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Sinclair J, McLaughlin G, Allan R, Brooks-Warburton J, Lawson C, Goh S, Desai T, Bottoms L. Health Benefits of Montmorency Tart Cherry Juice Supplementation in Adults with Mild to Moderate Ulcerative Colitis; A Placebo Randomized Controlled Trial. Life (Basel) 2025; 15:306. [PMID: 40003718 PMCID: PMC11857002 DOI: 10.3390/life15020306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 02/11/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
AIMS Ulcerative colitis (UC) significantly impacts individuals' self-perception, body image, and overall quality of life, while also imposing considerable economic costs. These challenges highlight the necessity for complementary therapeutic strategies with reduced adverse effects to support conventional pharmacological treatments. Among natural interventions, Montmorency tart cherries, noted for their high anthocyanin content have emerged as a natural anti-inflammatory agent for UC. The current trial aimed to investigate the effects of Montmorency tart cherries compared to placebo in patients with mild to moderate UC. MATERIALS AND METHODS Thirty-five patients with UC were randomly assigned to receive either placebo or Montmorency tart cherry juice, of which they drank 60 mL per day for 6 weeks. The primary outcomes and health-related quality of life, measured via the Inflammatory Bowel Disease Quality of Life Questionnaire (IBDQ), and the secondary measures, including other health-related questionnaires, blood biomarkers, and faecal samples, were measured before and after the intervention. Linear mixed-effects models were adopted to contrast the changes from baseline to 6 weeks between trial arms. Effect sizes were calculated using Cohen's d. RESULTS There were significantly greater improvements in the IBDQ (22.61 (95% CI = 5.24 to 39.99) d = 0.90) and simple clinical colitis activity index (-3.98 (95% CI = -6.69 to -1.28) d = -1.01) in the tart cherry trial arm compared to placebo. In addition, reductions in faecal calprotectin levels were significantly greater in the tart cherry trial arm compared to placebo (-136.17 µg/g (95% CI = -258.06 to -4.28) d = -1.14). Loss to follow-up (N = 1) and adverse events (N = 1) were low and compliance was very high in the tart cherry (95.8%) trial arm. CONCLUSIONS Given the profoundly negative effects of UC on health-related quality of life and its fiscal implications for global healthcare systems, this trial indicates that twice-daily tart cherry supplementation can improve IBD-related quality of life as well as the severity of symptoms and therefore may be important in the management of UC.
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Affiliation(s)
- Jonathan Sinclair
- Research Centre for Applied Sport, Physical Activity and Performance, School of Health Social Work & Sport, University of Central Lancashire, Preston PR1 2HE, UK
| | - Graham McLaughlin
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
| | - Robert Allan
- Research Centre for Applied Sport, Physical Activity and Performance, School of Health Social Work & Sport, University of Central Lancashire, Preston PR1 2HE, UK
| | - Johanne Brooks-Warburton
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
- Gastroenterology Department, Lister Hospital, Stevenage SG1 4AB, UK
| | - Charlotte Lawson
- School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK
| | - Shan Goh
- Department of Clinical, Pharmaceutical and Biological Science, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
| | - Terun Desai
- Division of Surgery & Interventional Science, University College London, London WC1E 6BT, UK
| | - Lindsay Bottoms
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
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Liu X, Cheng Y, Mu Y, Zhang Z, Tian D, Liu Y, Hu X, Wen T. Diverse drug delivery systems for the enhancement of cancer immunotherapy: an overview. Front Immunol 2024; 15:1328145. [PMID: 38298192 PMCID: PMC10828056 DOI: 10.3389/fimmu.2024.1328145] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 01/03/2024] [Indexed: 02/02/2024] Open
Abstract
Despite the clear benefits demonstrated by immunotherapy, there is still an inevitable off-target effect resulting in serious adverse immune reactions. In recent years, the research and development of Drug Delivery System (DDS) has received increased prominence. In decades of development, DDS has demonstrated the ability to deliver drugs in a precisely targeted manner to mitigate side effects and has the advantages of flexible control of drug release, improved pharmacokinetics, and drug distribution. Therefore, we consider that combining cancer immunotherapy with DDS can enhance the anti-tumor ability. In this paper, we provide an overview of the latest drug delivery strategies in cancer immunotherapy and briefly introduce the characteristics of DDS based on nano-carriers (liposomes, polymer nano-micelles, mesoporous silica, extracellular vesicles, etc.) and coupling technology (ADCs, PDCs and targeted protein degradation). Our aim is to show readers a variety of drug delivery platforms under different immune mechanisms, and analyze their advantages and limitations, to provide more superior and accurate targeting strategies for cancer immunotherapy.
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Affiliation(s)
- Xu Liu
- Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yang Cheng
- Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yao Mu
- Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | | | - Dan Tian
- Department of Thoracic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yunpeng Liu
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Treatment and Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xuejun Hu
- Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ti Wen
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Treatment and Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
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Sinclair J, Dillon S, Allan R, Brooks-Warburton J, Desai T, Lawson C, Bottoms L. Health Benefits of Montmorency Tart Cherry Juice Supplementation in Adults with Mild to Moderate Ulcerative Colitis: A Protocol for a Placebo Randomized Controlled Trial. Methods Protoc 2023; 6:76. [PMID: 37736959 PMCID: PMC10514793 DOI: 10.3390/mps6050076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 09/23/2023] Open
Abstract
Ulcerative colitis, characterized by its relapsing and remissive nature, negatively affects perception, body image, and overall quality of life. The associated financial burden underscores the need for alternative treatment approaches with fewer side effects, alongside pharmaceutical interventions. Montmorency tart cherries, rich in anthocyanins, have emerged as a potential natural anti-inflammatory agent for ulcerative colitis. This manuscript outlines the study protocol for a randomized placebo-controlled trial investigating the effects of Montmorency tart cherry in individuals with ulcerative colitis. The trial aims to recruit 40 participants with mild to moderate disease activity randomly assign them to either a Montmorency tart cherry or placebo group. The intervention will span 6 weeks, with baseline and 6-week assessments. The primary outcome measure is the Inflammatory Bowel Disease Quality of Life Questionnaire. Secondary outcomes include other health-related questionnaires and biological indices. Statistical analysis will adhere to an intention-to-treat approach using linear mixed effect models. Ethical approval has been obtained from the University of Hertfordshire (cLMS/SF/UH/05240), and the trial has been registered as a clinical trial (NCT05486507). The trial findings will be disseminated through a peer-reviewed publication in a scientific journal.
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Affiliation(s)
- Jonathan Sinclair
- Research Centre for Applied Sport, Physical Activity and Performance, School of Sport & Health Sciences, Faculty of Allied Health and Wellbeing, University of Central Lancashire, Preston PR1 2HE, UK
| | - Stephanie Dillon
- Research Centre for Applied Sport, Physical Activity and Performance, School of Sport & Health Sciences, Faculty of Allied Health and Wellbeing, University of Central Lancashire, Preston PR1 2HE, UK
| | - Robert Allan
- Research Centre for Applied Sport, Physical Activity and Performance, School of Sport & Health Sciences, Faculty of Allied Health and Wellbeing, University of Central Lancashire, Preston PR1 2HE, UK
| | - Johanne Brooks-Warburton
- Gastroenterology Department, Lister Hospital, Stevenage SG1 4AB, UK
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB, UK (L.B.)
| | - Terun Desai
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB, UK (L.B.)
| | - Charlotte Lawson
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK
| | - Lindsay Bottoms
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB, UK (L.B.)
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Sun K, Yu J, Hu J, Chen J, Song J, Chen Z, Cai Z, Lu Z, Zhang L, Wang Z. Salicylic acid-based hypoxia-responsive chemodynamic nanomedicines boost antitumor immunotherapy by modulating immunosuppressive tumor microenvironment. Acta Biomater 2022; 148:230-243. [PMID: 35724919 DOI: 10.1016/j.actbio.2022.06.026] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/05/2022] [Accepted: 06/12/2022] [Indexed: 11/19/2022]
Abstract
The delivery of salicylic acid or its derivatives to tumor tissue in the form of nanomedicine is critical for the studies on their potential synergistic mechanism in tumor therapy and chemoprevention considering the dangerous bleeding in the high-dose oral administration. To deepen the understanding of their role in adjusting immunosuppressive tumor microenvironment (ITM), herein, we firstly developed a hypoxia-sensitive Fe-5,5'-azosalicylic acid nanoscale coordination polymer nanomedicines (FeNCPs) via a "old drugs new tricks" strategy for synergistic chemodynamic therapy (CDT) and remodulation of ITM to elevate antitumor immunotherapy effect. PEGylated FeNCPs could be reductively cleaved to release 5-aminosalicylic acid (5-ASA) and ferric ions by azo-reductase under hypoxic conditions, which could induce tumor cell death by Fenton reaction-catalysis enhanced CDT and 5-ASA-converted carboxylquinone to promote the production of •OH. Meanwhile, cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E2 (PGE2), as immune negative regulatory molecules, can promote tumor progression and immune tolerance. The released 5-ASA as a COX inhibitor could suppress the expression of PGE2, and Fe3+ was employed to reeducate M2-like tumor-associated macrophages (TAMs) to M1-like phenotype, which could initiate antitumor immune response to reach better antitumor immunotherapy. This work broadens the application of salicylic acid derivatives in antitumor immunotherapy, and provides a new strategy for their "old drugs new tricks". STATEMENT OF SIGNIFICANCE: Cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E2 (PGE2), as immune negative regulatory molecules, facilitate the differentiation of immune cells into immunosuppressive cells to build the immunosuppressive tumor microenvironment, which can promote tumor progression and immune tolerance. Thus, down-regulation of COX-2/PGE2 expression may be a key approach to tumor treatments. Meanwhile, as a class of inhibitors of COX-2/PGE2, the potential mechanism of aspirin or 5-aminosalicylic acid has been a mystery in tumor therapy and chemoprevention. To expand the application of aspirin family nanomedicine in biomedicine, herein, we firstly developed a hypoxia-sensitive Fe-5,5'-azosalicylic acid nanoscale coordination polymer nanomedicines via a "old drugs new tricks" strategy for synergistic chemodynamic therapy and remodulation of immunosuppressive tumor microenvironment to elevate antitumor immunotherapy effect.
