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1
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Kantham S, Yu H, Cantelli CR, Chen G, Ma C, Chan JJ, Yang H, Tsai K, Lassueur K, Vallance BA, Jacobson K, Young RN. Development of novel GI-centric prostaglandin E 2 receptor type 4 (EP4) agonist prodrugs as treatment for ulcerative colitis and other intestinal inflammatory diseases. Bioorg Med Chem Lett 2025; 119:130093. [PMID: 39793629 DOI: 10.1016/j.bmcl.2025.130093] [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: 05/11/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 01/13/2025]
Abstract
Prostaglandin E2 receptor type 4 (EP4) agonists have been shown to be effective in treating experimental ulcerative colitis (UC) in animals and in human clinical trials, but their development has been impeded by unacceptable systemic side effects. In this study, a series of methylene phosphate prodrugs of a highly potent and selective prostaglandin EP4 receptor agonist were designed to target and remain localized in the gastrointestinal (GI) tract after either oral or rectal instillation. The prodrugs were designed to be converted to liberate active EP4 agonist by intestinal alkaline phosphate (IAP), a ubiquitous enzyme found at the luminal of the intestinal wall thus exposing the colon epithelial barrier while reducing systemic exposure to the active agonist. The prodrugs were shown to hydrolyze in plasma and after contact with GI tissue slices from ileum and colon. When optimized prodrugs were dosed orally, systemic peak exposure to the active agonist was not reduced, presumably due to IAP activity in the duodenum and small intestine. However, when dosed rectally, the prodrugs gave much reduced levels of EP4 agonist in the blood. An optimized prodrug was shown to be retained in the colon, when compared with free agonist after rectal administration in healthy mice and to be efficacious in a model of UC (the DSS mouse model). Plasma exposure to the active agonist was also much reduced in the mouse model of UC after 4 days of rectal dosing but after 7 days, one DSS mouse showed elevated systemic levels of the free agonist in the blood. The concept of efficacy and intestinal retention of an EP4 agonist-methylene phosphate prodrug was proven for rectal instillation but in DSS treated mice, severe disease appears to compromise the epithelia barrier sufficiently to allow some absorption of the prodrug to occur. Thus, further optimization of these prodrugs is required before a candidate can be selected for development for treating severe ulcerative colitis.
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Affiliation(s)
- Srinivas Kantham
- Department of Chemistry, Simon Fraser University Burnaby British Columbia Canada
| | - Hongbing Yu
- Department of Pediatrics, University of British Columbia Vancouver British Columbia Canada
| | | | - Gang Chen
- Department of Chemistry, Simon Fraser University Burnaby British Columbia Canada
| | - Caixia Ma
- Department of Pediatrics, University of British Columbia Vancouver British Columbia Canada
| | - Jocelyn J Chan
- Department of Pediatrics, University of British Columbia Vancouver British Columbia Canada
| | - Hyungjun Yang
- Department of Pediatrics, University of British Columbia Vancouver British Columbia Canada
| | - Kevin Tsai
- Department of Pediatrics, University of British Columbia Vancouver British Columbia Canada
| | - Kristiana Lassueur
- Department of Chemistry, Simon Fraser University Burnaby British Columbia Canada
| | - Bruce A Vallance
- Department of Pediatrics, University of British Columbia Vancouver British Columbia Canada
| | - Kevan Jacobson
- Department of Pediatrics, University of British Columbia Vancouver British Columbia Canada.
| | - Robert N Young
- Department of Chemistry, Simon Fraser University Burnaby British Columbia Canada.
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Sninsky JA, Shore BM, Lupu GV, Crockett SD. Risk Factors for Colorectal Polyps and Cancer. Gastrointest Endosc Clin N Am 2022; 32:195-213. [PMID: 35361331 DOI: 10.1016/j.giec.2021.12.008] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Colorectal cancer (CRC) is a common malignancy in the U.S. and worldwide. Most CRC cases arise from precancerous adenomatous and serrated polyps. Established risk factors for conventional adenomas and CRC include age, male sex, family history, obesity and physical inactivity, and red meat intake. White race and tobacco and alcohol use are important risk factors for serrated polyps, which have a distinct risk factor profile compared to conventional adenomas. A history of abdominopelvic radiation, acromegaly, hereditary hemochromatosis, or prior ureterosigmoidostomy also increases CRC risk. Understanding these risk factors allows for targeted screening of high-risk groups to reduce CRC incidence.
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Affiliation(s)
- Jared A Sninsky
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, CB 7080, 130 Mason Farm Road, Chapel Hill, NC 27599-7555, USA
| | - Brandon M Shore
- Department of Medicine, University of North Carolina School of Medicine, CB 7080, 130 Mason Farm Road, Chapel Hill, NC 27599-7555, USA
| | - Gabriel V Lupu
- Department of Medicine, University of North Carolina School of Medicine, CB 7080, 130 Mason Farm Road, Chapel Hill, NC 27599-7555, USA
| | - Seth D Crockett
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, CB 7080, 130 Mason Farm Road, Chapel Hill, NC 27599-7555, USA.
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Swoboda J, Mittelsdorf P, Chen Y, Weiskirchen R, Stallhofer J, Schüle S, Gassler N. Intestinal Wnt in the transition from physiology to oncology. World J Clin Oncol 2022; 13:168-185. [PMID: 35433295 PMCID: PMC8966512 DOI: 10.5306/wjco.v13.i3.168] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 09/07/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
Adult stem cells are necessary for self-renewal tissues and regeneration after damage. Especially in the intestine, which self-renews every few days, they play a key role in tissue homeostasis. Therefore, complex regulatory mechanisms are needed to prevent hyperproliferation, which can lead in the worst case to carcinogenesis or under-activation of stem cells, which can result in dysfunctional epithelial. One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway. It is a highly conserved pathway, with β-catenin, a transcription factor, as target protein. Translocation of β-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripo-tency, proliferation, cell differentiation and regulation of cell death. This review presents a brief overview of the Wnt/β-catenin signaling pathway, the regulatory mechanism of this pathway and its role in intestinal homeostasis. Additionally, this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation. Furthermore, the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.
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Affiliation(s)
- Julia Swoboda
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Patrick Mittelsdorf
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Johannes Stallhofer
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena 07747, Germany
| | - Silke Schüle
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
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Bersuder E, Terciolo C, Lechevrel M, Martin E, Quesnelle C, Freund JN, Reimund JM, Gross I. Mesalazine initiates an anti-oncogenic β-catenin / MUCDHL negative feed-back loop in colon cancer cells by cell-specific mechanisms. Biomed Pharmacother 2021; 146:112543. [PMID: 34929577 DOI: 10.1016/j.biopha.2021.112543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/06/2021] [Accepted: 12/13/2021] [Indexed: 01/18/2023] Open
Abstract
Chronic inflammation associated with intestinal architecture and barrier disruption puts patients with inflammatory bowel disease (IBD) at increased risk of developing colorectal cancer (CRC). Widely used to reduce flares of intestinal inflammation, 5-aminosalicylic acid derivatives (5-ASAs) such as mesalazine appear to also exert more direct mucosal healing and chemopreventive activities against CRC. The mechanisms underlying these activities are poorly understood and may involve the up-regulation of the cadherin-related gene MUCDHL (CDHR5). This atypical cadherin is emerging as a new actor of intestinal homeostasis and opposes colon tumorigenesis. Here, we showed that mesalazine increase mRNA levels of MUCDHL and of other genes involved in the intestinal barrier function in most intestinal cell lines. In addition, using gain / loss of function experiments (agonists, plasmid or siRNAs transfections), luciferase reporter genes and chromatin immunoprecipitation, we thoroughly investigated the molecular mechanisms triggered by mesalazine that lead to the up-regulation of MUCDHL expression. We found that basal transcription of MUCDHL in different CRC cell lines is regulated positively by CDX2 and negatively by β-catenin through a negative feed-back loop. However, mesalazine-stimulation of MUCDHL transcription is controlled by cell-specific mechanisms, involving either enhanced activation of CDX2 and PPAR-γ or repression of the β-catenin inhibitory effect. This work highlights the importance of the cellular and molecular context in the activity of mesalazine and suggests that its efficacy against CRC depends on the genetic alterations of transformed cells.
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Affiliation(s)
- Emilie Bersuder
- Université de Strasbourg, Inserm, IRFAC / UMR-S1113, FHU ARRIMAGE, FMTS, Strasbourg, France
| | - Chloe Terciolo
- Université de Strasbourg, Inserm, IRFAC / UMR-S1113, FHU ARRIMAGE, FMTS, Strasbourg, France
| | - Mathilde Lechevrel
- Université de Caen / Basse-Normandie, UFR de Médecine, EA 4652, F-14032 Caen, France
| | - Elisabeth Martin
- Université de Strasbourg, Inserm, IRFAC / UMR-S1113, FHU ARRIMAGE, FMTS, Strasbourg, France
| | - Celine Quesnelle
- Université de Caen / Basse-Normandie, UFR de Médecine, EA 4652, F-14032 Caen, France
| | - Jean-Noel Freund
- Université de Strasbourg, Inserm, IRFAC / UMR-S1113, FHU ARRIMAGE, FMTS, Strasbourg, France
| | - Jean-Marie Reimund
- Université de Strasbourg, Inserm, IRFAC / UMR-S1113, FHU ARRIMAGE, FMTS, Strasbourg, France; Université de Caen / Basse-Normandie, UFR de Médecine, EA 4652, F-14032 Caen, France; Service Hépato-Gastroentérologie, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France; Institut Hospitalo-Universitaire de Strasbourg, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France.
| | - Isabelle Gross
- Université de Strasbourg, Inserm, IRFAC / UMR-S1113, FHU ARRIMAGE, FMTS, Strasbourg, France.
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Hoffmann M, Kant TA, Emig R, Rausch JSE, Newe M, Schubert M, Künzel K, Winter L, Klapproth E, Peyronnet R, Ravens U, El-Armouche A, Künzel SR. Repurposing mesalazine against cardiac fibrosis in vitro. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:533-543. [PMID: 33064167 PMCID: PMC7892689 DOI: 10.1007/s00210-020-01998-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 10/08/2020] [Indexed: 12/11/2022]
Abstract
Cardiovascular diseases are exacerbated and driven by cardiac fibrosis. TGFβ induces fibroblast activation and differentiation into myofibroblasts that secrete excessive extracellular matrix proteins leading to stiffening of the heart, concomitant cardiac dysfunction, and arrhythmias. However, effective pharmacotherapy for preventing or reversing cardiac fibrosis is presently unavailable. Therefore, drug repurposing could be a cost- and time-saving approach to discover antifibrotic interventions. The aim of this study was to investigate the antifibrotic potential of mesalazine in a cardiac fibroblast stress model. TGFβ was used to induce a profibrotic phenotype in a human cardiac fibroblast cell line. After induction, cells were treated with mesalazine or solvent control. Fibroblast proliferation, key fibrosis protein expression, extracellular collagen deposition, and mechanical properties were subsequently determined. In response to TGFβ treatment, fibroblasts underwent a profound phenoconversion towards myofibroblasts, determined by the expression of fibrillary αSMA. Mesalazine reduced differentiation nearly by half and diminished fibroblast proliferation by a third. Additionally, TGFβ led to increased cell stiffness and adhesion, which were reversed by mesalazine treatment. Collagen 1 expression and deposition-key drivers of fibrosis-were significantly increased upon TGFβ stimulation and reduced to control levels by mesalazine. SMAD2/3 and ERK1/2 phosphorylation, along with reduced nuclear NFκB translocation, were identified as potential modes of action. The current study provides experimental pre-clinical evidence for antifibrotic effects of mesalazine in an in vitro model of cardiac fibrosis. Furthermore, it sheds light on possible mechanisms of action and suggests further investigation in experimental and clinical settings.
