our results showed that aspirin inhibits inflammation-related stemness gene expression (especially ICAM3) identified by a high-throughput siRNA platform. In regards to the underlying molecular mechanism of action, aspirin reduces histone demethylase (KDM6A/B) expression that mediates histone methylation and suppresses gene expression via a COX-independent manner. In regards to therapeutic strategies, aspirin combined HDM inhibitors, ICAM3 downstream signaling Src/PI3K inhibitors, or ICAM3 inhibitor Lifitigrast prevents cancer progression in vivo. Conclusions The aforementioned findings suggest a molecular model that explains how aspirin diminishes cancer cell stemness properties. These findings may provide novel targets for therapeutic strategies involving aspirin in the prevention of cancer progression.
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Affiliation(s)
- Xiaoyuan Zhang
- Department of Pathology and Institute of Precision Medicine, Jining Medical University, 133 Hehua Road, Jining, 272067, China
| | - Renle Du
- Department of Immunology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Na Luo
- Department of Immunology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Rong Xiang
- Department of Immunology, School of Medicine, Nankai University, Tianjin, 300071, China.,2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China
| | - Wenzhi Shen
- Department of Pathology and Institute of Precision Medicine, Jining Medical University, 133 Hehua Road, Jining, 272067, China.
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26
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Aspirin inhibits TGFβ2-induced epithelial to mesenchymal transition of lens epithelial cells: selective acetylation of K56 and K122 in histone H3. Biochem J 2020; 477:75-97. [PMID: 31815277 DOI: 10.1042/bcj20190540] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 12/04/2019] [Accepted: 12/09/2019] [Indexed: 12/12/2022]
Abstract
Posterior capsule opacification (PCO) is a complication after cataract surgery that can disrupt vision. The epithelial to mesenchymal transition (EMT) of lens epithelial cells (LECs) in response to transforming growth factor β2 (TGFβ2) has been considered an obligatory mechanism for PCO. In this study, we tested the efficacy of aspirin in inhibiting the TGFβ2-mediated EMT of human LECs, LECs in human lens capsular bags, and lensectomized mice. In human LECs, the levels of the EMT markers α-smooth muscle actin (α-SMA) and fibronectin were drastically reduced by treatment with 2 mM aspirin. Aspirin also halted the EMT response of TGFβ2 when introduced after EMT initiation. In human capsular bags, treatment with 2 mM aspirin significantly suppressed posterior capsule wrinkling and the expression α-SMA in capsule-adherent LECs. The inhibition of TGFβ2-mediated EMT in human LECs was not dependent on Smad phosphorylation or MAPK and AKT-mediated signaling. We found that aspirin significantly increased the acetylation of K56 and K122 in histone H3 of human LECs. Chromatin immunoprecipitation assays using acetyl-H3K56 or acetyl-H3K122 antibody revealed that aspirin blocked the TGFβ2-induced acetylation of H3K56 and H3K122 at the promoter regions of ACTA2 and COL1A1. After lensectomy in mice, we observed an increase in the proliferation and α-SMA expression of the capsule-adherent LECs, which was ameliorated by aspirin administration through drinking water. Taken together, our results showed that aspirin inhibits TGFβ2-mediated EMT of LECs, possibly from epigenetic down-regulation of EMT-related genes.
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Darwiche N. Epigenetic mechanisms and the hallmarks of cancer: an intimate affair. Am J Cancer Res 2020; 10:1954-1978. [PMID: 32774995 PMCID: PMC7407342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 06/22/2020] [Indexed: 06/11/2023] Open
Abstract
Epigenetic mechanisms comprising DNA methylation, histone modifications, and noncoding RNAs affect chromatin structure and regulate gene expression. These mechanisms control normal embryonic development and adult life and their deregulation contributes to several diseases including cancer. The process of tumorigenesis is complex and results from the evolution of different "hallmarks of cancer". Hanahan and Weinberg presented in 2000 and 2011 seminal contributions in the cancer field, first the six hallmarks of cancer and a decade later two additional hallmarks and two enabling characteristics were added. Here, we surmise that epigenetic mechanisms regulate and contribute to every single hallmark in cancer, and thus represent the hallmark of hallmarks in tumorigenesis. Focusing on epigenetics as a major hallmark in cancer formation has profound preventive, therapeutic, and clinical implications.