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Affiliation(s)
- Kai Sun
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China
| | - Jiaying Yu
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China
| | - Jinzhong Hu
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China
| | - Jian Chen
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China
| | - Jia Song
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China
| | - Zhixin Chen
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China
| | - Zhuoer Cai
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China
| | - Zhuoxuan Lu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, NHC Key Laboratory of Control of Tropical Diseases, School of Tropical Medicine, Hainan Medical University, Haikou, Hainan 571199, PR China
| | - Liming Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, NHC Key Laboratory of Control of Tropical Diseases, School of Tropical Medicine, Hainan Medical University, Haikou, Hainan 571199, PR China
| | - Zhifei Wang
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
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Miao Z, Gu M, Yan J, Lu L, Xu Y, Ning L, Xu Y. Dual-targeted colon-based integrated micelle drug delivery system for treatment of ulcerative colitis. J Drug Target 2022; 30:657-672. [PMID: 35285362 DOI: 10.1080/1061186x.2022.2052887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Zhiwei Miao
- Department of Gastroenterology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, China
| | - Mingjia Gu
- Department of Nephrology, Changshu Hospital affiliated to Nanjing university of Chinese medicine, Changshu 215000, China
| | - Jing Yan
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Lidan Lu
- Department of gynaecology, Changshu Hospital affiliated to Nanjing university of Chinese medicine, Changshu 215000, China.
| | - Yan Xu
- Department of Gastroenterology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, China
| | - Liqin Ning
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Yi Xu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
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Cerón-Carrasco JP, Jacquemin D. Using Theory To Extend the Scope of Azobenzene Drugs in Chemotherapy: Novel Combinations for a Specific Delivery. ChemMedChem 2021; 16:1764-1774. [PMID: 33619857 DOI: 10.1002/cmdc.202100046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/18/2021] [Indexed: 12/12/2022]
Abstract
Gut microorganisms metabolize azobenzene compounds (Ph1 -N=N-Ph2 ) into free aniline products (Ph1 -NH2 +H2 N-Ph2 ), a process that has been largely investigated to reduce dyes residues in the textile industry. However, the action of bacterial core enzymes such as azoreductases (AzoR) might also help to deliver prodrugs that become active when they reach the colonic region, a mechanism with potential applications for the treatment of inflammatory bowel disease (IBD) and colorectal cancer. So far, three azo-bonded prodrugs of 5-aminosalicylic acid (5-ASA), for example, sulfasalazine, olsalazine and balsalazide, have been used for colon-targeted delivery. The present contribution describes the first rational design of a novel azobenzene prodrug thanks to a computational approach, with a focus on linking 5-ASA to another approved anti-inflammatory drug. The resulting prodrugs were assessed for their degradation upon AzoR action. Replacing the original carriers by irsogladine is found to improve action.
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Affiliation(s)
- José P Cerón-Carrasco
- Reconocimiento y Encapsulación Molecular, Universidad Católica San Antonio de Murcia (UCAM) Campus los Jerónimos, 30107, Murcia, Spain
| | - Denis Jacquemin
- CEISAM UMR CNRS 6230, Université de Nantes, 44000, Nantes, France
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Zhang S, Fu J, Dogan B, Scherl EJ, Simpson KW. 5-Aminosalicylic acid downregulates the growth and virulence of Escherichia coli associated with IBD and colorectal cancer, and upregulates host anti-inflammatory activity. J Antibiot (Tokyo) 2018; 71:950-961. [PMID: 30050110 DOI: 10.1038/s41429-018-0081-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 06/20/2018] [Accepted: 06/24/2018] [Indexed: 02/07/2023]
Abstract
5-aminosalicylate (5-ASA) is widely prescribed for the treatment of inflammatory bowel disease (IBD) and prevention of inflammation-associated colorectal cancer (CRC). Its clinical effect is widely attributed to modulation of host inflammatory responses. However, the recent association of intestinal dysbiosis and selective enrichment in Escherichia coli in patients with IBD and CRC raises the possibility that 5-ASA might also affect the enteric microflora. The aim of this study was to investigate the effect of 5-ASA on the growth and virulence of E. coli associated with IBD and CRC, and its impact on host cell inflammatory responses. Our results show that 5-ASA inhibited E. coli growth in a dose-dependent manner and downregulated the expression of bacterial virulence genes associated with IBD (fliC, fimH, ompC, yfgL, nlpL, lpfA, htrA, dsbA, fyuA, and chuA) and CRC (pks). 5-ASA inhibited E. coli motility (30-70%), epithelial adherence and invasion, and IL-8 secretion (p < 0.05). 5-ASA reduced E. coli survival in J774A.1 macrophages by 20 to 50% (p < 0.01) and TNF-α secretion by infected macrophages up to 30% (p < 0.05). In addition, 5-ASA reduced DNA damage in epithelial cells (Caco-2) induced by pks-positive E. coli. Our results reveal a multifaceted and previously unrecognized effect of 5-ASA on the growth and virulence of IBD- and CRC-associated E. coli, in addition to its inhibitory effect on host cell inflammatory responses. These results suggest that 5-ASA may abrogate the proinflammatory and oncogenic effects of E. coli in patients with IBD and CRC.
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Affiliation(s)
- Shiying Zhang
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Jing Fu
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.,Zhongkai University of Agriculture and Engineering, Guangzhou, China
| | - Belgin Dogan
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Ellen J Scherl
- The Jill Roberts Center for Inflammatory Bowel Disease, Weill Cornell Medical College, 71st and York, New York, NY, USA
| | - Kenneth W Simpson
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
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8
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Looking for the best anti-colitis medicine: A comparative analysis of current and prospective compounds. Oncotarget 2018; 8:228-237. [PMID: 27974688 PMCID: PMC5352114 DOI: 10.18632/oncotarget.13894] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 11/15/2016] [Indexed: 12/15/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic lifelong inflammatory disorder of the colon, which, while untreated, has a relapsing and remitting course with increasing risk of progression toward colorectal cancer. Current medical treatment strategies of UC mostly focus on inhibition of the signs and symptoms of UC to induce remission and prevent relapse of disease activity, minimizing the impact on quality of life, but not affecting the cause of disease. To date, however, there is no single reliable treatment agent and/or strategy capable of effectively controlling colitis progression throughout the patient's life without side effects, remission, or resistance. Taking into consideration an urgent need for the new colitis treatment strategies, targets and/or modulators of inflammation, we have tested current and prospective compounds for colitis treatment and directly compared their anti-colitis potency using a dextran sulfate sodium (DSS) mouse model of colitis. We have introduced a composite score - a multi-parameters comparison tool - to assess biological potency of different compounds.
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Bermejo F, Aguas M, Chaparro M, Domènech E, Echarri A, García-Planella E, Guerra I, Gisbert JP, López-Sanromán A. Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the use of thiopurines in inflammatory bowel disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2018; 41:205-221. [PMID: 29357999 DOI: 10.1016/j.gastrohep.2017.11.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 11/26/2017] [Indexed: 12/17/2022]
Abstract
Thiopurines (azathioprine and mercaptopurine) are widely used in patients with inflammatory bowel disease. In this paper, we review the main indications for their use, as well as practical aspects on efficacy, safety and method of administration. They are mainly used to maintain remission in steroid-dependent disease or with ciclosporin to control a severe ulcerative colitis flare-up, as well as to prevent postoperative Crohn's disease recurrence, and also in combination therapy with biologics. About 30-40% of patients will not respond to treatment and 10-20% will not tolerate it due to adverse effects. Before they are prescribed, immunisation status against certain infections should be checked. Determination of thiopurine methyltransferase activity (TPMT) is not mandatory but it increases initial safety. The appropriate dose is 2.5mg/kg/day for azathioprine and 1.5mg/kg/day for mercaptopurine. Some adverse effects are idiosyncratic (digestive intolerance, pancreatitis, fever, arthromyalgia, rash and some forms of hepatotoxicity). Others are dose-dependent (myelotoxicity and other types of hepatotoxicity), and their surveillance should never be interrupted during treatment. If therapy fails or adverse effects develop, management can include switching from one thiopurine to the other, reducing the dose, combining low doses of azathioprine with allopurinol and assessing metabolites, before their use is ruled out. Non-melanoma skin cancer, lymphomas and urinary tract tumours have been linked to thiopurine therapy. Thiopurine use is safe during conception, pregnancy and breastfeeding.