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Affiliation(s)
- Maximilian Hoffmann
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fiedlerstraße 42, 01309, Dresden, Germany
| | - Theresa A Kant
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fiedlerstraße 42, 01309, Dresden, Germany
| | - Ramona Emig
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Medical Center-University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Johanna S E Rausch
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fiedlerstraße 42, 01309, Dresden, Germany
| | - Manja Newe
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fiedlerstraße 42, 01309, Dresden, Germany
| | - Mario Schubert
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fiedlerstraße 42, 01309, Dresden, Germany
| | - Karolina Künzel
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fiedlerstraße 42, 01309, Dresden, Germany
| | - Luise Winter
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fiedlerstraße 42, 01309, Dresden, Germany
| | - Erik Klapproth
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fiedlerstraße 42, 01309, Dresden, Germany
| | - Rémi Peyronnet
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Medical Center-University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ursula Ravens
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Medical Center-University of Freiburg, Freiburg, Germany
| | - Ali El-Armouche
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fiedlerstraße 42, 01309, Dresden, Germany
| | - Stephan R Künzel
- Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fiedlerstraße 42, 01309, Dresden, Germany.
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6
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Mak JWY, So J, Tang W, Yip TCF, Leung WK, Li M, Lo FH, Ng KM, Sze SF, Leung CM, Tsang SWC, Shan EHS, Chan KH, Lam BCY, Hui AJ, Chow WH, Chan FKL, Ng SC. Cancer risk and chemoprevention in Chinese inflammatory bowel disease patients: a population-based cohort study. Scand J Gastroenterol 2020; 55:279-286. [PMID: 32119788 DOI: 10.1080/00365521.2020.1731760] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Background and aim: Role of 5-aminosalicylic acid (5-ASA), statin and aspirin in reducing cancer risks in inflammatory bowel disease (IBD) remains controversial. We aimed to examine chemo-preventive effects of these drugs in all cancers in IBD in population-based setting.Methods: IBD patients diagnosed between 2000 and 2016 were identified from the Hong Kong IBD Registry and followed from IBD diagnosis until first cancer occurrence. Primary outcome was cancer development ≥6 months after IBD diagnosis. Adjusted hazard ratio (aHR) with 95% confidence interval (CI) was estimated with Cox proportional hazards model. Additional effects of statin and aspirin on chemoprevention were also assessed.Results: Amongst 2103 IBD patients (857 Crohn's disease, 1246 ulcerative colitis; mean age 40.0 ± 15.6; 60.3% male) with 16,856 person-years follow-up, 48 patients (2.3%) developed cancer. The 5-r, 10-r and 15-year (95% CI) cumulative incidence of cancer were 1% (0.6 - 1.5%), 2.8 (2.0 - 3.9%) and 4.8 (3.4 - 6.5%), respectively. Total 1891 (89.9%) and 222 (10.6%) patients have received one or more prescriptions of 5-ASA and statin respectively. In multivariable analysis adjusted for age, gender, smoking status, IBD type and use of other medications, use of 5-ASA or statin was not associated with a reduced risk of cancer development (5-ASA: aHR 1.22, 95% CI: 0.60-2.48, p = .593; statin: aHR 0.48, 95% CI: 0.14-1.59, p = .227). Adding aspirin was not associated with a lowered cancer risk (aHR 1.18, 95% CI: 0.32-4.35, p = .799).Conclusion: Use of 5-ASA was not associated with a lowered cancer risk in Chinese IBD patients. Addition of statin/aspirin provided no additional benefit.Key summaryInflammatory bowel diseases (IBD) including Crohn's disease and ulcerative colitis are associated with increased risk of both intestinal and extra- intestinal cancers.Various medications including 5-aminosalicylate acid (5-ASA), statins and aspirin have been studied for their chemoprevention effects. However, most studies focused on colorectal cancer only and showed conflicting evidence. No studies so far looked at the effects of these medications on all cancer development in IBD.The 5-, 10- and 15-year (95% confidence interval) cumulative incidence of cancer in Chinese IBD patients were 1 (0.6-1.5%), 2.8 (2.0-3.9%) and 4.8 (3.4-6.5%), respectively.Use of 5-ASA was not associated with a lowered cancer risk in Chinese IBD patients. Addition of statin/aspirin provided no additional benefit.
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Affiliation(s)
- Joyce Wing Yan Mak
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, New Territories, Hong Kong.,Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, New Territories, Hong Kong
| | - Jacqueline So
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong
| | - Whitney Tang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, New Territories, Hong Kong.,Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, New Territories, Hong Kong
| | - Terry Cheuk Fung Yip
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, New Territories, Hong Kong
| | - Wai Keung Leung
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong
| | - Michael Li
- Department of Medicine and Geriatrics, Tuen Mun Hospital, Tuen Mun, Hong Kong
| | - Fu Hang Lo
- Department of Medicine and Geriatrics, United Christian Hospital, Kwun Tong, Hong Kong
| | - Ka Man Ng
- Department of Medicine and Geriatrics, Princess Margaret Hospital, Lai King, Hong Kong
| | - Shun Fung Sze
- Department of Medicine, Queen Elizabeth Hospital, Jordan, Hong Kong
| | - Chi Man Leung
- Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
| | | | - Edwin Hok Shing Shan
- Department of Medicine and Geriatrics, Caritas Medical Centre, Sham Shui Po, Hong Kong
| | - Kam Hon Chan
- Department of Medicine, North District Hospital, Sheung Shui, Hong Kong
| | - Belsy C Y Lam
- Department of Medicine and Geriatrics, Kwong Wah Hospital, Mongkok, Hong Kong
| | - Aric J Hui
- Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Taipo, Hong Kong
| | - Wai Hung Chow
- Department of Medicine, Yan Chai Hospital, Tsuen Wan, Hong Kong
| | - Francis Ka Leung Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, New Territories, Hong Kong.,Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, New Territories, Hong Kong
| | - Siew Chien Ng
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, New Territories, Hong Kong.,Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, New Territories, Hong Kong
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Mei XL, Zheng QF. Role of Cellular Biomolecules in Screening, Diagnosis and Treatment of Colorectal Cancer. Curr Drug Metab 2019; 20:880-888. [PMID: 31656148 DOI: 10.2174/1389200220666191018153428] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/19/2019] [Accepted: 10/01/2019] [Indexed: 12/24/2022]
Abstract
Background:
Prevention is the primary strategy to avoid the occurrence and mortality of colorectal cancer.
Generally, the concentrations of tumor markers tested during the diagnosis and believed to assist the detection of
disease in the early stages of cancer. Some of the biomarkers are also important during treatment and real-time monitoring
of the progress of treatment.
Methods:
We considered a rationale search of key references from the database of peer-reviewed research and review
literatures of colorectal cancer. The topic of search was focused on the novel methods and modern techniques
of Screening, Diagnosis, and Treatment of colorectal cancer. The screened publications were critically analysed
using a deductive content analysis and the matter was put in separate headings and sub headings.
Results:
It was found that endoscopic examination, early detection, and surgery are some of the common strategies to
manage colorectal cancer because late stages are difficult to treat due to the high-cost requirement and fewer chances
of survival. As far as chemotherapy is concerned, systemic chemotherapy has been shown to offer the maximum
benefit to patients with cancer metastasis. Among different chemotherapy measures, primary colorectal cancer prevention
agents involve pharmaceuticals, phytochemicals, and dietary supplements are some of the standard options.
Conclusion:
In this review article, we have provided a comprehensive analysis of different biomarkers for the detection
of colorectal cancer as well as different formulations developed for efficient treatment of the disease. The use of
dietary supplements, the combinatorial approach, and nanotechnology-based strategies for colorectal cancer diagnosis
and treatment are some of the recent and modern methods of cancer management.
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Affiliation(s)
- Xiang-Lin Mei
- Department of Pathology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Qing-Fan Zheng
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
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Effect of Long-Term Mesalamine Therapy on Cancer-Associated Gene Expression in Colonic Mucosa of Patients with Ulcerative Colitis. Dig Dis Sci 2019; 64:740-750. [PMID: 30478770 DOI: 10.1007/s10620-018-5378-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 11/13/2018] [Indexed: 01/20/2023]
Abstract
BACKGROUND The role of 5-aminosalicylic acid (5-ASA or mesalamine) in the prevention of colorectal cancer in ulcerative colitis (UC) patients was reported, but the effect on molecular targets in UC colon mucosa is unknown. AIM This observational study evaluates gene expression levels of 5-ASA targets using serial colon biopsy specimens from UC patients undergoing long-term 5-ASA therapy. METHODS Transcript levels were compared between colonoscopic biopsy specimens collected from 62 patients at initial and final follow-up colonoscopy at 2-6 years. All patients had mild-to-moderate UC and were undergoing long-term 5-ASA maintenance. Stepwise multiple linear regression analyses were performed to correlate changes in transcript levels with therapeutic response (Mayo clinical score endoscopy and DAI and/or Nancy histopathology score) and nonclinical variables. RESULTS The transcript levels of colorectal carcinogenesis-associated known 5-ASA target genes were significantly reduced after prolonged 5-ASA therapy (P < 0.005-0.03). Multiple linear regression models predicted significant association between transcript levels of Ki-67, NF-kB (p65), PPARγ, COX-2 and IL-8, CDC25A, and CXCL10 with duration of drug (5-ASA) exposure (P ≤ 0.05). Ki-67, NF-kB (p65), and CXCL10 transcripts were also correlated with reduced endoscopy sub-score (P ≤ 0.05). COX-2, IL-8, CDC25A, and TNF transcripts strongly correlated with DAI sub-scores (P ≤ 0.05). Only COX-2 and IL-8 transcript levels correlated (P ≤ 0.05) with Nancy histological score. CONCLUSION This study provides molecular evidence of changes in carcinogenesis-related targets/pathways in colon tissue during long-term 5-ASA maintenance therapy that may contribute to the observed chemopreventive effects of 5-ASA in UC patients.
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9
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Low prevalence of dysplastic polyps in patients with ulcerative colitis. Clin Res Hepatol Gastroenterol 2017; 41:204-209. [PMID: 27838112 DOI: 10.1016/j.clinre.2016.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 09/20/2016] [Accepted: 09/27/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Patients with ulcerative colitis (UC) are prone to colorectal cancer and dysplastic polyps and also have sporadic adenomas. There is scant information, however, relating the prevalence of sporadic adenomas in UC patients compared with normal subjects. The aim of this study was to assess the prevalence of all dysplastic lesions in UC and compare the prevalence of adenomas to that in the general population. METHODS A single-center retrospective study, in which all patients with diagnosed UC were followed during a ten-year period. The incidence of polyps and colorectal cancers were recorded and compared to that of an age-matched group in the general population who had screening colonoscopy. RESULTS A total of 229 UC patients were included compared with 450 age-matched subjects who underwent a single colonoscopy. The average number of colonoscopies per UC patient was 3. The rate of sporadic adenomas among UC patients (9.6%), as well as the rate of all dysplastic polyps (11.2%) in these patients, were significantly lower than the rate of adenomas among the control population (24%; OR 0.33-0.44; P<0.0001). Despite this, the rates of colon cancer were comparable between the groups (2.1% vs. 1.5%, P=0.55). CONCLUSIONS In spite of the observed lower rate of dysplastic polyps in UC patients, this should not preclude tight surveillance in this high-risk population.