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Affiliation(s)
- Nadine Darwiche
- Department of Biochemistry and Molecular Genetics, American University of Beirut Beirut, Lebanon
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Song M, Lan Y, Wu X, Han Y, Wang M, Zheng J, Li Z, Li F, Zhou J, Xiao J, Cao Y, Xiao H. The chemopreventive effect of 5-demethylnobiletin, a unique citrus flavonoid, on colitis-driven colorectal carcinogenesis in mice is associated with its colonic metabolites. Food Funct 2020; 11:4940-4952. [PMID: 32459257 PMCID: PMC10726105 DOI: 10.1039/d0fo00616e] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2023]
Abstract
5-Demethylnobiletin (5DN) is a unique flavonoid mainly found in citrus fruits. In this study, we determined the chemopreventive effects of 5DN and its major colonic metabolites on both a colitis-driven colon carcinogenesis mouse model and a human colon cancer cell model. In azoxymethane/dextran sulfate sodium-treated mice, dietary 5DN (0.05% w/w in the diet) significantly decreased the tumor incidence, multiplicity and burden, and showed potent anti-proliferative, proapoptotic, and anti-inflammatory activities in mouse colon tissue. Three major metabolites of 5DN, named 5,3'-didemethylnobiletin (M1), 5,4'-didemethylnobiletin (M2) and 5,3',4'-tridemethylnobiletin (M3), were found in the colonic mucosa of 5DN-treated mice, and the combined level of these metabolites in mouse colonic mucosa was 1.56-fold higher than that of 5DN. Cell culture studies revealed that 5DN and its colonic metabolites profoundly inhibited the growth of human colon cancer cells by inducing cell cycle arrest, triggering apoptosis and modulating key signaling proteins related to cell proliferation and apoptosis. Importantly, the colonic metabolites, especially M1, showed much stronger effects than those produced by 5DN itself. Overall, our results demonstrated that dietary 5DN significantly inhibited colitis-driven colon carcinogenesis in mice, and this chemopreventive effect was associated with its metabolites in the colon.
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Affiliation(s)
- Mingyue Song
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou, Guangdong, P.R. China and Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, Guangdong, P.R. China and Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Yaqi Lan
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou, Guangdong, P.R. China and Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, Guangdong, P.R. China
| | - Xian Wu
- Department of Food Science, University of Massachusetts, Amherst, MA, USA. and Department of Kinesiology and Health, Miami University, Oxford, OH, USA
| | - Yanhui Han
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Minqi Wang
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Jinkai Zheng
- Department of Food Science, University of Massachusetts, Amherst, MA, USA. and Institute of Agro-Products Processing Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, P.R. China
| | - Zhengze Li
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Fang Li
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Jiazhi Zhou
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Jie Xiao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou, Guangdong, P.R. China and Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, Guangdong, P.R. China
| | - Yong Cao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou, Guangdong, P.R. China and Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, Guangdong, P.R. China
| | - Hang Xiao
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
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Ibuprofen mediates histone modification to diminish cancer cell stemness properties via a COX2-dependent manner. Br J Cancer 2020; 123:730-741. [PMID: 32528119 PMCID: PMC7463005 DOI: 10.1038/s41416-020-0906-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 03/18/2020] [Accepted: 04/29/2020] [Indexed: 02/06/2023] Open
Abstract
Background The anticancer potential of ibuprofen has created a broad interest to explore the clinical benefits of ibuprofen in cancer therapy. However, the current understanding of the molecular mechanisms involved in the anticancer potential of ibuprofen remains limited. Methods Cancer stemness assays to validate ibuprofen function in vitro and in vivo. Histone modification assays to check the effect of ibuprofen on histone acetylation/methylation, as well as the activity of HDAC and KDM6A/B. Inhibitors’ in vivo assays to evaluate therapeutic effects of various inhibitors’ combination manners. Results In our in vitro studies, we report that ibuprofen diminishes cancer cell stemness properties that include reducing the ALDH + subpopulation, side population and sphere formation in three cancer types. In our in vivo studies, we report that ibuprofen decreases tumour growth, metastasis and prolongs survival. In addition, our results showed that ibuprofen inhibits inflammation-related stemness gene expression (especially ICAM3) identified by a high-throughput siRNA platform. In regard to the underlying molecular mechanism of action, we report that ibuprofen reduces HDACs and histone demethylase (KDM6A/B) expression that mediates histone acetylation and methylation, and suppresses gene expression via a COX2-dependent way. In regard to therapeutic strategies, we report that ibuprofen combined HDAC/HDM inhibitors prevents cancer progression in vivo. Conclusions The aforementioned findings suggest a molecular model that explains how ibuprofen diminishes cancer cell stemness properties. These may provide novel targets for therapeutic strategies involving ibuprofen in the prevention of cancer progression.