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Affiliation(s)
- Fernando Bermejo
- Servicio de Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, España.
| | - Mariam Aguas
- Servicio de Digestivo, Hospital Universitari La Fe, Valencia, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Chaparro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Servicios de Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, España
| | - Eugeni Domènech
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Servicio de Digestivo, Hospital Universitari Germans Trias i Pujol, Badalona, España
| | - Ana Echarri
- Servicio de Digestivo, Complejo Hospitalario Universitario de Ferrol, Ferrol, España
| | | | - Iván Guerra
- Servicio de Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, España
| | - Javier P Gisbert
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Servicios de Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, España
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10
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Vetter M, Neurath MF. Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges. Therap Adv Gastroenterol 2017; 10:773-790. [PMID: 29051788 PMCID: PMC5638182 DOI: 10.1177/1756283x17727388] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Accepted: 07/31/2017] [Indexed: 02/04/2023] Open
Abstract
To improve quality of life and prevent long-term risks in patients with inflammatory bowel diseases (IBDs: Crohn's disease, ulcerative colitis), it is essential to suppress inflammatory activity adequately. However, corticosteroids are only suitable for therapy of acute flares and the evidence for positive effects of immunosuppressive substances like azathioprine or 6-mercapropurine is mainly limited to maintenance of remission. In addition, only subgroups of patients benefit from biologicals targeting tumour necrosis factor α or α4β7 integrins. In summary, until now the disease activity is not sufficiently controlled in a relevant fraction of the patients with IBD. Thus, there is an urge for the development of new substances in the therapy of ulcerative colitis and Crohn's disease. Fortunately, new oral and parenteral substances are in the pipeline. This review will focus on oral substances, which have already passed phase II studies successfully at this stage. In this article, we summarize data regarding AJM300, phosphatidylcholine (LT-02), mongersen, ozanimod, filgotinib and tofacitinib. AJM300 and ozanimod were tested in patients with ulcerative colitis and target lymphocyte trafficking through inhibition of the α subunit of integrin, respectively binding to the sphingosine-1-phosphate receptor (subtypes 1 and 5) on lymphocytes. Mongersen was utilized in patients with Crohn's disease and accelerates the degradation of SMAD7 mRNA, which consequently strengthens the mainly anti-inflammatory signalling pathway of transforming growth factor β1. Various Janus kinase (JAK) inhibitors were developed, which inhibit the intracellular signalling pathway of cytokines. For example, the JAK1 blocker filgotinib was tested in Crohn's disease, whereas the JAK1/3 inhibitor tofacitinib was tested in clinical trials for both Crohn's disease and ulcerative colitis. A different therapeutic approach is the substitution of phosphatidylcholine (LT-02), which might recover the colonic mucus. Taken together, clinical trials with these new agents have opened avenues for further clinical studies and it can be expected that at least some of these agents will be finally approved for clinical therapy.
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Affiliation(s)
- Marcel Vetter
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, Erlangen, 91054, Germany
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11
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Maiuri AR, O'Hagan HM. Interplay Between Inflammation and Epigenetic Changes in Cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 144:69-117. [PMID: 27865469 DOI: 10.1016/bs.pmbts.2016.09.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Immune responses can suppress tumorigenesis, but also contribute to cancer initiation and progression suggesting a complex interaction between the immune system and cancer. Epigenetic alterations, which are heritable changes in gene expression without changes to the DNA sequence, also play a role in carcinogenesis through silencing expression of tumor suppressor genes and activating oncogenic signaling. Interestingly, epithelial cells at sites of chronic inflammation undergo DNA methylation alterations that are similar to those present in cancer cells, suggesting that inflammation may initiate cancer-specific epigenetic changes in epithelial cells. Furthermore, epigenetic changes occur during immune cell differentiation and participate in regulating the immune response, including the regulation of inflammatory cytokines. Cancer cells utilize epigenetic silencing of immune-related genes to evade the immune response. This chapter will detail the interactions between inflammation and epigenetics in tumor initiation, promotion, and immune evasion and how these connections are being leveraged in cancer prevention and treatment.
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Affiliation(s)
- A R Maiuri
- Medical Sciences, Indiana University School of Medicine, Bloomington, IN, United States
| | - H M O'Hagan
- Medical Sciences, Indiana University School of Medicine, Bloomington, IN, United States; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, United States.
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Wang X, Sun Y, Zhao Y, Ding Y, Zhang X, Kong L, Li Z, Guo Q, Zhao L. Oroxyloside prevents dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-κB pathway through PPARγ activation. Biochem Pharmacol 2016; 106:70-81. [PMID: 26947454 DOI: 10.1016/j.bcp.2016.02.019] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 02/26/2016] [Indexed: 01/12/2023]
Abstract
Oroxyloside, as a metabolite of oroxylin A, may harbor various beneficial bioactivities which have rarely been reported in the previous studies. Here we established the dextran sulfate sodium (DSS)-induced experimental colitis and evaluated the anti-inflammatory effect of oroxyloside in vivo. As a result, oroxyloside attenuated DSS-induced body weight loss, colon length shortening and colonic pathological damage. Furthermore, oroxyloside inhibited inflammatory cell infiltration and decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities as well. The production of pro-inflammatory cytokines in serum and colon was also significantly reduced by oroxyloside. We unraveled the underlying mechanisms that oroxyloside inhibited NF-κB pathway by activating Peroxisome Proliferator-Activated Receptor γ (PPARγ) to attenuate DSS-induced colitis. Moreover, we investigated the anti-inflammatory effect and mechanisms of oroxyloside in the mouse macrophage cell line RAW264.7 and bone marrow derived macrophages (BMDM). Oroxyloside decreased several LPS-induced inflammatory cytokines, including IL-1β, IL-6 and TNF-α in RAW264.7 and BMDM. We also found that oroxyloside inhibited LPS-induced activation of NF-κB signaling pathway via activating PPARγ in RAW 264.7 and BMDM. Docking study showed that oroxyloside could bind with PPARγ. GW9662, the inhibitor of PPARγ, and PPARγ siRNA transfection blocked the effect of oroxyloside on PPARγ activation. Our study suggested that oroxyloside prevented DSS-induced colitis by inhibiting NF-κB pathway through PPARγ activation. Therefore, oroxyloside may be a promising and effective agent for inflammatory bowel disease (IBD).
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Affiliation(s)
- Xiaoping Wang
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Yang Sun
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Yue Zhao
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Youxiang Ding
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Xiaobo Zhang
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Lingyi Kong
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Zhiyu Li
- School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Qinglong Guo
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
| | - Li Zhao
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
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Physician Perspectives on Unresolved Issues in the Management of Ulcerative Colitis: The UC Horizons Project. Inflamm Bowel Dis 2016; 22:583-98. [PMID: 26529561 DOI: 10.1097/mib.0000000000000617] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND There is still uncertainty about what constitutes the best therapeutic practice in ulcerative colitis (UC). OBJECTIVE The purpose of the "UC Horizons Project" was to raise a series of questions regarding the management of UC to provide responses based on the best scientific evidence available. METHODS The 11 members of the scientific committee prepared draft answers to the 10 questions from available evidence after a literature search. A total of 48 Spanish gastroenterology specialists nationwide participated in the project. The national meeting discussed the 10 issues in working groups and reached consensus regarding the recommendations by anonymous, interactive vote following the Delphi methodology. Final answers were developed, based on evidence and clinical experience of the participants. RESULTS All the recommendations achieved a high level of agreement in the plenary vote, although the quality of the evidence was markedly heterogeneous. The lowest percentage of agreement corresponded to the questions with the weakest level of evidence, highlighting the necessity of conducting further studies in these areas. The recommendations focused on (1) aminosalicylates therapy (regarding dose and appropriateness of coadministration with thiopurines), (2) corticosteroid therapy (regarding dose and route of administration), (3) thiopurine treatment (regarding indications and possibility of withdrawal), (4) anti-tumor necrosis factor therapy (regarding appropriateness of combination with thiopurines, intensification, or discontinuation of treatment), and (5) colorectal cancer (regarding risk and time trends). CONCLUSIONS The UC Horizons Project raised a series of eminently practical questions about the management of UC and provided responses based on the best scientific evidence available.