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Eo HJ, Kwon TH, Park GH, Song HM, Lee SJ, Park NH, Jeong JB. In Vitro Anticancer Activity of Phlorofucofuroeckol A via Upregulation of Activating Transcription Factor 3 against Human Colorectal Cancer Cells. Mar Drugs 2016; 14:md14040069. [PMID: 27043582 PMCID: PMC4849073 DOI: 10.3390/md14040069] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 03/18/2016] [Accepted: 03/24/2016] [Indexed: 01/08/2023] Open
Abstract
Phlorofucofuroeckol A (PFF-A), one of the phlorotannins found in brown algae, has been reported to exert anti-cancer property. However, the molecular mechanism for the anti-cancer effect of PFF-A has not been known. Activating transcription factor 3 (ATF3) has been reported to be associated with apoptosis in colorectal cancer. The present study was performed to investigate the molecular mechanism by which PFF-A stimulates ATF3 expression and apoptosis in human colorectal cancer cells. PFF-A decreased cell viability through apoptosis of human colorectal cancer cells. PFF-A increased ATF3 expression through regulating transcriptional activity. The responsible cis-element for ATF3 transcriptional activation by PFF-A was cAMP response element binding protein (CREB), located between positions −147 and −85 of the ATF3 promoter. Inhibition of p38, c-Jun N-terminal kinases (JNK), glycogen synthase kinase (GSK) 3β, and IκB kinase (IKK)-α blocked PFF-A-mediated ATF3 expression. ATF3 knockdown by ATF3 siRNA attenuated the cleavage of poly (ADP-ribose) polymerase (PARP) by PFF-A, while ATF3 overexpression increased PFF-A-mediated cleaved PARP. These results suggest that PFF-A may exert anti-cancer property through inducing apoptosis via the ATF3-mediated pathway in human colorectal cancer cells.
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Affiliation(s)
- Hyun Ji Eo
- Department of Bioresource Sciences, Andong National University, Andong 36729, Korea.
| | - Tae-Hyung Kwon
- Chuncheon Bioindustry Foundation, Chuncheon 24234, Korea.
| | - Gwang Hun Park
- Department of Bioresource Sciences, Andong National University, Andong 36729, Korea.
| | - Hun Min Song
- Department of Bioresource Sciences, Andong National University, Andong 36729, Korea.
| | - Su-Jin Lee
- Department of Herbal Medicine Resource, Kangwon National University, Dogye 25949, Korea.
| | - Nyun-Ho Park
- Gyeongbuk Institute for Marine Bioindustry, Uljin 36315, Korea.
| | - Jin Boo Jeong
- Department of Bioresource Sciences, Andong National University, Andong 36729, Korea.
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KAG-308, a newly-identified EP4-selective agonist shows efficacy for treating ulcerative colitis and can bring about lower risk of colorectal carcinogenesis by oral administration. Eur J Pharmacol 2015; 754:179-89. [DOI: 10.1016/j.ejphar.2015.02.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 02/10/2015] [Accepted: 02/11/2015] [Indexed: 12/21/2022]
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12
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Abstract
Colorectal cancer has become one of the most prevalent malignant diseases for both men and women. Patients with inflammatory bowel diseases or certain inherited cancer syndromes are at high risk of developing colorectal cancer and have naturally the highest need for cancer prevention. In familial adenomatous polyposis (FAP) and Lynch syndrome, most of the underlying germline mutations can be detected by DNA sequencing, and medical counselling of affected individuals involves both surveillance tests and chemopreventive measures. However, as the mechanisms leading to colorectal cancer differ in these high-risk groups, the molecular action of chemopreventive drugs needs to be adjusted to the certain pathway of carcinogenesis. In the last decades, a number of drugs have been tested, including sulindac, aspirin, celecoxib, and mesalazine, but some of them are still controversially discussed. This review summarizes the advances and current standards of colorectal cancer prevention in patients with inflammatory bowel disease, FAP and Lynch syndrome.
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Affiliation(s)
- Michaela Lang
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
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13
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The effects of selected drugs and dietary compounds on proliferation and apoptosis in colorectal carcinoma. Contemp Oncol (Pozn) 2014; 18:222-6. [PMID: 25258577 PMCID: PMC4171476 DOI: 10.5114/wo.2014.44296] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 07/15/2014] [Accepted: 07/23/2014] [Indexed: 12/13/2022] Open
Abstract
Like many malignancies, the development of colorectal carcinoma (CRC) can be considered as an imbalance between the compromised process of programmed cell death (apoptosis) and excessive, uncontrolled proliferation. Several mutations and epigenetic alterations are acquired during colorectal carcinogenesis. These are responsible for the cell cycle regulation, cellular sensitivity to pro- and antiapoptotic factors, cell proliferation, angiogenesis, invasiveness, as well as metastatic potential. The molecular alterations, along with their morphological expressions, have been recognised in detail, and most of the CRC cases can be attributed to either adenoma-carcinoma or serrated neoplasia pathways: in the first, the antiapoptotic features prevail; while in the second, the proliferative activity is of the utmost importance. The aim of the work is to discuss the influence of selected drugs and dietary compounds on the proliferation and apoptosis in CRC.
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Bafutto M, Almeida JRD, Leite NV, Costa MBG, Oliveira ECD, Resende-Filho J. Treatment of diarrhea-predominant irritable bowel syndrome with mesalazine and/or Saccharomyces boulardii. ARQUIVOS DE GASTROENTEROLOGIA 2014; 50:304-9. [PMID: 24474234 DOI: 10.1590/s0004-28032013000400012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 06/25/2013] [Indexed: 11/22/2022]
Abstract
CONTEXT Irritable bowel syndrome (IBS) is a functional bowel disease characterized by abdominal pain and altered intestinal habits. The pathophysiology of IBS remains unclear. Recent studies have demonstrated that some IBS patients, especially in diarrhea-predominant IBS (IBS-D), display persistent signs of minor mucosal inflammation and a modified intestinal microflora. The mesalazine has known intestinal anti-inflammatory properties. Saccharomyces boulardii is a probiotic used for a long time in treatment of diarrhea, including infectious diarrhea. OBJECTIVE Evaluate the effects of mesalazine alone, combined therapy of mesalazine with liophylised Saccharomyces boulardii or alone on symptoms of IBS-D patients. METHODS Based on Rome III criteria, 53 IBS-D patients (18 year or more) were included. To exclude organic diseases all patients underwent colonoscopy, stool culture, serum anti-endomisium antibody, lactose tolerance test and ova and parasite exam. Patients were divided in three groups: mesalazine group (MG) - 20 patients received mesalazine 800 mg t.i.d. for 30 days; mesalazine and Saccharomyces boulardii group (MSbG) - 21 patients received mesalazine 800 mg t.i.d. and Saccharomyces boulardii 200 mg t.i.d. for 30 days and; Saccharomyces boulardii group (SbG) - 12 patients received Sb 200 mg t.i.d. for 30 days. Drugs that might have any effect on intestinal motility or secretion were not allowed. Symptom evaluations at baseline and after treatment were performed by means of a 4-point likert scale including: stool frequency, stool form and consistency (Bristol scale), abdominal pain and distension. Paired t test and Kruskal-Wallis test were used for statistical analyses. RESULTS Compared to baseline, there were statistically significant reduction of symptom score after 30 th day therapy in all three groups: MG (P<0.0001); MSbG (P<0.0001) and in SbG (P = 0.003). There were statistically significant differences in the symptom score at 30 th day therapy of the MG, MSbG and SbG groups (P = 0.03). There were no statistical differences between MSbG and MG symptom score at 30th day therapy (P = 0.9). CONCLUSIONS The use of mesalazine alone, Saccharomyces boulardii alone or combined treatment with mesalasine and Saccaromyces boulardii improved IBS-D symptoms. The improvement of the symptom score was greater with mesalazine alone or combined with Sb as compared with Sb treatment alone. These preliminary results suggest that mezalazine may be useful in treatment of IBS-d patients, and warrant further larger studies.
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Affiliation(s)
- Mauro Bafutto
- Instituto Goiano de Gastroenterologia, GoiâniaGO, Brasil
| | - José Roberto de Almeida
- Departamento de Medicina Clínica, Faculdade de Medicina, Universidade Federal de Pernambuco (UFPE), RecifePE, Brasil
| | | | | | - Enio Chaves de Oliveira
- Departamento de Medicina Clínica, Faculdade de Medicina, Universidade Federal de Pernambuco (UFPE), RecifePE, Brasil
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15
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Oz HS, Chen T, de Villiers WJS. Green Tea Polyphenols and Sulfasalazine have Parallel Anti-Inflammatory Properties in Colitis Models. Front Immunol 2013; 4:132. [PMID: 23761791 PMCID: PMC3672863 DOI: 10.3389/fimmu.2013.00132] [Citation(s) in RCA: 139] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 05/21/2013] [Indexed: 12/21/2022] Open
Abstract
Background: There is no cure for autoimmune chronic inflammatory bowel disease (IBD). IBD patients commonly use complementary and alternative medications of which the safety, efficacy, and interaction with standard-of-care therapies are not fully known. Thus the consequences can become life-threatening. Sulfasalazine commonly used in IBD, potentially has severe adverse effects, including infertility, pulmonary fibrosis, lack of response, and ultimately patients may require intestinal resection. We hypothesized that green tea polyphenols (GrTP, EGCG) and sulfasalazine have similar anti-inflammatory properties. Methods: BALB/c mice received Dextran sodium sulfate (DSS) to induce colitis (ulcerative colitis model). Exposure of IL-10 deficient mice (BALB/c-background) to normal microbiota provoked enterocolitis (mimics Crohn’s disease). Animals were treated with agents incorporated into daily diets. Control animals received sham treatment. Results: DSS-treated animals developed severe bloody diarrhea and colitis (score 0–4, 3.2 ± 0.27). IL-10 deficient mice developed severe enterocolitis as manifested by diarrhea, rectal prolapse, and colonic lesions. Animals tolerated regimens (GrTP, EGCG, sulfasalazine) with no major side effects, and further developed less severe colitis. IL-10 deficient animals became moribund on high dose, while tolerated low and Mid doses with significant improved symptoms of enterocolitis. GrTP, EGCG, and sulfasalazine significantly ameliorated colonic damage and histological scores in treated animals in a similar manner (GrTP vs. DSS p < 0.05; EGCG, sulfasalazine vs. DSS p < 0.01). The inflammatory markers TNFα (3-fold), IL-6 (14-fold), and serum amyloid A (40-fold) increased in colitic animals and significantly decreased with treatment regiments. In contrast, circulatory leptin levels decreased in colitic animals (twofold). EGCG additionally reduced leptin levels (p < 0.01) while GrTP and sulfasalazine had no effect on leptin levels (p < 0.05). Hepatic and colonic antioxidants were significantly depleted in colitic animals and treatment regiments significantly restored antioxidants levels. Conclusion: GrTP and EGCG improved antioxidants levels and attenuated severity of colitis analogous to sulfasalazine. Future studies will reveal whether polyphenols can become an alternative/additive therapy for IBD therapy in humans.