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Indomethacin-grafted and pH-sensitive dextran micelles for overcoming inflammation-mediated multidrug resistance in breast cancer. Carbohydr Polym 2020; 237:116139. [DOI: 10.1016/j.carbpol.2020.116139] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 03/06/2020] [Accepted: 03/06/2020] [Indexed: 12/14/2022]
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Chen M, Li Q, Cao N, Deng Y, Li L, Zhao Q, Wu M, Ye M. Profiling of histone 3 lysine 27 acetylation reveals its role in a chronic DSS-induced colitis mouse model. Mol Omics 2020; 15:296-307. [PMID: 31147658 DOI: 10.1039/c9mo00070d] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract. In current dogma, pathogenesis of IBD is attributed to the dysregulated mucosal immune response to gut flora in genetically susceptible individuals, but the genetics evidence from GWAS studies so far is insufficient to explain the observed heritability in IBD. For this discordance, epigenetics has emerged to be one of the important causes. Recent studies have reported that histone acetylation is correlated with the development of IBD, whereas its role and underlying molecular mechanism in the disease still remain elusive. Here, we established a dextran sulfate sodium (DSS)-induced chronic colitis model and performed RNA-sequencing (RNA-seq) and Chromatin Immunoprecipitation followed by NGS sequencing (ChIP-seq) for H3K27ac in the mice colon tissues to investigate whether H3K27ac is involved in the development of intestinal inflammation. We found that the global H3K27ac level and distribution in colon tissue had no significant difference after DSS treatment, while H3K27ac signals were significantly enriched in the typical-enhancers of the DSS group compared with the control. By combining with RNA-seq data (fold change >2), we identified 56 candidate genes as potential target genes for H3K27ac change upon DSS treatment. We further predicted transcription factors (TFs) involved in DSS-induced colitis according to the enhancers with increased H3K27ac. H3K27ac increase in special typical-enhancers in the DSS group is possibly related to the development of intestinal inflammation by up-regulating adjacent gene expression and shifting TF networks, which will provide new insight into the pathogenesis and therapy of IBD.
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Affiliation(s)
- Meng Chen
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
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Treatment with a Zinc Metalloprotease Purified from Bothrops moojeni Snake Venom (BmooMP-Alpha-I) Reduces the Inflammation in an Experimental Model of Dextran Sulfate Sodium-Induced Colitis. Mediators Inflamm 2019; 2019:5195134. [PMID: 31467484 PMCID: PMC6701296 DOI: 10.1155/2019/5195134] [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: 10/31/2018] [Revised: 03/05/2019] [Accepted: 05/14/2019] [Indexed: 12/11/2022] Open
Abstract
It has been described that the metalloprotease BmooMP-alpha-I purified from Bothrops moojeni snake venom is able to hydrolyze the TNF molecule. However, this observation has been based mainly on in vitro investigation, in addition to molecular modeling and docking approaches. Considering that there is no in vivo study to demonstrate the biological effects of this enzyme, the major aim to the present work was to investigate whether the BmooMP-alpha-I has any anti-inflammatory efficacy by setting up a murine experimental design of colitis induced by dextran sulfate sodium (DSS). For this purpose, C57BL/6 mice were divided into six groups, as follows: (i) animals without intestinal inflammation, (ii) animals without intestinal inflammation treated with BmooMP-alpha-I (50 μg/animal/day), and (iii) animals with intestinal inflammation induced by 3% of DSS, (iv) mice with intestinal inflammation induced by DSS and treated with BmooMP-alpha-I enzyme at the 50, 25, or 12.5 μg/animal/day dosages by intraperitoneal route. Clinical signs of colitis were observed daily for calculating the morbidity scores, cytokine measurements, and histological features. We observed that the animals treated with different doses of the enzyme presented a remarkable improvement of colitis signs, as confirmed by a significant increase of the intestine length in comparison to the DSS group. Also, no difference was observed between the groups treated with the enzyme or vehicle, as the colon length of these animals was slightly lower than that of the group of healthy animals, without induction of intestinal inflammation. The cytokine quantification in supernatants of intestinal tissue homogenates showed a significant reduction of 38% in IFN-gamma levels, when the animals were treated with 50 μg of the BmooMP-alpha-I compared to the animals receiving DSS only. A significant reduction of 39% in TNF levels was also observed in all doses of treatment with BmooMP-alpha-I, in addition to a significant reduction of 35% in the amount of IL-12p40. Histological examinations revealed that the BmooMP-alpha-I 50 μg treated group preserved colon architecture and goblet cells and reduced the ulcer area, when compared with DSS mice, which showed typical inflammatory changes in tissue architecture, such as ulceration, crypt dilation, loss of tissue architecture, and goblet cell depletion, accompanied by a significant cell infiltration. In conclusion, our results suggest that the improvement of clinical scores and histological findings related to BmooMP-alpha-I treatment in this experimental model could be attributed to the metalloprotease ability to modulate cytokine production locally at the inflamed intestine. These findings highlight the potential anti-inflammatory role and effectiveness of this enzyme as a therapeutic alternative in this type of immunopathological condition.