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Dammann K, Khare V, Lang M, Claudel T, Harpain F, Granofszky N, Evstatiev R, Williams JM, Pritchard DM, Watson A, Gasche C. PAK1 modulates a PPARγ/NF-κB cascade in intestinal inflammation. BIOCHIMICA ET BIOPHYSICA ACTA 2015; 1853:2349-60. [PMID: 26036343 PMCID: PMC4576212 DOI: 10.1016/j.bbamcr.2015.05.031] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 05/13/2015] [Accepted: 05/28/2015] [Indexed: 02/07/2023]
Abstract
P21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases with both kinase and scaffolding activity. Here, we investigated the effects of inflammation on PAK1 signaling and its role in colitis-driven carcinogenesis. PAK1 and p-PAK1 (Thr423) were assessed by immunohistochemistry, immunofluorescence, and Western blot. C57BL6/J wildtype mice were treated with a single intraperitoneal TNFα injection. Small intestinal organoids from these mice and from PAK1-KO mice were cultured with TNFα. NF-κB and PPARγ were analyzed upon PAK1 overexpression and silencing for transcriptional/translational regulation. PAK1 expression and activation was increased on the luminal intestinal epithelial surface in inflammatory bowel disease and colitis-associated cancer. PAK1 was phosphorylated upon treatment with IFNγ, IL-1β, and TNFα. In vivo, mice administered with TNFα showed increased p-PAK1 in intestinal villi, which was associated with nuclear p65 and NF-κB activation. p65 nuclear translocation downstream of TNFα was strongly inhibited in PAK1-KO small intestinal organoids. PAK1 overexpression induced a PAK1-p65 interaction as visualized by co-immunoprecipitation, nuclear translocation, and increased NF-κB transactivation, all of which were impeded by kinase-dead PAK1. Moreover, PAK1 overexpression downregulated PPARγ and mesalamine recovered PPARγ through PAK1 inhibition. On the other hand PAK1 silencing inhibited NF-κB, which was recovered using BADGE, a PPARγ antagonist. Altogether these data demonstrate that PAK1 overexpression and activation in inflammation and colitis-associated cancer promote NF-κB activity via suppression of PPARγ in intestinal epithelial cells.
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Affiliation(s)
- Kyle Dammann
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria
| | - Vineeta Khare
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria
| | - Michaela Lang
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria
| | - Thierry Claudel
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Hans Popper Laboratory for Molecular Hepatology, Vienna, Austria
| | - Felix Harpain
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria
| | - Nicolas Granofszky
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria
| | - Rayko Evstatiev
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria
| | - Jonathan M Williams
- Department of Gastroenterology, University of Liverpool, Liverpool, United Kingdom
| | - D Mark Pritchard
- Department of Gastroenterology, University of Liverpool, Liverpool, United Kingdom
| | - Alastair Watson
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
| | - Christoph Gasche
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria.
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Dammann K, Khare V, Harpain F, Lang M, Kurtovic A, Mesteri I, Evstatiev R, Gasche C. PAK1 promotes intestinal tumor initiation. Cancer Prev Res (Phila) 2015; 8:1093-101. [PMID: 26304465 DOI: 10.1158/1940-6207.capr-15-0205-t] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 08/04/2015] [Indexed: 11/16/2022]
Abstract
p21-activated kinase 1 (PAK1) is a serine/threonine kinase that is overexpressed in colorectal cancer. PAK1 is a target of mesalamine [5-aminosylicylic acid (5-ASA)], a common drug for the treatment of ulcerative colitis with prospective chemopreventive properties. Here, we investigated whether PAK1 deletion impedes tumorigenesis in murine intestinal cancer models. Ten-week-old APC(min) or APC(min)/PAK1(-/-) mice were monitored for 8 weeks, euthanized, and assessed for tumor number and size. Six- to 8-week-old PAK1(-/-) and wild-type (WT) mice received one 10 mg/kg intraperitoneal injection of azoxymethane (AOM) and four cycles of 1.7% dextran sodium sulfate (DSS) for 4 days followed by 14 days of regular water. Mice also received 5-ASA via diet. Tumor incidence and size was assessed via colonoscopy and pathology. Molecular targets of PAK1 and 5-ASA were evaluated via immunohistochemistry (IHC) in both models. PAK1 deletion reduced tumor multiplicity and tumor burden but did not alter average tumor size in APC(min) mice. IHC revealed that PAK1 deletion reduced p-AKT, β-catenin, and c-Myc expression in APC(min) adenomas. Colonoscopy and pathologic analysis revealed that PAK1 deletion reduced tumor multiplicity without affecting tumor size in AOM/DSS-treated mice. 5-ASA treatment and PAK1 deletion impeded tumor multiplicity and dysplastic lesions in AOM/DSS mice. IHC further revealed that 5-ASA blocked β-catenin signaling via inhibition of PAK1/p-AKT. These data indicate that PAK1 contributes to initiation of intestinal carcinogenesis.
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Affiliation(s)
- Kyle Dammann
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
| | - Vineeta Khare
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
| | - Felix Harpain
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
| | - Michaela Lang
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
| | - Azra Kurtovic
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
| | - Ildiko Mesteri
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - Rayko Evstatiev
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
| | - Christoph Gasche
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.
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Manzat-Saplacan RM, Mircea PA, Balacescu L, Chira RI, Berindan-Neagoe I, Balacescu O. Can we change our microbiome to prevent colorectal cancer development? Acta Oncol 2015; 54:1085-95. [PMID: 26073561 DOI: 10.3109/0284186x.2015.1054949] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Colorectal cancer represents an important disease as one of the major causes of death worldwide. Although a lot of genetic and epigenetic research has been conducted, all the pieces of the puzzle of colorectal cancer carcinogenesis have not yet been identified. New recent data has highlighted that gut microbiota could have an influence on colorectal carcinogenesis. Gut microbiota represents the microbe population living in the human intestine and contains tens of trillions of microorganisms. MATERIAL AND METHODS A systematic search in Medline and PubMed for studies reporting the influence of gut microbiota and inflammation on patients with colorectal cancer was made. RESULTS In this review we discuss many of the specific bacteria, as well as their metabolites which may have an important role in development of colorectal cancer. Furthermore, we emphasize the molecular mechanisms modulated by gut microbiota, which promote inflammation, toxic metabolites, DNA damaging and pro-carcinogenic compounds, as support for colorectal carcinogenesis. The interrelation between microbiota and inflammation is complex because bacteria and inflammation could mutually impact upon each other. In this context, both endogenous and exogenous miRNAs may have an important role to modulate tumor-related inflammation in colorectal cancer. CONCLUSIONS Better understanding of the role of gut microbiota in colorectal carcinogenesis could provide promising new directions to improve both prevention and treatment of colorectal cancer. Moreover, the discovery of novel biomarkers in the gut microbiome in order to detect colorectal cancer in an early stage or even in a precancerous stage is of outmost importance.
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Affiliation(s)
- Roberta M Manzat-Saplacan
- a University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj-Napoca, 1st Medical Clinic , Cluj-Napoca , Romania
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Barrett CW, Reddy VK, Short SP, Motley AK, Lintel MK, Bradley AM, Freeman T, Vallance J, Ning W, Parang B, Poindexter SV, Fingleton B, Chen X, Washington MK, Wilson KT, Shroyer NF, Hill KE, Burk RF, Williams CS. Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage. J Clin Invest 2015; 125:2646-60. [PMID: 26053663 DOI: 10.1172/jci76099] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 04/30/2015] [Indexed: 12/19/2022] Open
Abstract
Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.
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Stocco G, Cuzzoni E, Iudicibus SD, Favretto D, Malusà N, Martelossi S, Pozzi E, Lionetti P, Ventura A, Decorti G. Thiopurine metabolites variations during co-treatment with aminosalicylates for inflammatory bowel disease: Effect of N-acetyl transferase polymorphisms. World J Gastroenterol 2015; 21:3571-3578. [PMID: 25834322 PMCID: PMC4375579 DOI: 10.3748/wjg.v21.i12.3571] [Citation(s) in RCA: 13] [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: 10/01/2014] [Revised: 11/23/2014] [Accepted: 01/16/2015] [Indexed: 02/07/2023] Open
Abstract
AIM: To evaluate variation of the concentration of thiopurine metabolites after 5-aminosalicylate (5-ASA) interruption and the role of genetic polymorphisms of N-acetyl transferase (NAT) 1 and 2.
METHODS: Concentrations of thioguanine nucleotides (TGN) and methymercaptopurine nucleotides (MMPN), metabolites of thiopurines, were measured by high performance liquid chromatography in 12 young patients (3 females and 9 males, median age 16 years) with inflammatory bowel disease (6 Crohn’s disease and 6 ulcerative colitis) treated with thiopurines (7 mercaptopurine and 5 azathioprine) and 5-ASA. Blood samples were collected one month before and one month after the interruption of 5-ASA. DNA was extracted and genotyping of NAT1, NAT2, inosine triphosphate pyrophosphatase (ITPA) and thiopurine methyl transferase (TPMT) genes was performed using PCR assays.
RESULTS: Median TGN concentration before 5-ASA interruption was 270 pmol/8 x 108 erythrocytes (range: 145-750); after the interruption of the aminosalicylate, a 35% reduction in TGN mean concentrations (absolute mean reduction 109 pmol/8 × 108 erythrocytes) was observed (median 221 pmol/8 × 108 erythrocytes, range: 96-427, P value linear mixed effects model 0.0011). Demographic and clinical covariates were not related to thiopurine metabolites concentrations. All patients were wild-type for the most relevant ITPA and TPMT variants. For NAT1 genotyping, 7 subjects presented an allele combination corresponding to fast enzymatic activity and 5 to slow activity. NAT1 genotypes corresponding to fast enzymatic activity were associated with reduced TGN concentration (P value linear mixed effects model 0.033), putatively because of increased 5-ASA inactivation and consequent reduced inhibition of thiopurine metabolism. The effect of NAT1 status on TGN seems to be persistent even after one month since the interruption of the aminosalicylate. No effect of NAT1 genotypes was shown on MMPN concentrations. NAT2 genotyping revealed that 6 patients presented a genotype corresponding to fast enzymatic activity and 6 to slow activity; NAT2 genotypes were not related to thiopurine metabolites concentration in this study.