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Affiliation(s)
- Helieh S Oz
- Department of Internal Medicine, University of Kentucky Medical Center , Lexington, KY , USA
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16
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Abstract
5-aminosalicylates (5-ASA) are widely used to treat patients with ulcerative colitis. Experimental data suggest that these agents can potentially be used in a chemopreventive fashion to inhibit the development of colitis-associated colorectal cancer (CRC); however, observational studies investigating a possible risk reduction of CRC by 5-ASA therapy have revealed conflicting results. Currently, it appears that 5-ASA have no or only a very limited effect as a deterrence against CRC. Thus, a general recommendation for long-term use of 5-ASA solely for chemopreventive measures is not warranted.
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Affiliation(s)
- Hans Herfarth
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC 27599, USA.
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17
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Colorectal cancer chemoprevention by mesalazine and its derivatives. J Biomed Biotechnol 2012; 2012:980458. [PMID: 22701310 PMCID: PMC3373216 DOI: 10.1155/2012/980458] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 04/20/2012] [Indexed: 01/12/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) face an increased lifetime risk of developing colorectal cancer (CRC). Independent factors associated with increased risk include long disease duration, extensive colonic involvement, young age at onset of IBD, severity of inflammation, primary sclerosing cholangitis, backwash ileitis, and a family history of CRC, thus emphasising the role of intestinal inflammation as an underlying mechanism. This notion is also supported by the demonstration that the use of certain drugs used to attenuate the ongoing mucosal inflammation, such as mesalazine, seems to associate with a reduced incidence of colitis-associated CRC. In the last decade, work from many laboratories has contributed to delineate the mechanisms by which mesalazine alters CRC cell behaviour. In this paper, we review the available experimental data supporting the ability of mesalazine and its derivatives to interfere with intracellular signals involved in CRC cell growth.
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18
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Munding J, Ziebarth W, Pox CP, Ladigan S, Reiser M, Hüppe D, Brand L, Schmiegel W, Tannapfel A, Reinacher-Schick AC. The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the β-catenin signaling pathway. Carcinogenesis 2011; 33:637-43. [PMID: 22198215 DOI: 10.1093/carcin/bgr306] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients. The current study analyses the effect of 5-ASA on Wnt/β-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a β-catenin/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo-controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of β-catenin and target genes Cox2, cyclin D1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low-risk and a high-risk group according to the number of adenomas at initial colonoscopy. ß-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in ß-catenin levels. Moreover, 5-ASA significantly reduced ß-catenin levels and nuclear localization in patients' adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 and E-cadherin, correlating with ß-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment. Our study shows a significant in vitro and long-term in vivo effect of 5-ASA on ß-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma.
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Affiliation(s)
- Johanna Munding
- Institute of Pathology, Ruhr-University Bochum, D-44789, Germany.
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19
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Bafutto M, Almeida JRD, Leite NV, Oliveira EC, Gabriel-Neto S, Rezende-Filho J. Treatment of postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome with mesalazine. ARQUIVOS DE GASTROENTEROLOGIA 2011; 48:36-40. [PMID: 21537540 DOI: 10.1590/s0004-28032011000100008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Accepted: 07/28/2010] [Indexed: 12/22/2022]
Abstract
CONTEXT Recent studies support the hypothesis that postinfectious irritable bowel syndrome and some irritable bowel syndrome patients display persistent signs of minor mucosal inflammation. Mesalazine has intestinal anti-inflammatory properties including cyclooxygenase and prostaglandin inhibition. The effects of mesalazine on postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome patients are still unknown. OBJECTIVE To observe the effects of mesalazine on postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome with diarrhea patients. METHODS Based on Rome III criteria, 61 irritable bowel syndrome with diarrhea patients (18 years old or more) were included in the evaluation. Patients were divided into two groups: postinfectious irritable bowel syndrome group, with 18 patients medicated with mesalazine 800 mg 3 times a day for 30 days; noninfective irritable bowel syndrome group, with 43 patients medicated with mesalazine 800 mg 3 times a day for 30 days. Symptom evaluations at baseline and after treatment were performed by means of a four-point Likert scale including stool frequency, stool form and consistency (Bristol Stool Scale), abdominal pain and distension (maximum score: 16; minimum score: 4). RESULTS Postinfectious irritable bowel syndrome group presented a statistically significant reduction of the total symptom score (P<0.0001). The stool frequency was significantly reduced (P<0.0001), and stool consistency, improved (P<0.0001). Abdominal pain (P<0.0001) and abdominal distension were significantly reduced (P<0.0001). Noninfective irritable bowel syndrome group presented a statistically significant reduction of total symptom score (P<0.0001). Also, the stool frequency was significantly reduced (P<0.0001) and stool consistency, improved (P<0.0001). Abdominal pain (P<0.0001) and abdominal distention were significantly reduced (P<0.0001). There was no statistical difference between postinfectious irritable bowel syndrome group and noninfective irritable bowel syndrome group on total symptom score results at 30th day of therapy with mesalazine 800 mg 3 times a day. (P = 0.13). CONCLUSION Mesalazine reduced key symptoms of postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome with diarrhea patients.
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Affiliation(s)
- Mauro Bafutto
- Disciplina de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Goiás.
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20
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Campregher C, Gasche C. Aminosalicylates. Best Pract Res Clin Gastroenterol 2011; 25:535-46. [PMID: 22122769 DOI: 10.1016/j.bpg.2011.10.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 08/21/2011] [Accepted: 10/27/2011] [Indexed: 02/08/2023]
Abstract
Aminosalicylates are the most common drugs for the primary treatment of inflammatory bowel disease. Various pro-drugs and formulations were developed in order to improve pharmacological profiles, optimize bioavailability and to gain highest efficacy in the treatment of ulcerative colitis (UC) and Crohn's disease. In vitro studies have greatly contributed to the understanding of the molecular actions in vivo and clinical studies have proven aminosalicylates to be effective and safe. This review summarizes the current knowledge on the molecular, pharmacological and clinical properties of aminosalicylates with respect to chemoprevention for UC-associated colorectal cancer.
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Affiliation(s)
- Christoph Campregher
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria
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21
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Mattar MC, Lough D, Pishvaian MJ, Charabaty A. Current management of inflammatory bowel disease and colorectal cancer. GASTROINTESTINAL CANCER RESEARCH : GCR 2011; 4:53-61. [PMID: 21673876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 09/07/2009] [Accepted: 04/06/2010] [Indexed: 09/28/2022]
Abstract
INFLAMMATORY BOWEL DISEASES (IBDS) CAN BE DIVIDED INTO TWO MAJOR DISORDERS: ulcerative colitis and Crohn's disease. Although IBD-associated colorectal cancer (IBD-CRC) accounts for only 1-2% of all cases of colorectal cancer, IBD with colon involvement is among the top three high-risk conditions for colorectal cancer. Today, colorectal cancer accounts for approximately 10-15% of all deaths among IBD patients. Indeed, patients with IBD colitis are six times more likely to develop colorectal cancer than the general population and have a higher frequency of multiple synchronous colorectal cancers. Since IBD-CRC was first described in 1925, the colon remains the primary site of neoplasms in IBD patients today. Ulcerative colitis-associated colorectal cancer is most common in the rectum and sigmoid colon, whereas Crohn's disease-associated colorectal cancer is evenly distributed between the different colon segments. Chemoprevention of colorectal cancer remains an important goal, and colonoscopy surveillance programs are critical to early detection in these patients. Newer methods, such as chromoendoscopy, are currently being investigated as complementary techniques to enhance early detection of dysplasia and cancer in this high-risk population. We present a comprehensive review of the relationship between inflammatory bowel disease and colorectal cancer. Major themes covered include risk factors for IBD-CRC and the molecular pathobiology of progression from dysplasia to cancer, endoscopic surveillance and new methods for early detection of dysplasia, approaches to prevention of IBD-CRC, and current recommendations and controversies regarding the treatment of dysplasia. In particular, disagreement has arisen over optimal management of low-grade dysplasia, with some IBD experts now advocating close colonoscopic surveillance of patients with low-grade dysplasia rather then total colectomy.
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Jiang GL, Im WB, Donde Y, Wheeler LA. Comparison of prostaglandin E2 receptor subtype 4 agonist and sulfasalazine in mouse colitis prevention and treatment. J Pharmacol Exp Ther 2010; 335:546-52. [PMID: 20833794 DOI: 10.1124/jpet.110.173252] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
Prodrugs of 5-aminosalicylic acid (5-ASA), such as sulfasalazine, have been the mainstay for the treatment and maintenance of inflammatory bowel disease (IBD) for decades, which is attributable to their antiadaptive immune activity. However, 5-ASA compromises regeneration of intestinal epithelia and induces apoptosis. The majority of patients eventually undergo colectomy. Agonists for the prostaglandin E(2) subtype 4 (EP4) receptor have been shown to protect epithelial barrier against colitis-inducing agents and could be valuable alternatives for sulfasalazine. Here, we compared sulfasalazine and a novel EP4 agonist for their abilities to prevent colitis induction and relieve symptoms of established colitis in a dextran sulfate sodium-indomethacin mouse model. The EP4 agonist dose-dependently alleviated weight loss in colitis mice. Compared with sulfasalazine at 100 mg/kg on the colitis induction model, the EP4 agonist at 0.2 mg/kg was superior in reducing colitis symptoms, preventing increase of innate immune cells, and ameliorating inflammation in colon. In mice with established colitis, sulfasalazine quickly reversed weight loss but with fading efficacy. The EP4 agonist, in contrast, had slow but sustained effects on body weight gain and was more efficacious in epithelial regeneration. Such temporal differences between sulfasalazine and the EP4 agonist actions seemingly led to no additive effect in combination therapy. In conclusion, the EP4 agonist would be more efficacious in the maintenance of remission because of both anti-innate immune responses and epithelial regeneration activity, whereas sulfasalazine would be more suitable for induction of remission because of its rapid onset of antiadaptive inflammation action.
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Affiliation(s)
- Guang-Liang Jiang
- Research and Development, Allergan Pharmaceuticals, Inc, 2525 Dupont Dr, Irvine, California 92612.
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23
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Campregher C, Luciani MG, Biesenbach P, Evstatiev R, Lyakhovich A, Gasche C. The position of the amino group on the benzene ring is critical for mesalamine's improvement of replication fidelity. Inflamm Bowel Dis 2010; 16:576-82. [PMID: 19821510 DOI: 10.1002/ibd.21112] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND Individuals with ulcerative colitis are at high risk of developing colitis-associated cancer. 5-Aminosalicylate (5-ASA) protects from cancer by its antiinflammatory activity as well as by altering cell growth, inducing apoptosis, and reducing replication errors. So far neither 5-ASA's structural specificity nor its pharmacophore group have been identified. Here we compared 5-ASA with its analogs (4-ASA and 3-ASA) and its metabolite N-acetyl-5-ASA (NAc-5-ASA). METHODS Superoxide scavenging was analyzed by lucigenin-amplified chemiluminescence. Cell growth, cell cycle distribution, and replication fidelity at a (CA)13 microsatellite were measured in HCT116 and HT29 colon epithelial cells by MTT and flow cytometry. Nuclear protein extracts were blotted for replication protein A (RPA), claspin, p53, and p53(Ser15). RESULTS All compounds inhibited the growth of colon epithelial cells at a similar level and displayed potent scavenging properties, with 3-ASA being the most active, followed by 5-ASA, 4-ASA, and NAc-5-ASA. Besides 5-ASA, only 4-ASA caused an increase in the S-phase population (56%-69% and 49%-62% in HCT116 and HT29 cells, respectively). This was accompanied by nuclear recruitment of replication proteins RPA and claspin as well as phosphorylation of p53(Ser15), both of which were weaker or absent with 3-ASA or NAc-5-ASA. 5-ASA was the only compound that lowered mutations at a (CA)13 microsatellite. CONCLUSIONS 5-ASA shares its growth inhibitory and superoxide scavenging properties with its structural analogs and metabolite, but the position of the amino group is critical for reducing replication errors.