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Vallée A, Lecarpentier Y, Vallée JN. Targeting the Canonical WNT/β-Catenin Pathway in Cancer Treatment Using Non-Steroidal Anti-Inflammatory Drugs. Cells 2019; 8:cells8070726. [PMID: 31311204 PMCID: PMC6679009 DOI: 10.3390/cells8070726] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 07/11/2019] [Accepted: 07/14/2019] [Indexed: 12/19/2022] Open
Abstract
Chronic inflammation and oxidative stress are common and co-substantial pathological processes accompanying and contributing to cancers. Numerous epidemiological studies have indicated that non-steroidal anti-inflammatory drugs (NSAIDs) could have a positive effect on both the prevention of cancer and tumor therapy. Numerous hypotheses have postulated that NSAIDs could slow tumor growth by acting on both chronic inflammation and oxidative stress. This review takes a closer look at these hypotheses. In the cancer process, one of the major signaling pathways involved is the WNT/β-catenin pathway, which appears to be upregulated. This pathway is closely associated with both chronic inflammation and oxidative stress in cancers. The administration of NSAIDs has been observed to help in the downregulation of the WNT/β-catenin pathway and thus in the control of tumor growth. NSAIDs act as PPARγ agonists. The WNT/β-catenin pathway and PPARγ act in opposing manners. PPARγ agonists can promote cell cycle arrest, cell differentiation, and apoptosis, and can reduce inflammation, oxidative stress, proliferation, invasion, and cell migration. In parallel, the dysregulation of circadian rhythms (CRs) contributes to cancer development through the upregulation of the canonical WNT/β-catenin pathway. By stimulating PPARγ expression, NSAIDs can control CRs through the regulation of many key circadian genes. The administration of NSAIDs in cancer treatment would thus appear to be an interesting therapeutic strategy, which acts through their role in regulating WNT/β-catenin pathway and PPARγ activity levels.
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Affiliation(s)
- Alexandre Vallée
- Diagnosis and Therapeutic Center, Hypertension and Cardiovascular Prevention Unit, Hotel-Dieu Hospital, AP-HP, Université Paris Descartes, 75004 Paris, France.
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), 6-8 rue Saint-fiacre, 77100 Meaux, France
| | - Jean-Noël Vallée
- Centre Hospitalier Universitaire (CHU) Amiens Picardie, Université Picardie Jules Verne (UPJV), 80054 Amiens, France
- Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, 86000 Poitiers, France
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Yang ZH, Dang YQ, Ji G. Role of epigenetics in transformation of inflammation into colorectal cancer. World J Gastroenterol 2019; 25:2863-2877. [PMID: 31249445 PMCID: PMC6589733 DOI: 10.3748/wjg.v25.i23.2863] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/24/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer (CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The NF-κB and STAT3 signaling pathways play a particularly important role in the transformation of inflammation into CRC, and both are critical to cellular signal transduction and constantly activated in cancer by various abnormal changes including epigenetics. The NF-κB and STAT3 signals contribute to the microenvironment for tumorigenesis through secretion of a large number of pro-inflammatory cytokines and their crosstalk in the nucleus makes it even more difficult to treat CRC. Compared with gene mutation that is irreversible, epigenetic inheritance is reversible or can be altered by the intervention. Therefore, understanding the role of epigenetic inheritance in the inflammation-cancer transformation may elucidate the pathogenesis of CRC and promote the development of innovative drugs targeting transformation to prevent and treat this malignancy. This review summarizes the literature on the roles of epigenetic mechanisms in the occurrence and development of inflammation-induced CRC. Exploring the role of epigenetics in the transformation of inflammation into CRC may help stimulate futures studies on the role of molecular therapy in CRC.
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Affiliation(s)
- Zhen-Hua Yang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Digestive Endoscopy Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yan-Qi Dang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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Yang Y, Wu R, Sargsyan D, Yin R, Kuo HC, Yang I, Wang L, Cheng D, Wang C, Li S, Hudlikar R, Lu Y, Kong AN. UVB drives different stages of epigenome alterations during progression of skin cancer. Cancer Lett 2019; 449:20-30. [PMID: 30771437 PMCID: PMC6411449 DOI: 10.1016/j.canlet.2019.02.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 02/04/2019] [Accepted: 02/08/2019] [Indexed: 01/02/2023]
Abstract
Exposure to ultraviolet B (UVB) irradiation results in multitude of cellular responses including generation of reactive oxygen species and DNA damage and is responsible for non-melanoma skin cancers (NMSCs). Although genetic mutation is well documented, the epi-mutation, the alteration in epigenetics, remains elusive. In this study, we utilized CpG Methyl-seq to identify a genome-wide DNA CpG methylation, to profile the DNA methylation in UVB-irradiated SKH-1 mouse skin epidermis and non-melanoma skin papillomas at various stages. Methyl-seq and RNA-seq were performed to examine the methylation and corresponding transcriptome alterations. The methylation profiles in mouse epidermis were altered by UVB-irradiation as time progresses. Ingenuity Pathways Analysis (IPA) identified many cancer related pathways including PTEN, p53, Nrf2 and inflammatory signaling in UVB-irradiation induced carcinogenesis. Additionally, some novel genes involved in skin carcinogenesis that were not previously reported were differentially methylated, including Enf2, Mgst2, Vegfa, and Cdk4. Taken together, the current study provides novel profiles and insights of methylation and transcriptomic changes at different stages of carcinogenesis in UVB-irradiation induced NMSC and offers potential targets for prevention and treatment of NMSC at different stages of human skin cancer.