CONCLUSION: NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drugs; however the number of patients evaluated is limited and this has to be considered a pilot study.
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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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20
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Foersch S, Neurath MF. Colitis-associated neoplasia: molecular basis and clinical translation. Cell Mol Life Sci 2014; 71:3523-35. [PMID: 24830703 PMCID: PMC11113942 DOI: 10.1007/s00018-014-1636-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Revised: 04/07/2014] [Accepted: 04/28/2014] [Indexed: 02/07/2023]
Abstract
Crohn's disease and ulcerative colitis are both associated with an increased risk of inflammation-associated colorectal carcinoma. Colitis-associated cancer (CAC) is one of the most important causes for morbidity and mortality in patients with inflammatory bowel diseases (IBD). Colitis-associated neoplasia distinctly differs from sporadic colorectal cancer in its biology and the underlying mechanisms. This review discusses the molecular mechanisms of CAC and summarizes the most important genetic alterations and signaling pathways involved in inflammatory carcinogenesis. Then, clinical translation is evaluated by discussing new endoscopic techniques and their contribution to surveillance and early detection of CAC. Last, we briefly address different types of concepts for prevention (i.e., anti-inflammatory therapeutics) and treatment (i.e., surgical intervention) of CAC and give an outlook on this important aspect of IBD.
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Affiliation(s)
- Sebastian Foersch
- Department of Medicine 1, FAU Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany,
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21
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Systematic review of cuff and pouch cancer in patients with ileal pelvic pouch for ulcerative colitis. Inflamm Bowel Dis 2014; 20:1296-308. [PMID: 24681656 DOI: 10.1097/mib.0000000000000026] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Ileal pouch-anal anastomosis (IPAA) is the procedure of choice for refractory or complicated ulcerative colitis (UC). Since 1990, pouch-related adenocarcinomas have been described. The aim of this study was to review the literature to evaluate the burden of this complication, seeking for risk factors, prevention, and ideal management. METHODS We performed a systematic review of the literature to identify all described pouch-related adenocarcinoma in patients operated on with IPAA for UC. Studies were thoroughly evaluated to select authentic de novo pouch carcinomas. Some authors were contacted for additional information. Data of patients were pooled. Meta-analyses of suitable studies were attempted to identify risk factors. RESULTS Thirty-four articles reported on 49 patients (2:1, male:female) who developed unequivocal pouch-related adenocarcinoma, 14 (28.6%) and 33 (67.3%) arising from the pouch and anorectal mucosa, respectively. Origin was not reported in 2 (4%). Pooled cumulative incidence of pouch-related adenocarcinoma was 0.33% (95% confidence interval [CI], 0.31-0.34) 50 years after the diagnosis and 0.35% (95% CI, 0.34-0.36) 20 years after IPAA. Primary pouch cancer incidence was below 0.02% 20 years after IPAA. Neoplasia on colectomy specimen was the strongest risk factor (odds ratio, 8.8; 95% CI, 4.61-16.80). Mucosectomy did not abolish the risk of subsequent cancer but avoiding it increased 8 times the risk of cancer arising from the residual anorectal mucosa (odds ratio, 8; 95% CI, 1.3-48.7; P = 0.02). Surveillance is currently performed yearly starting 10 years since diagnosis, but cancers escaping this pathway are reported. In patients receiving mucosectomy, a 5-year delay for surveillance could be proposed. CONCLUSIONS Pouch-related adenocarcinomas are rare. Diagnosis of Crohn's disease in the long term may further decrease the rates in UC. Presumed evolution from dysplasia might offer a time window for cancer prevention. Abdominoperineal excision should be recommended for pouch-related adenocarcinomas.
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Chapman CG, Rubin DT. The potential for medical therapy to reduce the risk of colorectal cancer and optimize surveillance in inflammatory bowel disease. Gastrointest Endosc Clin N Am 2014; 24:353-65. [PMID: 24975527 PMCID: PMC4165430 DOI: 10.1016/j.giec.2014.03.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
It has been proposed that effective disease control through abrogation of inflammation in IBD may also reduce CRC risk in these individual patients. This article summarizes the potential for medical therapy to reduce the risk of CRC via primary and secondary prevention, and offers practical ways in which a goal of mucosal improvement or healing may be incorporated into clinical practice.
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23
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Rousseaux C, El-Jamal N, Fumery M, Dubuquoy C, Romano O, Chatelain D, Langlois A, Bertin B, Buob D, Colombel JF, Cortot A, Desreumaux P, Dubuquoy L. The 5-aminosalicylic acid antineoplastic effect in the intestine is mediated by PPARγ. Carcinogenesis 2013; 34:2580-6. [PMID: 23843037 PMCID: PMC3810841 DOI: 10.1093/carcin/bgt245] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Epidemiological evidences suggested that 5-aminosalicylic acid (5-ASA) therapy may prevent the development of colorectal cancer in inflammatory bowel disease patients. Our aim is to investigate whether peroxisome proliferator-activated receptor-γ (PPARγ) mediates the antineoplastic effects of 5-ASA. HT-29 and Caco-2 cells were treated by 5-ASA, rosiglitazone (PPARγ ligand) or etoposide (anticarcinogenic drug). Epithelial cell growth, proliferation and apoptosis were assessed by cell count, Ki-67 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, respectively. The antineoplastic effect of 5-ASA was evaluated in a xenograft tumor model in SCID mice and in azoxymethane (AOM)-induced colon carcinogenesis in A/JOlaHsd mice. The role of PPARγ was examined by administration of PPARγ antagonist, GW9662 and in PPAR knockdown cells. Compared with untreated cells, treatment of HT-29 cells by 5-ASA inhibited significantly cell growth and cell proliferation (respectively, 60% and 63%) and induced apoptosis in 75% of cells. These effects were abolished by co-treatment with GW9662 and blunted in PPAR knockdown cells. Contrarily to etoposide, similar inhibitory effects of GW9662 were obtained in HT-29 cells treated with rosiglitazone. In the xenograft model, GW9662 abolished the therapeutic effect of 5-ASA, which decreased tumor weight and volume by 80% in SCID mice compared with untreated mice. In A/JOlaHsd mice, 5-ASA suppressed colon carcinogenesis by decreasing the number of aberrant crypt foci (75%) and aberrant crypts (22%) induced by AOM treatment with an absence of 5-ASA response after GW9662 administration. In conclusion, 5-ASA exerts potent antineoplastic effects that are mediated through PPARγ. These data provide new rational for designing more effective and safe antineoplastic PPARγ ligands with topical effects.
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Affiliation(s)
- Christel Rousseaux
- Department of Project Management, Intestinal Biotech Development, 59045 Lille, France
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Matsuoka H, Ikeuchi H, Uchino M, Bando T, Takesue Y, Nishigami T, Tomita N. Clinicopathological features of ulcerative colitis-associated colorectal cancer pointing to efficiency of surveillance colonoscopy in a large retrospective Japanese cohort. Int J Colorectal Dis 2013; 28:829-34. [PMID: 23080343 DOI: 10.1007/s00384-012-1592-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/09/2012] [Indexed: 02/04/2023]
Abstract
PURPOSE Cancer surveillance has been conducted in patients with ulcerative colitis (UC), and the number of operative cases of ulcerative colitis-associated colorectal cancer (UC-CRC) has been increasing. The aim of this study was to clarify the clinicopathological features and prognoses of UC-CRC patients and the relationship between surveillance colonoscopy and UC-CRC. METHODS The clinical records of 1,274 UC patients who required surgery between 1984 and 2010 at a single institution were reviewed retrospectively. Of these, 83 patients had CRC (107 sections). All cases were extracted from the database, along with their clinicopathological data. RESULTS The 5-year survival rate of the UC-CRC group was 89 %. The 5-year survival rate was 100 % in stages 0 and II, 96 % in stage I, 56 % in stage III, and 0 % in stage IV. Surveillance colonoscopy was performed for 40 of the 83 patients. Of 40 patients, 30 with UC who underwent surveillance colonoscopies and 22 of 43 patients without surveillance colonoscopies were in stages 0 to I (P = 0.04). CONCLUSION The number of UC-CRC patients who are diagnosed by surveillance colonoscopy is increasing, and many of them are detected in the very early stages (stages 0 or I). Thus, the survival rate of UC-CRC is better than before. Surveillance colonoscopy proofs efficient as CRC are detected in earlier stages.
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Affiliation(s)
- Hiroki Matsuoka
- Department of Surgery, Hyogo College of Medicine, 663-8501, Mukogawa-cho, Nishinomiya, Hyogo, Japan.