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Affiliation(s)
- Christoph Campregher
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, and Christian Doppler Laboratory on Molecular Cancer Chemoprevention, Vienna, Austria
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Koelink PJ, Mieremet-Ooms MAC, Corver WE, Wolanin K, Hommes DW, Lamers CBHW, Verspaget HW. 5-aminosalicylic acid interferes in the cell cycle of colorectal cancer cells and induces cell death modes. Inflamm Bowel Dis 2010; 16:379-89. [PMID: 19774649 DOI: 10.1002/ibd.21086] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Epidemiological data suggests that 5-aminosalicylic acid (5-ASA), a nonsteroidal antiinflammatory drug used in the treatment of inflammatory bowel diseases, prevents colorectal cancer development in these patients, although the mechanisms remain incompletely understood. METHODS AND RESULTS Here we report that 5-ASA prevents growth of several colorectal cancer cell lines by interfering in the cell cycle, i.e., an S-phase and G2/M phase arrest, dependent on 5-ASA dosage and concentration, together with an increased mitotic index. In addition, prolonged cell cycle arrest by repeated 5-ASA treatment induced apoptosis and caused abnormal spindle organization leading to mitotic catastrophe, another form of cell death. CONCLUSION These observations illustrate that 5-ASA has chemopreventive and chemotherapeutic properties.
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Affiliation(s)
- Pim J Koelink
- Department of Gastroenterology and Hepatology, and Leiden University Medical Center, Leiden, The Netherlands
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Low A, Love M, Walt R, Kane K, Eksteen B, Goh J. Understanding of chemoprophylaxis and concordance in inflammatory bowel disease. World J Gastroenterol 2010; 16:578-82. [PMID: 20128025 PMCID: PMC2816269 DOI: 10.3748/wjg.v16.i5.578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess patients’ understanding for the reasons for taking 5-aminosalicylic acid or ursodeoxycholic acid as chemoprophylaxis against colorectal carcinoma associated with inflammatory bowel disease (IBD).
METHODS: A questionnaire-based study using a 5-point opinion scale was performed. One hundred and ninety-two patients with colitis only and 74 patients with primary sclerosing cholangitis and IBD were invited to take part.
RESULTS: Overall response rate was 58%. Sixty-four percent of patients claimed full concordance with chemoprophylaxis for maintenance of remission. Eighty-four percent of patients considered daily concordance during remission to be very important. Seventy-five percent stated they understood the reasons for taking the drugs. However, only 50% of the patients were aware of any link of their condition to bowel cancer. Seventy-nine percent of patients felt their concordance and understanding would be improved if they were informed of the chemoprophylactic potential of the medication.
CONCLUSION: Despite good self-reported concordance, half of the patients were unaware of an association between colitis and bowel cancer. Explaining the potential chemoprophylactic benefits may enhance patients’ overall concordance to 5-aminosalicylic acid and ursodeoxycholic acid and help maintain remission.
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Brown JB, Lee G, Managlia E, Grimm GR, Dirisina R, Goretsky T, Cheresh P, Blatner NR, Khazaie K, Yang GY, Li L, Barrett TA. Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis. Gastroenterology 2010; 138:595-605, 605.e1-3. [PMID: 19879273 PMCID: PMC2819654 DOI: 10.1053/j.gastro.2009.10.038] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2009] [Revised: 09/21/2009] [Accepted: 10/20/2009] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Mesalamine is a mainstay therapeutic agent in chronic ulcerative colitis (CUC) in which condition it reverses crypt architectural changes and reduces colitis-associated cancer (CAC). The present study addressed the possibility that mesalamine reduces beta-catenin-associated progenitor cell activation, Akt-phosphorylated beta-catenin(Ser552) (P-beta-catenin), and colitis-induced dysplasia (CID). METHODS Effects of mesalamine on P-beta-catenin staining and function were assessed by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in biopsy specimens of CUC in mild or "refractory" severe mucosal inflammation. Effects of mesalamine on epithelial proliferation and activation of Akt and beta-catenin were assessed in interleukin (IL)-10(-/-) colitis and CID by immunohistochemistry and Western blotting. Dysplasia was assessed by counting the number and lengths of lesions per colon. RESULTS Data from IL-10(-/-) and human colitis samples show that mesalamine reduced Akt activation and P-beta-catenin levels in the middle and upper crypt. Reductions in P-beta-catenin in CUC biopsy specimens with severe inflammation suggested that mesalamine reduced P-beta-catenin levels in tissue refractory to mesalamine's anti-inflammatory effects. In IL-10(-/-) mice, mesalamine reduced CID concordant with inhibition of crypt Akt and beta-catenin signaling. CONCLUSIONS The results are consistent with the model that mesalamine contributes to chemoprevention in CAC by reducing beta-catenin signaling within intestinal progenitors.
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Affiliation(s)
- Jeffrey B. Brown
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children’s Memorial Hospital, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
| | - Goo Lee
- Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
| | - Elizabeth Managlia
- Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
| | - Gery R. Grimm
- Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
| | - Ramanarao Dirisina
- Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
| | - Tatiana Goretsky
- Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
| | - Paul Cheresh
- Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
| | - Nichole R. Blatner
- Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
| | - Khashayarsha Khazaie
- Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
| | - Linheng Li
- Stowers Institute for Medical Research, Kansas City, MO, 64110, U.S.A
| | - Terrence A. Barrett
- Division of Gastroenterology, Northwestern University, Feinberg School of Medicine, Chicago, U.S.A
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Kübler I, Koslowski MJ, Gersemann M, Fellermann K, Beisner J, Becker S, Rothfuss K, Herrlinger KR, Stange EF, Wehkamp J. Influence of standard treatment on ileal and colonic antimicrobial defensin expression in active Crohn's disease. Aliment Pharmacol Ther 2009; 30:621-33. [PMID: 19549264 DOI: 10.1111/j.1365-2036.2009.04070.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Crohn's Disease (CD), a chronic intestinal inflammation, is currently treated primarily by therapeutics which are directed against inflammatory responses. Recent findings though suggest a central role of the innate immune barrier in the pathophysiology. Important factors providing this barrier are antimicrobial peptides like the alpha- and beta-defensins. Little is known about in vivo effects of common drugs on their expression. AIM To analyse the influence of corticosteroids, azathioprine and aminosalicylate treatment on ileal and colonic antimicrobial peptides in active CD and also assess the role of inflammation. METHODS We measured the expression of antimicrobial peptides and pro-inflammatory cytokines in 75 patients with active CD. RESULTS Ileal and colonic alpha- and beta-defensins as well as LL37 remained unaffected by corticosteroids, azathioprine or aminosalicylate treatment. Additionally, we did not observe a negative coherency between Paneth cell alpha-defensins and any measured cytokines. HBD2 and LL37 unlike HBD1 levels were linked to inflammatory cytokines and increased in highly inflamed samples. CONCLUSIONS Current oral drug treatment seems to have no major effect on the expression of antimicrobial peptides. In contrast to HBD2 and LL37, ileal levels of HD5 and HD6 and colonic HBD1 level are independent of current inflammation. Innovative drugs should aim to strengthen protective innate immunity.
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Affiliation(s)
- I Kübler
- Robert-Bosch-Hospital, Stuttgart, Germany
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Abstract
OBJECTIVES Colorectal cancer (CRC) is a feared complication of chronic ulcerative colitis (UC). Annual endoscopic surveillance is recommended for the detection of early neoplasia. 5-Aminosalicylates (5-ASAs) may prevent some UC-associated CRC. Therefore, in patients prescribed 5-ASAs for maintenance of remission, annual surveillance might be overly burdensome and inefficient. We aimed to determine the ideal frequency of surveillance in patients with UC maintained on 5-ASAs. METHODS We performed systematic reviews of the literature, and created a Markov computer model simulating a cohort of 35-year-old men with chronic UC, followed until the age of 90 years. Twenty-two strategies were modeled: natural history (no 5-ASA or surveillance), surveillance without 5-ASA at intervals of 1-10 years, 5-ASA plus surveillance every 1-10 years, and 5-ASA alone. The primary outcome was the ideal interval of surveillance in the setting of 5-ASA maintenance, assuming a third-party payer was willing to pay $100,000 for each quality-adjusted life-year (QALY) gained. RESULTS In the natural history strategy, the CRC incidence was 30%. Without 5-ASA, annual surveillance was the ideal strategy, preventing 89% of CRC and costing $69,100 per QALY gained compared with surveillance every 2 years. 5-ASA alone prevented 49% of CRC. In the setting of 5-ASA, surveillance every 3 years was ideal, preventing 87% of CRC. 5-ASA with surveillance every 2 years cost an additional $147,500 per QALY gained, and 5-ASA with annual surveillance cost nearly $1 million additional per QALY gained compared with every 2 years. In Monte Carlo simulations, surveillance every 2 years or less often was ideal in 95% of simulations. CONCLUSIONS If 5-ASA is efficacious chemoprevention for UC-associated CRC, endoscopic surveillance might be safely performed every 2 years or less often. Such practice could decrease burdens to patients and on endoscopic resources with a minimal decrease in quality-adjusted length of life, because 5-ASA with annual surveillance may cost nearly $1 million per additional QALY gained.
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Das KK, Bajpai M, Kong Y, Liu J, Geng X, Das KM. Mesalamine suppresses the expression of TC22, a novel tropomyosin isoform associated with colonic neoplasia. Mol Pharmacol 2009; 76:183-91. [PMID: 19369484 PMCID: PMC2701462 DOI: 10.1124/mol.109.056028] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2009] [Accepted: 04/07/2009] [Indexed: 01/06/2023] Open
Abstract
Although a protective role for mesalamine against colon cancer in ulcerative colitis has been shown epidemiologically, its molecular mechanism is unknown. We cloned and sequenced a novel human tropomyosin (hTM) isoform, TC22, which is an alternatively spliced variant of normal epithelial hTM isoform 5 (hTM5), identical apart from 25 C-terminal amino acids. TC22 is expressed in 100% of colorectal carcinoma but is not expressed in normal colon epithelial cells. To explore a molecular mechanism of chemoprevention, we examined the effect of mesalamine on TC22 expression using LS180 colon cancer cells. Expression of hTM5 and TC22 was investigated at the protein and gene levels by fluorescence-activated cell sorting and real-time reverse transcription-polymerase chain reaction. Small interference RNA (siRNA) against the TC22 variant were transfected into LS180 colon cancer cells, reducing protein and transcript levels by 45 to 50%. Mesalamine or sulfasalazine (2 mM), but not sulfapyridine, significantly (p < 0.02-0.006) reduced the expression of the TC22 transcript and significantly (p < 0.05 to <0.0002) reduced the expression of TC22 protein in a dose-dependent and reversible manner. Rosiglitazone, a specific peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, similarly and significantly (p < 0.002) reduced TC22 protein expression. A polymerase chain reaction array of 84 cancer-related genes performed on TC22 siRNA-transfected cells demonstrated a significant (more than two times) change in targets involved in apoptosis, adhesion, angiogenesis, and tissue remodeling. We conclude that mesalamine, sulfasalazine, and rosiglitazone significantly reduced the cellular expression of TC22, implicating PPARgamma in this modulation. Similar suppression of TC22 by siRNA produced gene level changes on several critical carcinogenic pathways. These findings suggest a novel antineoplastic molecular effect of mesalamine.