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Affiliation(s)
- Yuqing Yang
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Renyi Wu
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Davit Sargsyan
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Ran Yin
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Hsiao-Chen Kuo
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Irene Yang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Lujing Wang
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - David Cheng
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Chao Wang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Shanyi Li
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Rasika Hudlikar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Yaoping Lu
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Ah-Ng Kong
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.
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Guo Y, Wu R, Gaspar JM, Sargsyan D, Su ZY, Zhang C, Gao L, Cheng D, Li W, Wang C, Yin R, Fang M, Verzi MP, Hart RP, Kong AN. DNA methylome and transcriptome alterations and cancer prevention by curcumin in colitis-accelerated colon cancer in mice. Carcinogenesis 2019; 39:669-680. [PMID: 29547900 DOI: 10.1093/carcin/bgy043] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 03/12/2018] [Indexed: 12/17/2022] Open
Abstract
Inflammation is highly associated with colon carcinogenesis. Epigenetic mechanisms could play an important role in the initiation and progression of colon cancer. Curcumin, a dietary phytochemical, shows promising effects in suppressing colitis-associated colon cancer in azoxymethane-dextran sulfate sodium (AOM-DSS) mice. However, the potential epigenetic mechanisms of curcumin in colon cancer remain unknown. In this study, the anticancer effect of curcumin in suppressing colon cancer in an 18-week AOM-DSS colon cancer mouse model was confirmed. We identified lists of differentially expressed and differentially methylated genes in pairwise comparisons and several pathways involved in the potential anticancer effect of curcumin. These pathways include LPS/IL-1-mediated inhibition of RXR function, Nrf2-mediated oxidative stress response, production of NO and ROS in macrophages and IL-6 signaling. Among these genes, Tnf stood out with decreased DNA CpG methylation of Tnf in the AOM-DSS group and reversal of the AOM-DSS induced Tnf demethylation by curcumin. These observations in Tnf methylation correlated with increased and decreased Tnf expression in RNA-seq. The functional role of DNA methylation of Tnf was further confirmed by in vitro luciferase transcriptional activity assay. In addition, the DNA methylation level in a group of inflammatory genes was decreased in the AOM+DSS group but restored by curcumin and was validated by pyrosequencing. This study shows for the first time epigenomic changes in DNA CpG methylation in the inflammatory response from colitis-associated colon cancer and the reversal of their CpG methylation changes by curcumin. Future clinical epigenetic studies with curcumin in inflammation-associated colon cancer would be warranted.
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Affiliation(s)
- Yue Guo
- Graduate Program in Pharmaceutical Science, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.,Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Renyi Wu
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - John M Gaspar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Davit Sargsyan
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Zheng-Yuan Su
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.,Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan City, Taiwan
| | - Chengyue Zhang
- Graduate Program in Pharmaceutical Science, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.,Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Linbo Gao
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - David Cheng
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Wenji Li
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Chao Wang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Ran Yin
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Mingzhu Fang
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Michael P Verzi
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Ronald P Hart
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Ah-Ng Kong
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
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Zhang H, Lu J, Jiao Y, Chen Q, Li M, Wang Z, Yu Z, Huang X, Yao A, Gao Q, Xie W, Li L, Yao P. Aspirin Inhibits Natural Killer/T-Cell Lymphoma by Modulation of VEGF Expression and Mitochondrial Function. Front Oncol 2019; 8:679. [PMID: 30693272 PMCID: PMC6339948 DOI: 10.3389/fonc.2018.00679] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 12/24/2018] [Indexed: 12/21/2022] Open
Abstract
Extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) is an Epstein-Barr virus (EBV)-associated lymphoma with a strong tendency relapse or be refractory in response to chemotherapy. Development of a new strategy for NKTCL treatment is still quite necessary. In this study, we found that aspirin treatment suppresses VEGF expression in NKTCL SNK-6 cells. Further investigation showed that aspirin treatment increases histone methylation in the range of −100~0 that is proximal to the transcription start site on the VEGF promoter, subsequently decreasing the binding ability of Sp1 to the VEGF promoter with VEGF suppression. Furthermore, aspirin treatment modulates mitochondrial function with increased ROS formation and apoptosis in NKTCL cells. Aspirin treatment alone slightly inhibits NKTCL SNK-6 tumor growth and EBV replication; while in the presence of histone deacetylase inhibitor (HDACi) chidamide (CDM), aspirin significantly suppresses the VEGF signaling pathway with increased ROS overgeneration and EBV inhibition. We also showed that with the addition of chidamide, aspirin significantly suppresses NKTCL tumor growth in both in vitro cell culture and in vivo mouse model with prolonged mouse survival. This is the first time that the potential mechanism for aspirin-mediated VEGF suppression and anti-tumor effect has been discovered, and this study provides a new strategy for anti-tumor drug development for NKTCL treatment based on aspirin-mediated targeting of the VEGF signaling pathway and ROS formation.