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Bermejo F, Gisbert JP. Usefulness of salicylate and thiopurine coprescription in steroid-dependent ulcerative colitis and withdrawal strategies. Ther Adv Chronic Dis 2012; 1:107-14. [PMID: 23251733 DOI: 10.1177/2040622310374897] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
5-aminosalicylic acid (5-ASA) and thiopurines (azathioprine and mercaptopurine) are the most common drugs used as a maintenance treatment for ulcerative colitis. A considerable proportion of these patients develop corticosteroid dependency, and thiopurines are the standard treatment in this scenario. Dual prescriptions of both thiopurines and 5-ASA are common practice in steroid-dependent ulcerative colitis, in an attempt to optimize the efficacy of therapy. On the one hand, the potential protective role of 5-ASA against colorectal cancer argues in favour of prescription of both medications. The possible synergism between the two drugs, because of the inhibition of thiopurine methyltransferase (TPMT) enzyme activity by 5-ASA, has been postulated as another justification for dual prescription. However, existing evidence does not support that this combined strategy is superior to monotherapy with thiopurines. On the other hand, in patients showing prolonged disease remission, the possibility of discontinuing maintenance treatment can be considered on an individualized basis. The high frequency of relapses after thiopurine withdrawal should always be taken into account, but the potential adverse effects of the medication also need to be considered. A properly indicated treatment with thiopurines may need to be continued for life in many patients.
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Affiliation(s)
- Fernando Bermejo
- Javier P. Gisbert, MD, PhD Hospital Universitario de La Princesa and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
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26
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Grivennikov SI. Inflammation and colorectal cancer: colitis-associated neoplasia. Semin Immunopathol 2012; 35:229-44. [PMID: 23161445 DOI: 10.1007/s00281-012-0352-6] [Citation(s) in RCA: 407] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Accepted: 09/27/2012] [Indexed: 12/12/2022]
Abstract
Connection between inflammation and cancer is a rapidly developing field. Epidemiological data suggests that inflammation along with distinct arms of host immune system plays a very important role in the development and progression of many different cancers. Inflammatory bowel disease (IBD) is an important risk factor for the development of colon cancer, namely, colitis-associated cancer (CAC). The molecular mechanisms by which inflammation promotes cancer development are still being uncovered and may differ between CAC and other forms of colorectal cancer. Recent work has shed light on the role of distinct immune cells, cytokines, and other immune mediators in virtually all of the steps of colonic tumorigenesis, including tumor initiation and promotion as well as progression and metastasis. The close proximity of colonic tumors to the myriad of intestinal microbes, as well as instrumental role of microbiota in IBD, introduces microbes as new players capable of triggering inflammation and possibly promoting tumorigenesis. Various mechanisms of CAC tumorigenesis as well as new possible hints for the future approaches for prevention and therapy are discussed in this review.
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Affiliation(s)
- Sergei I Grivennikov
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
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Latella G, Papi C. Crucial steps in the natural history of inflammatory bowel disease. World J Gastroenterol 2012; 18:3790-9. [PMID: 22876029 PMCID: PMC3413049 DOI: 10.3748/wjg.v18.i29.3790] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Revised: 04/18/2012] [Accepted: 05/05/2012] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic, progressive and disabling disorders. Over the last few decades, new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD. The identification of clinical, genetic and serological prognostic factors has permitted a better stratification of the disease, thus allowing the opportunity to indicate the most appropriate therapy. Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change, at least in the short term, the course of the disease by reducing, in a subset of patients with IBD, hospitalization and the need for surgery. In this review, the crucial steps in the natural history of both UC and CD will be discussed, as well as the factors that may change their clinical course. The methodological requirements for high quality studies on the course and prognosis of IBD, the true impact of environmental and dietary factors on the clinical course of IBD, the clinical, serological and genetic predictors of the IBD course (in particular, which of these are relevant and appropriate for use in clinical practice), the impact of the various forms of medical treatment on the IBD complication rate, the role of surgery for IBD in the biologic era, the true magnitude of risk of colorectal cancer associated with IBD, as well as the mortality rate related to IBD will be stressed; all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.
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2-Methoxy-5-amino-N-hydroxybenzamide, a derivative of mesalamine, inhibits colon cancer cell growth through cyclo-oxygenase-2-dependent and -independent mechanisms. Clin Sci (Lond) 2012; 123:295-306. [PMID: 22435743 DOI: 10.1042/cs20110556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
COX-2 (cyclo-oxygenase-2) and PGE₂ (prostaglandin E₂) play a key role in sustaining CRC (colorectal cancer) cell growth and survival. Indeed, the use of agents targeting the COX-2/PGE₂ axis has been associated with a reduction in the development of CRC in both humans and murine models of colon carcinogenesis. In the present study, we investigated whether 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a derivative of mesalamine that inhibits CRC cell growth both in vitro and in vivo, negatively regulates COX-2/PGE₂ expression in CRC cells and assessed whether the 2-14-mediated anti-neoplastic effect is strictly dependent on the inhibition of this pathway. Our results show that 2-14 blocks the growth and enhances the death of HT-115, a CRC cell line overexpressing COX-2, and that these effects associate with inhibition of COX-2 but not COX-1. 2-14 also down-regulates TNFα (tumour necrosis factor α)-induced COX-2 in HT-29 cells as well as COX-2/PGE₂ expression in ex vivo cultures of human CRC explants. Similarly, 2-14 reduces COX-2, but not COX-1, in tumoural areas developing in a mouse model of CAC (colitis-associated colon cancer). Finally, we show that 2-14 exhibits in vitro and in vivo anti-mitogenic effects in DLD-1, a COX-deficient CRC cell line. Taken together, these results suggest that 2-14 inhibits CRC cell growth through COX-2-dependent and -independent mechanisms.
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Gerlach K, Daniel C, Lehr HA, Nikolaev A, Gerlach T, Atreya R, Rose-John S, Neurath MF, Weigmann B. Transcription factor NFATc2 controls the emergence of colon cancer associated with IL-6-dependent colitis. Cancer Res 2012; 72:4340-50. [PMID: 22738913 DOI: 10.1158/0008-5472.can-11-4155] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
NFAT transcription factors control T-cell activation and function. Specifically, the transcription factor NFATc2 affects the regulation of cell differentiation and growth and plays a critical role in the development of colonic inflammation. Here, we used an experimental model of colitis-associated colorectal carcinoma to investigate the contribution of NFATc2 to the promotion of colonic tumors. Compared with wild-type animals that readily presented with multiple colon tumors, NFATc2-deficient mice were protected from tumor development. This observed decrease in colonic tumor progression was associated with reduced endoscopic inflammation, increased apoptosis of lamina propria T lymphocytes, and significantly reduced levels of the critical proinflammatory cytokines interleukin (IL)-21 and IL-6. Administration of hyper IL-6 abrogated protection from tumor progression in NFATc2-knockout mice and restored tumor incidence to control levels. Taken together, our findings highlight a pivotal role for NFATc2 in the establishment of inflammation-associated colorectal tumors mediated by control of IL-6 expression.
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Affiliation(s)
- Katharina Gerlach
- I. Medical Clinic, University of Erlangen-Nuremberg, Erlangen; Institute of Diabetes Research, Helmholtz Zentrum Muenchen, Neuherberg, Switzerland
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30
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Poudyal D, Le PM, Davis T, Hofseth AB, Chumanevich A, Chumanevich AA, Wargovich MJ, Nagarkatti M, Nagarkatti PS, Windust A, Hofseth LJ. A hexane fraction of American ginseng suppresses mouse colitis and associated colon cancer: anti-inflammatory and proapoptotic mechanisms. Cancer Prev Res (Phila) 2012; 5:685-96. [PMID: 22293630 DOI: 10.1158/1940-6207.capr-11-0421] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ulcerative colitis is a chronic inflammatory condition associated with a high colon cancer risk. We have previously reported that American ginseng extract significantly reduced the inflammatory parameters of chemically induced colitis. The aim of this study was to further delineate the components of American ginseng that suppress colitis and prevent colon cancer. Among five different fractions of American ginseng (butanol, hexane, ethylacetate, dichloromethane, and water), a hexane fraction has particularly potent antioxidant and proapoptotic properties. The effects of this fraction were shown in a mouse macrophage cell line (ANA-1 cells), in a human lymphoblastoid cell line (TK6), and in an ex vivo model (CD4(+)/CD25(-) primary effector T cells). A key in vivo finding was that compared with the whole American ginseng extract, the hexane fraction of American ginseng was more potent in treating colitis in a dextran sodium sulfate (DSS) mouse model, as well as suppressing azoxymethane/DSS-induced colon cancer. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) labeling of inflammatory cells within the colonic mesenteric lymph nodes was elevated in mice consuming DSS + the hexane fraction of American ginseng. Results are consistent with our in vitro data and with the hypothesis that the hexane fraction of American ginseng has anti-inflammatory properties and drives inflammatory cell apoptosis in vivo, providing a mechanism by which this fraction protects from colitis in this DSS mouse model. This study moves us closer to understanding the molecular components of American ginseng that suppress colitis and prevent colon cancer associated with colitis.