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Affiliation(s)
- Koushik K Das
- Crohn's and Colitis Center of New Jersey, Division of Gastroenterology and Hepatology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
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Johnson IT. Mechanisms and anticarcinogenic effects of diet-related apoptosis in the intestinal mucosa. Nutr Res Rev 2009; 14:229-56. [DOI: 10.1079/nrr200128] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Schwab M, Reynders V, Steinhilber D, Stein J. Combined treatment of Caco-2 cells with butyrate and mesalazine inhibits cell proliferation and reduces Survivin protein level. Cancer Lett 2008; 273:98-106. [PMID: 18774638 DOI: 10.1016/j.canlet.2008.07.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2008] [Revised: 07/28/2008] [Accepted: 07/28/2008] [Indexed: 01/16/2023]
Abstract
There is epidemiological evidence, that mesalazine can inhibit colon cancer development by affecting proliferation and apoptosis. Several studies suggest that supplementary intake of butyrate may yield to improved efficacy of mesalazine. However, the underlying molecular mechanisms of such interaction remain unknown. This study addressed the combinatory effect of both substances on the growth of Caco-2 cells. Challenging of cells with mesalazine and butyrate provoked a time-dependent decrease in both cell counts and proliferation. Co-treatment with the substances could further intensify these effects. The growth-inhibitory action of mesalazine and butyrate was accompanied by a significant increase in caspase-3 activity, cleavage of PARP and caspase-8, while decreasing the expression of Xiap and Survivin simultaneously. Co-incubation of both substances exaggerated effects on all examined apoptosis-regulatory proteins except for Xiap. Our data demonstrate that co-treatment of mesalazine and butyrate evoked additive effects on inhibition of cell growth and induction of apoptosis in Caco-2 cells.
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Affiliation(s)
- Markus Schwab
- First Department of Medicine-ZAFES, Division of Gastroenterology, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
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Tursi A, Brandimarte G, Elisei W, Giorgetti GM, Inchingolo CD, Aiello F. Effect of mesalazine on epithelial cell proliferation in colonic diverticular disease. Dig Liver Dis 2008; 40:737-42. [PMID: 18387861 DOI: 10.1016/j.dld.2008.02.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2007] [Revised: 12/25/2007] [Accepted: 02/18/2008] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Increased epithelial cell proliferation may be detected in diverticular disease, but antibiotics have failed in reducing it. We assess therefore the effect of mesalazine on epithelial cell proliferation in diverticular disease. METHODS A prospective study was conducted on 20 consecutive patients with a new endoscopic diagnosis of symptomatic uncomplicated diverticular disease. The patients were treated with mesalazine 1.6 mg/day for 1 year. The Ki-67 antigen index of the whole crypt and in the upper third was separately evaluated before and after starting the treatment. RESULTS Cell proliferation index was higher in diverticular disease patients than healthy controls both in the whole crypt (median 6.7%, range 2-9% vs. median 1.6%, range 1-3%, p=0.001) and in the upper third of the crypt (median 6.8%, range 2-8% vs. median 1.8%, range 1-3%, p=0.001). Cell proliferation decreased throughout the follow-up. In the whole crypt it was 6.7% at entry and 3.8% at the end of treatment (p<0.005), whereas it was 6.8% at entry and 2.9% at the end of treatment in the upper third of the crypt (p<0.005). CONCLUSIONS We found mesalazine effective in reducing the colonic cell proliferation in long-term treatment for colonic diverticular disease.
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Affiliation(s)
- A Tursi
- Digestive Endoscopy Unit, Lorenzo Bonomo Hospital, Via Torino, 49, 70031 Andria, BA, Italy.
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Stolfi C, Pellegrini R, Franzè E, Pallone F, Monteleone G. Molecular basis of the potential of mesalazine to prevent colorectal cancer. World J Gastroenterol 2008; 14:4434-9. [PMID: 18680220 PMCID: PMC2731267 DOI: 10.3748/wjg.14.4434] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Patients with ulcerative colitis (UC) and Crohn's disease (CD) are at increased risk for developing colorectal cancer (CRC), and this is believed to be a result of chronic inflammation. Although conclusive evidence is still missing, both epidemiological and experimental observations suggest that certain drugs used to treat inflammation, such as mesalazine, can reduce the incidence of colitis-associated CRC. Therefore, in recent years, several studies have been conducted to dissect the mechanisms by which mesalazine interferes with CRC cell growth and survival. This review summarizes the current information on the molecular mechanisms that underlie the antineoplastic action of mesalazine.
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Schwab M, Reynders V, Loitsch S, Shastri YM, Steinhilber D, Schröder O, Stein J. PPARgamma is involved in mesalazine-mediated induction of apoptosis and inhibition of cell growth in colon cancer cells. Carcinogenesis 2008; 29:1407-14. [PMID: 18544567 DOI: 10.1093/carcin/bgn118] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Mesalazine has been identified as a candidate chemopreventive agent in colon cancer prophylaxis because of its pro-apoptotic and anti-proliferative effects. However, the precise mechanisms of action are not entirely understood. The aim of our study was to investigate the involvement of peroxisome proliferator-activated receptor gamma (PPARgamma) in mesalazine's anticarcinogenic actions in colorectal cancer cells. EXPERIMENTAL DESIGN The effects of mesalazine on cell cycle distribution, cell count, proliferation and caspase-mediated apoptosis were examined in Caco-2, HT-29 and HCT-116 cells used as wild-type, dominant-negative PPARgamma mutant and empty vector cultures. We focused on caspase-3 activity, cleavage of poly(ADP-ribose) polymerase (PARP), caspase-8 and caspase-9, as well as on expression of survivin, X-linked inhibitor of apoptosis (Xiap), phosphatase and tensin homolog deleted from chromosome ten (PTEN) and c-Myc. Techniques employed included transfection assays, immunoblotting, flow cytometry analysis, colorimetric and fluorometric assays. RESULTS Mesalazine caused a time- and dose-dependent decrease in both cell growth and proliferation. Growth inhibition was accompanied by a G1/G0 arrest, a significant increase in PTEN, caspase-3 activity, cleavage of PARP and caspase-8, whereas the expressions of Xiap, survivin and c-Myc were decreased simultaneously. Cleavage of caspase-9 was not observed. Moreover, PPARgamma expression and activity were elevated. The growth-inhibitory effect of mesalazine was partially reduced in dominant-negative PPARgamma mutant cells, whereas the expression of c-Myc was not affected. Mesalazine-mediated increased caspase-3 activity, the expression of PTEN, cleavage of PARP and caspase-8 as well as reduced levels of survivin and Xiap were completely abolished in the PPARgamma mutant cell lines. CONCLUSION This study clearly demonstrates that mesalazine-mediated pro-apoptotic and anti-proliferative actions are regulated via PPARgamma-dependent and -independent pathways in colonocytes.
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Affiliation(s)
- Markus Schwab
- First Department of Medicine-ZAFES, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
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VSL#3 probiotic upregulates intestinal mucosal alkaline sphingomyelinase and reduces inflammation. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2008; 22:237-42. [PMID: 18354751 DOI: 10.1155/2008/520383] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Alkaline sphingomyelinase, an enzyme found exclusively in bile and the intestinal brush border, hydrolyzes sphingomyelin into ceramide, sphingosine and sphingosine-1-phosphate, thereby inducing epithelial apoptosis. Reduced levels of alkaline sphingomyelinase have been found in premalignant and malignant intestinal epithelia and in ulcerative colitis tissue. Probiotic bacteria can be a source of sphingomyelinase. OBJECTIVE To determine the effect of VSL#3 probiotic therapy on mucosal levels of alkaline sphingomyelinase, both in a mouse model of colitis and in patients with ulcerative colitis. METHODS Interleukin-10 gene-deficient (IL10KO) and wild type control mice were treated with VSL#3 (10(9) colony-forming units per day) for three weeks, after which alkaline sphingomyelinase activity was measured in ileal and colonic tissue. As well, 15 patients with ulcerative colitis were treated with VSL#3 (900 billion bacteria two times per day for five weeks). Alkaline sphingomyelinase activity was measured through biopsies and comparison of ulcerative colitis disease activity index scores obtained before and after treatment. RESULTS Lowered alkaline sphingomyelinase levels were seen in the colon (P=0.02) and ileum (P=0.04) of IL10KO mice, as compared with controls. Treatment of these mice with VSL#3 resulted in upregulation of mucosal alkaline sphingomyelinase activity in both the colon (P=0.04) and the ileum (P=0.01). VSL#3 treatment of human patients who had ulcerative colitis decreased mean (+/- SEM) ulcerative colitis disease activity index scores from 5.3+/-1.8946 to 0.70+/-0.34 (P=0.02) and increased mucosal alkaline sphingomyelinase activity. CONCLUSION Mucosal alkaline sphingomyelinase activity is reduced in the intestine of IL10KO mice with colitis and in humans with ulcerative colitis. VSL#3 probiotic therapy upregulates mucosal alkaline sphingomyelinase activity.
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DA-6034, a Derivative of Flavonoid, Prevents and Ameliorates Dextran Sulfate Sodium–Induced Colitis and Inhibits Colon Carcinogenesis. Exp Biol Med (Maywood) 2008; 233:180-91. [DOI: 10.3181/0707-rm-186] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Previously, we have shown that DA-6034, a synthetic derivative of flavonoid eupatilin, inhibited NF-κB activation in colon epithelial cells and prevented trinitrobenzene sulfonic acid–induced rat colitis. The aim of this study was to investigate the preventive and therapeutic effect of DA-6034 on dextran sulfate sodium (DSS)–induced colitis and on inflammation-related cancer. C57BL/6 mice were given 4% DSS for 5 days with and without DA-6034 in the acute preventive model. In the acute therapeutic model, mice were given 4% DSS for 5 days followed by rectal administration of DA-6034. Colitis was quantified by body weight, disease activity index (DAI), colon length, and histology. In the inflammation-related cancer model, mice were given a single intraperitoneal injection of azoxymethane, then three cycles of 2% DSS for 5 days, then 2 weeks of free water consumption. Apoptosis was determined by in situ terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling assay, and the expression of Ki-67, phospho-κB kinase α (IKKα), and COX-2 were evaluated by immunohistochemistry. In both the acute preventive and acute therapeutic models, DA-6034 significantly attenuated DSS-induced weight loss, an increase in DAI, and a shortening of colon length. DA-6034–treated mice maintained crypt architecture and revealed a scanty infiltration of inflammatory cells in both the preventive and therapeutic models. In the inflammation-related cancer model, DA-6034 reduced the number of colon tumors and ameliorated weight loss and shortening of colon length. DA-6034 strongly enhanced apoptosis and inhibited the expression of COX-2 and phospho-IKKα in inflammation-related colon cancer models. Our results suggest that DA-6034 prevents acute murine colitis and inhibits inflammation-related colon carcinogenesis. DA-6034 could be a potential therapeutic agent for inflammatory bowel disease.