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Affiliation(s)
- Hongyu Zhang
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jianping Lu
- Department of Child Psychiatry, Kangning Hospital of Shenzhen, Shenzhen, China
| | - Yun Jiao
- Department of Pediatrics, Hainan Maternal and Child Health Hospital, Haikou, China
| | - Qi Chen
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Min Li
- Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, Wuhan, China
| | - Zichen Wang
- Department of Child Psychiatry, Kangning Hospital of Shenzhen, Shenzhen, China
| | - Zhendong Yu
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Xiaodong Huang
- Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, Wuhan, China
| | - Athena Yao
- Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, Wuhan, China
| | - Qiong Gao
- Department of Gynecology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Weiguo Xie
- Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, Wuhan, China
| | - Ling Li
- Department of Pediatrics, Hainan Maternal and Child Health Hospital, Haikou, China
| | - Paul Yao
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China.,Department of Child Psychiatry, Kangning Hospital of Shenzhen, Shenzhen, China.,Department of Pediatrics, Hainan Maternal and Child Health Hospital, Haikou, China.,Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, Wuhan, China
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38
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Zhan Y, He Z, Liu X, Miao N, Lin F, Xu W, Mu S, Mu H, Yuan M, Cao X, Jin H, Liu Z, Li Y, Zhang B. Aspirin-induced attenuation of adipogenic differentiation of bone marrow mesenchymal stem cells is accompanied by the disturbed epigenetic modification. Int J Biochem Cell Biol 2018; 98:29-42. [DOI: 10.1016/j.biocel.2018.02.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 02/05/2018] [Accepted: 02/13/2018] [Indexed: 12/15/2022]
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Servais L, Wéra O, Dibato Epoh J, Delierneux C, Bouznad N, Rahmouni S, Mazzucchelli G, Baiwir D, Delvenne P, Lancellotti P, Oury C. Platelets contribute to the initiation of colitis-associated cancer by promoting immunosuppression. J Thromb Haemost 2018; 16:762-777. [PMID: 29369476 DOI: 10.1111/jth.13959] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Indexed: 02/06/2023]
Abstract
Essentials Inflammation plays a key role in the development of colorectal cancer. Understanding mechanisms of cancer initiation might reveal new anticancer preventive strategy. Hyperactive platelets promote tumor formation by fostering immune evasion of cancer. Platelet inhibition by clopidogrel prevents carcinogenesis by restoring antitumor immunity. SUMMARY Background Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, although the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors in inflammation; they have also been shown to be involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and platelet reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at the pretumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results At the pretumoral stage, hyperactive platelets constituted a major source of circulating protumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of the plasma SAA protein level, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells, as well as their infiltration into tumors, but increased the number of tissue CD8+ T cells. Platelets and releasates of platelets from mice with cancer were both able to polarize myeloid cells towards an immunosuppressive phenotype. Conclusions Thus, platelets promote the initiation of colitis-associated cancer by enhancing myeloid cell-dependent immunosuppression. Antiplatelet agents may help to prevent inflammation-elicited carcinogenesis by restoring antitumor immunity.
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Affiliation(s)
- L Servais
- Laboratory of Thrombosis and Hemostasis and Valvular Heart Disease, GIGA-Cardiovascular Sciences, Department of Cardiology, University of Liège, CHU Sart-Tilman, Liège, Belgium
| | - O Wéra
- Laboratory of Thrombosis and Hemostasis and Valvular Heart Disease, GIGA-Cardiovascular Sciences, Department of Cardiology, University of Liège, CHU Sart-Tilman, Liège, Belgium
| | - J Dibato Epoh
- Laboratory of Thrombosis and Hemostasis and Valvular Heart Disease, GIGA-Cardiovascular Sciences, Department of Cardiology, University of Liège, CHU Sart-Tilman, Liège, Belgium
| | - C Delierneux
- Laboratory of Thrombosis and Hemostasis and Valvular Heart Disease, GIGA-Cardiovascular Sciences, Department of Cardiology, University of Liège, CHU Sart-Tilman, Liège, Belgium
| | - N Bouznad
- Laboratory of Thrombosis and Hemostasis and Valvular Heart Disease, GIGA-Cardiovascular Sciences, Department of Cardiology, University of Liège, CHU Sart-Tilman, Liège, Belgium
| | - S Rahmouni
- Immunology and Infectious Diseases Unit, GIGA-R, University of Liège, Liège, Belgium
| | - G Mazzucchelli
- Laboratory of Mass Spectrometry, Chemistry Department, GIGA-R, CART, University of Liège, Liège, Belgium
| | - D Baiwir
- Laboratory of Mass Spectrometry, Chemistry Department, GIGA-R, CART, University of Liège, Liège, Belgium
| | - P Delvenne
- Department of Pathology, Laboratory of Experimental Pathology, University of Liège, Liège, Belgium
| | - P Lancellotti