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Affiliation(s)
- Deepak Poudyal
- Department of Biomedical and Pharmaceutical Sciences, South Carolina College of Pharmacy, University of South Carolina, 770 Sumter St., Coker Life Sciences, Columbia, SC 29208, USA
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Ruiz JFM, Kedziora K, Keogh B, Maguire J, Reilly M, Windle H, Kelleher DP, Gilmer JF. A double prodrug system for colon targeting of benzenesulfonamide COX-2 inhibitors. Bioorg Med Chem Lett 2011; 21:6636-40. [PMID: 21983446 DOI: 10.1016/j.bmcl.2011.09.071] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 09/17/2011] [Accepted: 09/19/2011] [Indexed: 11/24/2022]
Abstract
The design, synthesis and delivery potential of a new type of benzenesulfonamide cyclo-oxygenase-2 (COX-2) inhibitor prodrug is investigated using celecoxib. The approach involves a double prodrug that is activated first by azoreductases and then by cyclization triggering drug release. We studied the intramolecular aminolysis of the acylsulfonamide. The cyclization was surprisingly rapid at physiological pH and very fast at pH 5. The prodrug is activated specifically under conditions found in the colon but highly stable in the presence of human and rodent intestinal extracts. Finally, the prototype with celecoxib was transported much more slowly in the Caco-2 transepithelial model than the parent. The design therefore shows significant promise for the site specific delivery of benzenesulfonamide COX-2 inhibitors to the colon.
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Affiliation(s)
- Juan F Marquez Ruiz
- School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland
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33
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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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5-aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study. Am J Gastroenterol 2011; 106:731-6. [PMID: 21407180 DOI: 10.1038/ajg.2011.50] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES We aimed to determine if use of 5-aminosalicylates (5-ASA) was associated with a reduced risk of colorectal cancer (CRC) in people with inflammatory bowel disease (IBD). METHODS We used the population-based University of Manitoba IBD Epidemiology Database that tracks all health-care visits from 1984 to 2008 of all Manitobans with IBD and all prescription medication use since 1995. In 2008, there were 8,744 subjects with IBD (ulcerative colitis 4,325, Crohn's disease 4,419, females 4,851, males 3,893). In study I, we assessed the incidence of CRC among 5-ASA users (≥1 year, ≥5 years of cumulative use) compared with nonusers. In study II, we assessed a cohort of those with CRC (n=101) diagnosed in 1995-2008, matched to a control cohort by age, sex, disease duration, and disease diagnosis without CRC (n=303), and logistic analysis was undertaken. RESULTS For study I, the hazard ratio for CRC among 5-ASA users was 1.04 (95% confidence interval (CI) 0.67-1.62, P=0.87) at ≥1 year of use and 2.01 (95% CI 1.04-3.9, P=0.038) at ≥ 5 years of use with no difference when assessing by diagnosis. Males, but not females, using 5-ASA for ≥ 5 years had an increased risk of CRC. In study II, CRC cases had similar use of any 5-ASA compared with controls for ≥ 1 year of use (1.02, 95% CI 0.60-1.74) or ≥ 5 years (1.96, 95% CI 0.84-4.55), and a similar mean number of 5-ASA prescriptions at 10 vs. 11 (P=0.8) and a similar mean number of dose days at 330 vs. 410 (P=0.69). CONCLUSIONS Our results support the majority of studies to date that 5-ASA is not chemoprophylactic in IBD for CRC.
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Qualtrough D, Smallwood K, Littlejohns D, Pignatelli M. The actin-bundling protein fascin is overexpressed in inflammatory bowel disease and may be important in tissue repair. BMC Gastroenterol 2011; 11:14. [PMID: 21345224 PMCID: PMC3050849 DOI: 10.1186/1471-230x-11-14] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Accepted: 02/23/2011] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Fascin is associated with increased cell motility in colorectal tumours but is absent from the normal colonic epithelium. We examined the expression of fascin in inflammatory bowel disease (IBD) and its location at regions undergoing restitution and regeneration. Tissue repair is essential for disease remission and we sought to determine the effects of therapeutic modalities on fascin expression and function using an in vitro model. METHODS Immunohistochemistry was performed on colonic tissue from IBD patients to determine changes in fascin expression and distribution. A human colorectal epithelial cell line was treated with 5-aminosalicylate (a common treatment for IBD), or sodium butyrate to determine the effect on fascin expression and cell motility. RESULTS Fascin overexpression was observed in both ulcerative colitis and Crohn's colitis and expression correlated with disease severity. Immunoreactivity was more intense and widespread in Crohn's compared to ulcerative colitis. Interestingly, highly expressing foci were consistently observed at the edges of ulcers where flattened, motile epithelial cells are actively involved in restitution, and also in areas of mucosal regeneration.5-aminosalicylate reduced fascin expression in colorectal epithelial cells and inhibited their motility. Conversely, sodium butyrate increased fascin expression and stimulated cell motility in the same cells. CONCLUSIONS Our data shows that fascin is overexpressed in inflammatory bowel disease and its location is indicative of a role in tissue repair. Our in vitro studies show that different therapeutic modalities may have converse effects on fascin expression and may have significant consequences for disease remission and the clinical management of IBD.
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Affiliation(s)
- David Qualtrough
- School of Cellular and Molecular Medicine, University of Bristol, UK.
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Baars JE, Looman CWN, Steyerberg EW, Beukers R, Tan ACITL, Weusten BLAM, Kuipers EJ, van der Woude CJ. The risk of inflammatory bowel disease-related colorectal carcinoma is limited: results from a nationwide nested case-control study. Am J Gastroenterol 2011; 106:319-28. [PMID: 21045815 DOI: 10.1038/ajg.2010.428] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The risk for inflammatory bowel disease (IBD)-related colorectal cancer (CRC) remains a matter of debate. Initial reports mainly originate from tertiary referral centers, and conflict with more recent studies. Overall, epidemiology of IBD-related CRC is relevant to strengthen the basis of surveillance guidelines. We performed a nationwide nested case-control study to assess the risk for IBD-related CRC and associated prognostic factors in general hospitals. METHODS IBD patients diagnosed with CRC between January 1990 and July 2006 in 78 Dutch general hospitals were identified as cases, using a nationwide automated pathology database. Control IBD patients without CRC were randomly selected. Clinical data were collected from detailed chart review. Poisson regression analysis was used for univariable and multivariable analyses. RESULTS A total of 173 cases were identified through pathology and chart review and compared with 393 controls. The incidence rate of IBD-related CRC was 0.04%. Risk factors for IBD-related CRC were older age, concomitant primary sclerosing cholangitis (PSC, relative ratio (RR) per year duration 1.05; 95% confidence interval (CI) 1.01-1.10), pseudopolyps (RR 1.92; 95% CI 1.28-2.88), and duration of IBD (RR per year 1.04; 95% CI 1.02-1.05). Using immunosuppressive therapy (odds ratio (OR) 0.3; 95% CI 0.16-0.56, P<0.001) or anti-tumor necrosis factor (TNF) (OR 0.09; 95% CI 0.01-0.68, P<0.02) was protective. CONCLUSIONS We found a limited risk for developing IBD-related CRC in The Netherlands. Age, duration of PSC and IBD, concomitant pseudopolyps, and use immunosuppressives or anti-TNF were strong prognostic factors in general hospitals.
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Affiliation(s)
- Judith E Baars
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.
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Kariv R, Navaneethan U, Venkatesh PGK, Lopez R, Shen B. Impact of Clostridium difficile infection in patients with ulcerative colitis. J Crohns Colitis 2011; 5:34-40. [PMID: 21272802 DOI: 10.1016/j.crohns.2010.09.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2010] [Revised: 09/26/2010] [Accepted: 09/27/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND Clostridium difficile infection (CDI) is becoming prevalent in general population as well as in patients with inflammatory bowel disease (IBD). AIM The aim of the study was to identify risk factors for CDI in patients with ulcerative colitis (UC) and to assess outcome of UC in patients following CDI. METHODS UC inpatients or outpatients who had positive results for C. difficile toxins A and B between 2000 and 2006 were identified (N=39) and matched for age and gender to UC patients who were negative C. difficile toxins and had never been diagnosed with CDI (N=39). Records were reviewed for adverse clinical outcome, defined as colectomy within 3 months of C. difficile testing. Conditional logistic regression was used to analyze multivariable association to identify risk factors for CDI and for adverse clinical outcome. RESULTS A total of 78 subjects were analyzed, 60% were males. Median age was 39. Among 39 patients with CDI, 20 (47.2%) were diagnosed as outpatients, 50% failed treatment with the first antibiotic monotherapy, and 21.2% had recurrent infection. Antibiotic exposure within 30 days prior to C. difficile testing was found to be associated with an increased risk for CDI with an odds ratio of 12.0 (95% CI 1.2, 124.2) Subsequent colectomy within 3 months after CDI diagnosis, was not associated with CDI in both univariable and multivariable analyses. After adjusting for CDI, lack of 5-aminosalicylic acid (ASA) in the treatment regimen was significantly associated with colectomy with an odds ratio of 3.3 (95% CI: 1.2, 9.4). There was no UC- or CDI-associated mortality in this case series. CONCLUSIONS Recent antibiotic exposure was a risk factor for CDI in UC patients. Interestingly, CDI does not seem to adversely affect short-term adverse clinical outcome (colectomy).