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Stolfi C, Fina D, Caruso R, Caprioli F, Sarra M, Fantini MC, Rizzo A, Pallone F, Monteleone G. Cyclooxygenase-2-dependent and -independent inhibition of proliferation of colon cancer cells by 5-aminosalicylic acid. Biochem Pharmacol 2008; 75:668-76. [DOI: 10.1016/j.bcp.2007.09.020] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2007] [Revised: 09/24/2007] [Accepted: 09/25/2007] [Indexed: 01/27/2023]
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Chu EC, Chai J, Ahluwalia A, Tarnawski AS. Mesalazine downregulates c-Myc in human colon cancer cells. A key to its chemopreventive action? Aliment Pharmacol Ther 2007; 25:1443-9. [PMID: 17539984 DOI: 10.1111/j.1365-2036.2007.03336.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Dysplasia and malignant transformation of colonocytes in ulcerative colitis are associated with overexpression of c-Myc and genes regulating cell survival. 5-Aminosalicylates such as mesalazine may reduce the development of colorectal cancer in ulcerative colitis, but the mechanisms of its chemopreventive action are not clear. AIMS To examine whether mesalazine affects the expression of c-Myc in human colon cancer cell lines. METHODS Human colon cancer cells were treated with vehicle or mesalazine (4 mm or 40 mm). We examined: (i) mRNA expression by gene array, (ii) protein expression by Western blotting and immunohistochemistry and (iii) apoptosis by Annexin V labelling. RESULTS Mesalazine significantly reduced expression of c-Myc mRNA and protein. CONCLUSIONS Mesalazine downregulates gene and protein expression of c-Myc. The apoptotic and growth inhibitory effects of mesalazine are dose-dependent. Expression of c-Myc is significantly reduced by mesalazine 40 mm.
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Affiliation(s)
- E C Chu
- Department of Medicine, Division of Gastroenterology, VA Long Beach Healthcare System, Long Beach, CA, USA.
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Koelink PJ, Verspaget HW. 5-ASA and colorectal cell-cycle progression. Gastroenterology 2007; 132:1635-6; author reply 1636. [PMID: 17418160 DOI: 10.1053/j.gastro.2007.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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Terdiman JP, Steinbuch M, Blumentals WA, Ullman TA, Rubin DT. 5-Aminosalicylic acid therapy and the risk of colorectal cancer among patients with inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:367-71. [PMID: 17206695 DOI: 10.1002/ibd.20074] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) affecting the colon are at increased risk of developing colorectal cancer (CRC). Published data are conflicting about whether 5-aminosalicylic acid (5-ASA) has chemopreventive properties against IBD-related carcinogenesis. The objective of this observational study was to determine if an association between 5-ASA therapy and CRC risk exists in IBD patients. METHODS Adult patients with a new CRC diagnosis (n = 18,440) were identified from 2 large administrative claims databases. For each case, 20 control patients with no record of CRC diagnosis or bowel surgery (n = 368,800) were identified. RESULTS An IBD diagnosis was associated with a 6- to 7-fold increased risk of CRC (ulcerative colitis, crude odds ratio [OR] = 6.72, 95% CI, 5.79-7.81; Crohn's disease, crude OR = 6.60, 95% CI, 5.56-7.82). Among patients with IBD (364 CRC cases, 1172 controls), exposure to 5-ASA therapy of any dose or duration during the 12 months before CRC diagnosis was not associated with a reduced risk of CRC (OR = 0.97; 95% CI, 0.77-1.23). However, there was a trend toward a decreased risk of CRC with increasing number of mesalamine prescriptions in the previous year, though statistical significance was not achieved (trend P = 0.08). CONCLUSIONS Treating IBD patients with 5-ASA medications was not found to have a protective effect against colitis-related CRC when assessed over a short period of exposure.
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Affiliation(s)
- Jonathan P Terdiman
- University of California, San Francisco, San Francisco, California 94143-1623, USA.
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Luciani MG, Campregher C, Fortune JM, Kunkel TA, Gasche C. 5-ASA affects cell cycle progression in colorectal cells by reversibly activating a replication checkpoint. Gastroenterology 2007; 132:221-35. [PMID: 17241873 PMCID: PMC1839818 DOI: 10.1053/j.gastro.2006.10.016] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2006] [Accepted: 09/21/2006] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Individuals with inflammatory bowel disease are at risk of developing colorectal cancer (CRC). Epidemiologic, animal, and laboratory studies suggest that 5-amino-salicylic acid (5-ASA) protects from the development of CRC by altering cell cycle progression and by inducing apoptosis. Our previous results indicate that 5-ASA improves replication fidelity in colorectal cells, an effect that is active in reducing mutations. In this study, we hypothesized that 5-ASA restrains cell cycle progression by activating checkpoint pathways in colorectal cell lines, which would prevent tumor development and improve genomic stability. METHODS CRC cells with different genetic backgrounds such as HT29, HCT116, HCT116(p53-/-), HCT116+chr3, and LoVo were treated with 5-ASA for 2-96 hours. Cell cycle progression, phosphorylation, and DNA binding of cell cycle checkpoint proteins were analyzed. RESULTS We found that 5-ASA at concentrations between 10 and 40 mmol/L affects cell cycle progression by inducing cells to accumulate in the S phase. This effect was independent of the hMLH1, hMSH2, and p53 status because it was observed to a similar extent in all cell lines under investigation. Moreover, wash-out experiments demonstrated reversibility within 48 hours. Although p53 did not have a causative role, p53 Ser15 was strongly phosphorylated. Proteins involved in the ATM-and-Rad3-related kinase (ATR)-dependent S-phase checkpoint response (Chk1 and Rad17) were also phosphorylated but not ataxia telengectasia mutated kinase. CONCLUSIONS Our data demonstrate that 5-ASA causes cells to reversibly accumulate in S phase and activate an ATR-dependent checkpoint. The activation of replication checkpoint may slow down DNA replication and improve DNA replication fidelity, which increases the maintenance of genomic stability and counteracts carcinogenesis.
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Affiliation(s)
- M Gloria Luciani
- Medical University of Vienna, Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Währinger Gürtel 18, A-1090 Vienna, Austria
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van Bodegraven AA, Mulder CJJ. Indications for 5-aminosalicylate in inflammatory bowel disease: is the body of evidence complete? World J Gastroenterol 2006; 12:6115-23. [PMID: 17036381 PMCID: PMC4088103 DOI: 10.3748/wjg.v12.i38.6115] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2005] [Revised: 11/28/2005] [Accepted: 02/20/2006] [Indexed: 02/06/2023] Open
Abstract
Mesalazine is a safe drug, although adverse events may be seen in a minority of patients. This applies also to pregnant women and children. The role of mesalazine in combination therapy to improve efficacy and concomitant drug pharmacokinetics, or in chemoprevention against inflammatory bowel disease (IBD)-related colonic carcinoma has not yet been completely elucidated. Therapeutic success of mesalazine may be optimized by a combination of high dose and low frequency of dosage to improve compliance. Therefore, due to its superior safety profile and pharmacokinetic characteristics, mesalazine is preferable to sulphasalazine. This paper reviews the literature concerning mechanisms of action, indications and off-label use, pharmacokinetic properties and formulations, therapeutic efficacy, compliance, paediatric indications, chemoprevention, and safety issues and adverse event profile of mesalazine treatment versus sulphasalazine. It also highlights these controversies in order to clarify the potential benefits of mesalazines in IBD therapy and evidence for its use.
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Affiliation(s)
- A A van Bodegraven
- Department of Gastroenterology, VU University medical centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
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Speisky H, Rocco C, Carrasco C, Lissi EA, López-Alarcón C. Antioxidant screening of medicinal herbal teas. Phytother Res 2006; 20:462-7. [PMID: 16619353 DOI: 10.1002/ptr.1878] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Herbal tea consumption is deeply and widely rooted amongst South-American populations. In view of the involvement of oxygen- and nitrogen-reactive species in the ethiogenesis of several diseases, the antioxidant properties of some of the herbal teas most commonly consumed in the southern regions was assessed in vitro. Around one-third of the 13 examined herbs, displayed a substantially higher ability to scavenge ABTS(+.) radicals (TEAC assay), and to quench the pro-oxidant species, hypochlorite (HClO) and peroxynitrite (ONOO(-)). Amongst the tested herbs, teas prepared from Haplopappus baylahuen, Rosa moschata and Peumus boldus showed the highest TEAC and HClO-quenching activities. These herbs were around 5- to 7-fold more potent than the least active herbs. Based on the TEAC assay, 150 mL of tea prepared from H. baylahuen, R. moschata and P. boldus would be equivalent to around 200 mg of Trolox). Teas from H. baylahuen and P. boldus were also found to be particularly potent in quenching HClO. In the ONOO(-) assay, H. baylahuen and Buddleia globosa showed the highest activities. The results obtained suggest that the regular consumption of teas prepared from some of these herbs may be useful potentially to provide the organism with molecules capable of protecting the gastrointestinal tract against certain pathologically relevant oxidant species.
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Affiliation(s)
- Hernán Speisky
- Micronutrients Unit, Nutrition and Food Technology Institute and Faculty Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
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Giannini EG, Kane SV, Testa R, Savarino V. 5-ASA and colorectal cancer chemoprevention in inflammatory bowel disease: can we afford to wait for 'best evidence'? Dig Liver Dis 2005; 37:723-31. [PMID: 16023905 DOI: 10.1016/j.dld.2005.02.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2004] [Accepted: 02/28/2005] [Indexed: 12/11/2022]
Abstract
Patients with inflammatory bowel disease have a higher risk of developing colorectal cancer. The main risk factors for colorectal cancer are not suitable targets for therapeutic intervention, and primary chemoprevention is an intriguing therapeutic option. The analogies between acetyl-salicylic acid and 5-amino-salicylic acid, and the results obtained by using acetyl-salicylic acid as a chemopreventive agent in patients with sporadic colorectal cancer have prompted the study of potential chemopreventive effects of 5-amino-salicylic acid in inflammatory bowel disease. The results of both epidemiological and experimental studies have shown that long-term 5-amino-salicylic acid treatments appear to have a chemopreventive effect. The evidence for this effect is provided by retrospective and case-control studies whose results, however, do not reach the highest grades for evidence-based recommendations. Nevertheless, these results are supported by a series of experimental studies demonstrating the multiplicity of actions of 5-amino-salicylic acid. Although data regarding the chemopreventive effect of 5-amino-salicylic acid may not be rigorous enough to meet the criteria for the highest evidence-based medicine recommendations, we feel that the argument to wait until we have Grade A evidence is not necessarily rational in this case, because discontinuation of 5-amino-salicylic acid treatment to perform a randomised controlled trial would be unethical secondary to their proven efficacy for maintenance treatment.
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Affiliation(s)
- E G Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, no. 6, Genoa 16132, Italy.