- Laboratory of Thrombosis and Hemostasis and Valvular Heart Disease, GIGA-Cardiovascular Sciences, Department of Cardiology, University of Liège, CHU Sart-Tilman, Liège, Belgium
- Gruppo Villa Maria Care and Reseach, Anthea Hospital, Bari, Italy
| | - C Oury
- Laboratory of Thrombosis and Hemostasis and Valvular Heart Disease, GIGA-Cardiovascular Sciences, Department of Cardiology, University of Liège, CHU Sart-Tilman, Liège, Belgium
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40
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Guo Y, Su ZY, Zhang C, Gaspar JM, Wang R, Hart RP, Verzi MP, Kong ANT. Mechanisms of colitis-accelerated colon carcinogenesis and its prevention with the combination of aspirin and curcumin: Transcriptomic analysis using RNA-seq. Biochem Pharmacol 2017; 135:22-34. [PMID: 28267439 PMCID: PMC5541256 DOI: 10.1016/j.bcp.2017.02.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Accepted: 02/28/2017] [Indexed: 12/14/2022]
Abstract
Colorectal cancer (CRC) remains the leading cause of cancer-related death in the world. Aspirin (ASA) and curcumin (CUR) are widely investigated chemopreventive candidates for CRC. However, the precise mechanisms of their action and their combinatorial effects have not been evaluated. The purpose of the present study was to determine the effect of ASA, CUR, and their combination in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-accelerated colorectal cancer (CAC). We also aimed to characterize the differential gene expression profiles in AOM/DSS-induced tumors as well as in tumors modulated by ASA and CUR using RNA-seq. Diets supplemented with 0.02% ASA, 2% CUR or 0.01% ASA+1% CUR were given to mice from 1week prior to the AOM injection until the experiment was terminated 22weeks after AOM initiation. Our results showed that CUR had a superior inhibitory effect in colon tumorigenesis compared to that of ASA. The combination of ASA and CUR at a lower dose exhibited similar efficacy to that of a higher dose of CUR at 2%. RNA isolated from colonic tissue from the control group and from tumor samples from the experimental groups was subjected to RNA-seq. Transcriptomic analysis suggested that the low-dose combination of ASA and CUR modulated larger gene sets than the single treatment. These differentially expressed genes were situated in several canonical pathways important in the inflammatory network and liver metastasis in CAC. We identified a small subset of genes as potential molecular targets involved in the preventive action of the combination of ASA and CUR. Taken together, the current results provide the first evidence in support of the chemopreventive effect of a low-dose combination of ASA and CUR in CAC. Moreover, the transcriptional profile obtained in our study may provide a framework for identifying the mechanisms underlying the carcinogenesis process from normal colonic tissue to tumor development as well as the cancer inhibitory effects and potential molecular targets of ASA and CUR.
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Affiliation(s)
- Yue Guo
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Zheng-Yuan Su
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan City 32023, Taiwan
| | - Chengyue Zhang
- Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - John M Gaspar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Rui Wang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Shanghai Roche Pharmaceuticals Ltd, Shanghai 10020, China
| | - Ronald P Hart
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Michael P Verzi
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Ah-Ng Tony Kong
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
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Zhang Y, Kong W, Jiang J. Prevention and treatment of cancer targeting chronic inflammation: research progress, potential agents, clinical studies and mechanisms. SCIENCE CHINA-LIFE SCIENCES 2017. [PMID: 28639101 DOI: 10.1007/s11427-017-9047-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Numerous experimental and clinical studies indicate that chronic inflammation is closely related to the initiation, progression, and spread of cancer, in which proinflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α), and transcription factors, such as nuclear factor-κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3), play pivotal roles. Stimulated by proinflammatory cytokines, NF-κB and STAT3 can modulate the expression of target genes, most of which are oncogenic ones, and promote the survival, proliferation, invasion, and metastasis of cancer cells. Now it is generally accepted that inflammation-related molecules and pathways are useful targets for the prevention and treatment of cancer. In this review, we summarize the relationship between chronic inflammation and cancer and describe some potentially useful agents including aspirin, meformin, statins, and some natural products (green tea catechins, andrographolide, curcumin) for their cancer prevention and treatment activities targeting chronic inflammation. The results of typical clinical studies are included, and the influences of these agents on the proinflammatory cytokines and inflammation-related pathways are discussed. Data from the present review support that agents targeting chronic inflammation may have a broad application prospect for the prevention and treatment of cancer in the future.
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Affiliation(s)
- Yong Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Weijia Kong
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
| | - Jiandong Jiang
- Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
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Kanda Y, Osaki M, Okada F. Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction. Int J Mol Sci 2017; 18:E867. [PMID: 28422073 PMCID: PMC5412448 DOI: 10.3390/ijms18040867] [Citation(s) in RCA: 19] [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: 03/31/2017] [Revised: 04/14/2017] [Accepted: 04/17/2017] [Indexed: 02/07/2023] Open
Abstract
A sustained and chronically-inflamed environment is characterized by the presence of heterogeneous inflammatory cellular components, including neutrophils, macrophages, lymphocytes and fibroblasts. These infiltrated cells produce growth stimulating mediators (inflammatory cytokines and growth factors), chemotactic factors (chemokines) and genotoxic substances (reactive oxygen species and nitrogen oxide) and induce DNA damage and methylation. Therefore, chronic inflammation serves as an intrinsic niche for carcinogenesis and tumor progression. In this article, we summarize the up-to-date findings regarding definitive/possible causes and mechanisms of inflammation-related carcinogenesis derived from experimental and clinical studies. We also propose 10 strategies, as well as candidate agents for the prevention of inflammation-related carcinogenesis.
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Affiliation(s)
- Yusuke Kanda
- Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.
| | - Mitsuhiko Osaki
- Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.
- Chromosome Engineering Research Center, Tottori University, Yonago, Tottori 683-8503, Japan.
| | - Futoshi Okada
- Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.
- Chromosome Engineering Research Center, Tottori University, Yonago, Tottori 683-8503, Japan.
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43
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Zhou ZH, Yang J, Kong AN. Phytochemicals in Traditional Chinese Herbal Medicine: Cancer Prevention and Epigenetics Mechanisms. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s40495-017-0086-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Todoric J, Antonucci L, Karin M. Targeting Inflammation in Cancer Prevention and Therapy. Cancer Prev Res (Phila) 2016; 9:895-905. [PMID: 27913448 DOI: 10.1158/1940-6207.capr-16-0209] [Citation(s) in RCA: 270] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 10/03/2016] [Indexed: 12/14/2022]
Abstract
Inflammation is associated with the development and malignant progression of most cancers. As most of the cell types involved in cancer-associated inflammation are genetically stable and thus are not subjected to rapid emergence of drug resistance, the targeting of inflammation represents an attractive strategy both for cancer prevention and for cancer therapy. Tumor-extrinsic inflammation is caused by many factors, including bacterial and viral infections, autoimmune diseases, obesity, tobacco smoking, asbestos exposure, and excessive alcohol consumption, all of which increase cancer risk and stimulate malignant progression. In contrast, cancer-intrinsic or cancer-elicited inflammation can be triggered by cancer-initiating mutations and can contribute to malignant progression through the recruitment and activation of inflammatory cells. Both extrinsic and intrinsic inflammation can result in immunosuppression, thereby providing a preferred background for tumor development. In clinical trials, lifestyle modifications including healthy diet, exercise, alcohol, and smoking cessation have proven effective in ameliorating inflammation and reducing the risk of cancer-related deaths. In addition, consumption of certain anti-inflammatory drugs, including aspirin, can significantly reduce cancer risk, suggesting that common nonsteroidal anti-inflammatory drugs (NSAID) and more specific COX2 inhibitors can be used in cancer prevention. In addition to being examined for their preventative potential, both NSAIDs and more potent anti-inflammatory antibody-based drugs need to be tested for their ability to augment the efficacy of more conventional therapeutic approaches on the basis of tumor resection, radiation, and cytotoxic chemicals. Cancer Prev Res; 9(12); 895-905. ©2016 AACR.
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Affiliation(s)
- Jelena Todoric
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California.,Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Laura Antonucci
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California. .,Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California
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Maiuri AR, O'Hagan HM. Interplay Between Inflammation and Epigenetic Changes in Cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 144:69-117. [PMID: 27865469 DOI: 10.1016/bs.pmbts.2016.09.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Immune responses can suppress tumorigenesis, but also contribute to cancer initiation and progression suggesting a complex interaction between the immune system and cancer. Epigenetic alterations, which are heritable changes in gene expression without changes to the DNA sequence, also play a role in carcinogenesis through silencing expression of tumor suppressor genes and activating oncogenic signaling. Interestingly, epithelial cells at sites of chronic inflammation undergo DNA methylation alterations that are similar to those present in cancer cells, suggesting that inflammation may initiate cancer-specific epigenetic changes in epithelial cells. Furthermore, epigenetic changes occur during immune cell differentiation and participate in regulating the immune response, including the regulation of inflammatory cytokines. Cancer cells utilize epigenetic silencing of immune-related genes to evade the immune response. This chapter will detail the interactions between inflammation and epigenetics in tumor initiation, promotion, and immune evasion and how these connections are being leveraged in cancer prevention and treatment.
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Affiliation(s)
- A R Maiuri
- Medical Sciences, Indiana University School of Medicine, Bloomington, IN, United States
| | - H M O'Hagan
- Medical Sciences, Indiana University School of Medicine, Bloomington, IN, United States; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, United States.
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