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Baumgart DC, Vierziger K, Sturm A, Wiedenmann B, Dignass AU. Mesalamine promotes intestinal epithelial wound healing in vitro through a TGF-beta-independent mechanism. Scand J Gastroenterol 2005; 40:958-64. [PMID: 16165710 DOI: 10.1080/00365520510015854] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Treatment with 5-aminosalicylic acid (5-ASA) derivatives is one of the main principles in the therapy of uncomplicated mild to moderate inflammatory bowel diseases (IBD). The beneficial effect of 5-ASA in the treatment of IBD is attributed to its anti-inflammatory and anti-oxidant properties within the inflamed gut. The aim of this study was to investigate whether 5-ASA also modulates intestinal epithelial wound repair in vitro. MATERIAL AND METHODS The effects of 5-ASA on cell migration and proliferation, two key processes in mucosal healing, were studied in the non-transformed small-intestinal epithelial cell line IEC-6 using an in vitro wounding model and colorimetric MTT assays. Furthermore, the effects of 5-ASA on epithelial cell viability were determined by Trypan blue exclusion and flow cytometry-based cell cycle analysis. RESULTS Clinically relevant concentrations of 5-ASA caused a significant dose-dependent enhancement of epithelial cell migration and proliferation in vitro. An about 2-fold enhancement of intestinal epithelial cell proliferation and migration was observed for pharmacological doses of 100 microg/ml 5-ASA. Neutralizing antibodies against TGFbeta did not modulate 5-ASA effects on IEC-6 cell proliferation and migration, indicating that the effects of 5-ASA were TGFbeta independent. Trypan blue viability tests and cell cycle analysis did not reveal any toxic or apoptotic effects of pharmacological 5-ASA concentrations on IEC-6 cells. CONCLUSIONS 5-ASA promotes the rapid re-establishment of mucosal integrity in vitro by enhancing epithelial restitution and proliferation, suggesting that 5-ASA in addition to the well-characterized effects on the intestinal inflammatory cascade may also directly stimulate epithelial wound healing.
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Affiliation(s)
- Daniel C Baumgart
- Department of Medicine, Division of Hepatology & Gastroenterology, Charité Medical Center-Virchow Hospital, Medical School of the Humboldt-University of Berlin, Germany
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Cheng Y, Desreumaux P. 5-aminosalicylic acid is an attractive candidate agent for chemoprevention of colon cancer in patients with inflammatory bowel disease. World J Gastroenterol 2005; 11:309-14. [PMID: 15637733 PMCID: PMC4205326 DOI: 10.3748/wjg.v11.i3.309] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is classically subdivided into ulcerative colitis (UC) and Crohn’s disease (CD). Patients with IBD have increased risk for colorectal cancer. Because the pathogenesis of colorectal carcinoma has not been entirely defined yet and there is no ideal treatment for colon cancer, cancer prevention has become increasingly important in patients with IBD. The two adopted methods to prevent the development of colon cancer in clinical practice include the prophylactic colectomy and colonoscopic surveillance. But patients and physicians seldom accept colectomy as a routine preventive method and most patients do not undergo appropriate colonoscopic surveillance. Chemoprevention refers to the use of natural or synthetic chemical agents to reverse, suppress, or to delay the process of carcinogenesis. Chemoprevention is a particularly useful method in the management of patients at high risk for the development of specific cancers based on inborn genetic susceptibility, the presence of cancer-associated disease, or other known risk factors. Prevention of colorectal cancer by administration of chemopreventive agents is one of the most promising options for IBD patients who are at increased risks of the disease. The chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against intestinal tumors has been well established. But with reports that NSAIDs aggravated the symptoms of colitis, their sustained use for the purpose of cancer chemoprevention has been relatively contraindicated in IBD patients. Another hopeful candidate chemoprevention drug for IBD patients is 5-aminosalicylic acid (5-ASA), which is well tolerated by most patients and has limited systemic adverse effects, and no gastrointestinal toxicity. 5-ASA lacks the well-known side effects of long-term NSAIDs use. Retrospective correlative studies have suggested that the long-term use of 5-ASA in IBD patients may significantly reduce the risk of development of colorectal cancer. According to the literature, this agent might well satisfy clinical expectations with respect to a safe and effective chemopreventive agent.
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Affiliation(s)
- Yang Cheng
- Institute of Liver Disease, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Pudong District, Shanghai 201203, China.
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Raedler A, Behrens C, Bias P. Mesalazine (5-aminosalicylic acid) micropellets show similar efficacy and tolerability to mesalazine tablets in patients with ulcerative colitis--results from a randomized-controlled trial. Aliment Pharmacol Ther 2004; 20:1353-63. [PMID: 15606398 DOI: 10.1111/j.1365-2036.2004.02282.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Formulations containing 5-aminosalicylic acid, such as mesalazine, are the gold standard of treatment for mild-to-moderate ulcerative colitis. Current oral regimens require the use of large tablets and frequent dosing to reach the recommended treatment dose. Mesalazine micropellets were designed to allow less frequent dosing in an easier to swallow formulation. AIM To compare the efficacy of mesalazine micropellets with the tablet formulation in patients with mild-to-moderate ulcerative colitis. METHODS This phase 2, double-blind, active-controlled, parallel-group, multiple dose clinical trial randomized 362 patients to either mesalazine micropellets or tablets, at a dosage of 3 g/day. The primary efficacy end-point was the incidence of clinical remission within 8 weeks, defined as the sum of clinical activity index components 1-4 (CAI(C1-4)) < or = 2. RESULTS CAI(C1-4) decreased significantly in both treatment groups within 8 weeks. The micropellet formulation showed confirmatory non-inferiority with statistical significance compared with the tablet formulation, with regard to the incidence of clinical remission (odds ratio in according-to-protocol population 1.008; 95% CI: 0.623-1.632). There was no significant difference in the incidence of adverse events. CONCLUSIONS The mesalazine micropellet formulation is as effective as tablets in patients with mild-to-moderate ulcerative colitis, enabling a larger dose to be taken comfortably and conveniently, thereby potentially improving patient compliance, treatment response and quality of life.
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Affiliation(s)
- A Raedler
- Department of Internal Medicine II--Gastroenterology, Asklepios Westklinikum Hamburg, Teaching Hospital of the University of Hamburg, Hamburg, Germany
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Johnson IT. New approaches to the role of diet in the prevention of cancers of the alimentary tract. Mutat Res 2004; 551:9-28. [PMID: 15225578 DOI: 10.1016/j.mrfmmm.2004.02.017] [Citation(s) in RCA: 103] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2003] [Revised: 02/10/2004] [Accepted: 02/10/2004] [Indexed: 12/16/2022]
Abstract
Cancers of the alimentary tract are, collectively, amongst the major causes of morbidity and deaths from cancer across the world today. Of the 10 million new cases of cancer diagnosed in 2000, about 2.3 million were cancers of the pharynx, oesophagus, stomach or colorectum. Nevertheless, epidemiological studies indicate that cancers of the digestive organs are also amongst the most susceptible to modification by dietary factors. International variations in incidence suggest that round three quarters of all sporadic colorectal cancers are attributable to diet. Even within the relatively uniform environment of the European Union, there are variations in the incidence of colorectal and oesophageal cancers of about two- and six-fold, respectively. Carcinomas of the alimentary tract arise from epithelial cells via distinct sequences of neoplastic change, which require a large fraction of an individual's lifespan. The best characterised of these is the adenoma-carcinoma sequence of colorectal carcinogenesis, in which progressive loss of differentiation and normal morphology in a growing lesion is associated with the acquisition of somatic mutations, and of aberrant methylation of CpG-islands, leading to gene silencing. These molecular events are accompanied by functional changes, including increased mitosis and evasion of apoptosis. There is little evidence that diet exerts its effects primarily through food-borne carcinogens that can be identified and eliminated from the food-chain. It is far more probable that the adverse effects of diet are caused largely by over-consumption of energy, coupled with inadequate intakes of protective substances, including micronutrients, dietary fibre and a variety of phytochemicals. The latter are biologically active secondary plant metabolites, many of which modify cell proliferation and induce apoptosis in vitro. There is growing evidence that such effects also occur in vivo, and that they can suppress the progress of neoplasia. Carcinomas of the oesophagus, stomach and colon all appear to be partially preventable by diets rich in fruits and vegetables. Plant foods contain a variety of components including micronutrients, polyunsaturated fatty acids, and secondary metabolites such as glucosinolates and flavonoids, many of which can inhibit cell proliferation and induce apoptosis, and which may well act synergistically when combined in the human diet. The future challenge is to fully characterise and evaluate these effects at the cellular and molecular level, so at to exploit their full potential as protective mechanisms for the population as a whole.
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Affiliation(s)
- I T Johnson
- Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK.
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Abstract
PURPOSE OF REVIEW The past year has brought forth several controversies regarding the treatment of ulcerative colitis along with several potentially important clinical advances. The aim of this review is to provide the practicing gastroenterologist with a summation of these recent developments, with particular emphasis on advances that have already moved toward acceptance into clinical practice. RECENT FINDINGS Controversies remain regarding the optimal formulations and doses of aminosalicylates. At the same time, the potential for chemoprotective effects in patients using maintenance therapy with mesalamine derivatives has been expanded. In addition, advances in biologic therapy for Crohn disease are beginning to be formally evaluated in ulcerative colitis, although the benefits of anti-tumor necrosis factor therapy in this condition remain to be established. Biologic therapies are beginning to be explored as adjunctive therapy for steroid-refractory ulcerative colitis, where trials of calcineurin inhibitors are also advancing clinical practice for this poor prognostic subgroup of patients. Finally, after surgery for ulcerative colitis, the treatment and prevention of pouchitis has become the one established indication for probiotic therapy. SUMMARY Despite some inroads into the medical therapy of ulcerative colitis, controversies remain regarding the optimal dosing and delivery systems of the most fundamental therapies, and how to optimize therapy for severe ulcerative colitis. Clinical research will continue to investigate new biologic agents that inhibit tumor necrosis factor and other pro-inflammatory cytokines, and ongoing trials with leukocyte apheresis are currently under way.
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Affiliation(s)
- Stephen B Hanauer
- Department of Medicine and the Section of Gastroenterology and Nutrition, University of Chicago, Chicago, Illinois, USA.
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Abstract
Cancer chemopreventive agents are typically natural products or their synthetic analogs that inhibit the transformation of normal cells to premalignant cells or the progression of premalignant cells to malignant cells. These agents are believed to function by modulating processes associated with xenobiotic biotransformation, with the protection of cellular elements from oxidative damage, or with the promotion of a more differentiated phenotype in target cells. However, an increasing number of chemopreventive agents (e.g., certain retinoids, nonsteroidal anti-inflammatory drugs, polyphenols, and vanilloids) have been shown to stimulate apoptosis in premalignant and malignant cells in vitro or in vivo. Apoptosis is arguably the most potent defense against cancer because it is the mechanism used by metazoans to eliminate deleterious cells. Many chemopreventive agents appear to target signaling intermediates in apoptosis-inducing pathways. Inherently, the process of carcinogenesis selects against apoptosis to initiate, promote, and perpetuate the malignant phenotype. Thus, targeting apoptosis pathways in premalignant cells--in which these pathways are still relatively intact--may be an effective method of cancer prevention. In this review, we construct a paradigm supporting apoptosis as a novel target for cancer chemoprevention by highlighting recent studies of several chemopreventive agents that engage apoptosis pathways.
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Affiliation(s)
- Shi-Yong Sun
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX77030-4095, USA
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