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Affiliation(s)
- Revital Kariv
- Department of Gastroenterology, Digestive Disease Institute, The Cleveland Clinic, Cleveland, OH 44195, USA
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Laurent C, Svrcek M, Flejou JF, Chenard MP, Duclos B, Freund JN, Reimund JM. Immunohistochemical expression of CDX2, β-catenin, and TP53 in inflammatory bowel disease-associated colorectal cancer. Inflamm Bowel Dis 2011; 17:232-40. [PMID: 20815042 DOI: 10.1002/ibd.21451] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Accepted: 07/07/2010] [Indexed: 12/23/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) exposes patients to an increased risk of colorectal cancer (i-CRC) and differences between i-CRC and sporadic colorectal cancer (s-CRC) pathogenesis were reported. In s-CRC, studies indicate abnormalities in the tumor-suppressor gene Cdx2. This study compared CDX2, β-catenin, and TP53 expression in i-CRC, s-CRC, noncancer IBD, and normal control colonic mucosa. METHODS Expression was investigated by immunohistochemistry in 10 normal, 20 s-CRC, 11 noncancer colonic IBD and 30 i-CRC samples, and in four samples of Crohn's disease (CD)-associated small bowel adenocarcinoma (i-SBA). RESULTS In normal and noncancer IBD samples, CDX2 was confined to the colonocytes nuclei. CDX2 expression was normal in 90% of i-CRC, regardless of tumor differentiation or inflammation intensity. By contrast, CDX2 expression was altered in 45% s-CRC, particularly at the front of invasion in undifferentiated tumors. β-Catenin was restricted to cell membrane in all controls, in 91% noncancer IBD, and in 84% i-CRC samples, whereas 35% s-CRC showed cytoplasmic redistribution and exclusive nuclear staining at the front of invasion. TP53 was strongly and homogeneously expressed in i-CRC nuclei compared to normal control or s-CRC, and increases with inflammation intensity. Nested or diffuse TP53 was found in 81.8% of noncancer IBD samples with a higher proportion of TP53-expressing cells in the most inflamed samples. CDX2, β-catenin, and TP53 expression in CD-associated SBA appears similar to that of i-CRC. Neither Cdx2 nor β-catenin alterations are prominent features of i-CRC. CONCLUSIONS In i-CRC and CD-associated SBA, carcinogenesis is associated early with p53 mutations and to inflammation intensity.
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Affiliation(s)
- Camille Laurent
- Département de Pathologie, Pôle de Biologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.
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Gisbert JP, Gomollón F, Hinojosa J, López San Román A. Adherence of gastroenterologists to European Crohn's and Colitis Organisation consensus on ulcerative colitis: a real-life survey in Spain. J Crohns Colitis 2010; 4:567-74. [PMID: 21122561 DOI: 10.1016/j.crohns.2010.06.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2010] [Revised: 06/11/2010] [Accepted: 06/11/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS A European consensus on the management of ulcerative colitis (UC) was recently published; however, there is no adequate evidence about adherence to such guidelines among gastroenterologists. This knowledge would allow the local evaluation of the situation and the adoption of actions to reduce the existent clinical variability. METHODS A cross-sectional survey was conducted in Spain to assess the adherence to the European Crohn's and Colitis Organisation (ECCO) guidelines on mild to moderate UC. We surveyed 700 gastroenterologists, and finally a total of 530 gastroenterologists specialised in inflammatory bowel disease (GSIBDs) and general gastroenterologists (GGs), responded to the survey (76%). RESULTS Agreement with the guidelines was high; discrepancies included that only 25% of the GGs used the combination of oral and topical 5-aminosalycilic acid (5-ASA) for treating extensive UC vs 45% of the GISBDs. In addition, topical rectal steroids were considered as effective as topical mesalazine by 48% of the GGs vs 31% of the GSIBDs, indefinite treatment with 5-ASA was prescribed by only 26% of the GGs vs 41% of the GSIBDs, and the once daily dosing of 5-ASA was generally used by 46% of the GGs vs 51% of the GSIBDs. CONCLUSIONS The questionnaire showed a high degree of agreement between GGs and GSIBDs. Nevertheless, the GSIBD group showed closer agreement with the ECCO guidelines. Furthermore, some shortcomings were found in the GG group, in which increased maintenance treatment with 5-ASA, the use of a single daily dose of 5-ASA, and the use of combined oral and topical treatment for distal colitis should be advised.
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Affiliation(s)
- J P Gisbert
- Departamento de Gastroenterología, Hospital Universitario La Princesa and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain.
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Cui X, Jin Y, Poudyal D, Chumanevich AA, Davis T, Windust A, Hofseth A, Wu W, Habiger J, Pena E, Wood P, Nagarkatti M, Nagarkatti PS, Hofseth L. Mechanistic insight into the ability of American ginseng to suppress colon cancer associated with colitis. Carcinogenesis 2010; 31:1734-41. [PMID: 20729391 DOI: 10.1093/carcin/bgq163] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
We have recently shown that American ginseng (AG) prevents and treats mouse colitis. Because both mice and humans with chronic colitis have a high colon cancer risk, we tested the hypothesis that AG can be used to prevent colitis-driven colon cancer. Using the azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model of ulcerative colitis, we show that AG can suppress colon cancer associated with colitis. To explore the molecular mechanisms of the anticancer effects of AG, we also carried out antibody array experiments on colon cells isolated at a precancerous stage. We found there were 82 protein end points that were either significantly higher (41 proteins) or significantly lower (41 proteins) in the AOM + DSS group compared with the AOM-alone (control) group. In contrast, there were only 19 protein end points that were either significantly higher (10 proteins) or significantly lower (9 proteins) in the AOM + DSS + AG group compared with the AOM-alone (control) group. Overall, these results suggest that AG keeps the colon environment in metabolic equilibrium when mice are treated with AOM + DSS and gives insight into the mechanisms by which AG protects from colon cancer associated with colitis.
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Affiliation(s)
- Xiangli Cui
- Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina and Medical University of South Carolina, SC 29208, USA
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41
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Mesalamine protects against colorectal cancer in inflammatory bowel disease. Dig Dis Sci 2010; 55:1696-703. [PMID: 19705280 DOI: 10.1007/s10620-009-0942-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2009] [Accepted: 08/06/2009] [Indexed: 12/15/2022]
Abstract
BACKGROUND Individuals with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC) compared with the general population. Previous studies show this risk is strongly associated with dysplasia, extent of disease, duration of disease, and degree of inflammation, while chemoprevention of CRC has less support. AIM Evaluate factors influencing risk of colorectal cancer development in inflammatory bowel disease patients. METHODS IBD patients with CRC were matched to controls by IBD type, age at diagnosis, sex, race, extent of disease, and disease duration. We compared body mass index, family history of IBD, family history of CRC, tobacco use, and cumulative and daily use of aminosalicylates, immunomodulators, folic acid, steroids, and nonsteroidal anti-inflammatory drugs. Statistical analysis was performed with logistic regression and receiver operating characteristic (ROC) curves. RESULTS Of 1,594 IBD patients, 30 CRC patients were identified. Of these, 18 CRC patients were matched to 30 controls. More control patients used a cumulative aminosalicylate dose of >or=4,500 g (46.6% versus 5.6%; P = 0.047), folic acid (40.0% versus 16.7%; P = 0.002), cumulative folic acid dose of >or=1,400 mg (30.0% versus 11.1%; P = 0.014), and average daily folic acid dose of >or=1 mg (30.0% versus 16.7%; P = 0.002) compared with CRC patients. Multivariate analysis showed that a cumulative aminosalicylate dose of >or=4,500 g reduced the risk of CRC by 97.6% (P = 0.047). Folic acid reduced CRC risk by 89% (P = 0.002). CONCLUSIONS Aminosalicylate and folic acid use may decrease the risk of CRC among IBD patients.
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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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Campregher C, Honeder C, Chung H, Carethers JM, Gasche C. Mesalazine reduces mutations in transforming growth factor beta receptor II and activin type II receptor by improvement of replication fidelity in mononucleotide repeats. Clin Cancer Res 2010; 16:1950-6. [PMID: 20197483 DOI: 10.1158/1078-0432.ccr-09-2854] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
PURPOSE Mesalazine (5-aminosalicylic acid, 5-ASA) has chemopreventive properties in colitis-associated cancer. In vitro, it improves replication fidelity at (CA)13 microsatellites independent of mismatch repair proficiency. Therefore, 5-ASA might be advantageous in patients with hereditary nonpolyposis colorectal cancer. At this point, however, it is uncertain whether this improvement of replication fidelity is specific for (CA)13 repetitive sequences. Here, we tested the effect of 5-ASA on replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats. EXPERIMENTAL DESIGN HCT116 and HCT116+chr3 cells were transfected with pIREShyg2-EGFP reporter plasmids harboring the following microsatellites: A10, G10, (CA)13, (CA)26, (AAAG)17, poly-A tracts, and their flanking sequences of transforming growth factor beta receptor II (TGFBR2; A10) and activin type II receptor (ACVR2; A8). Stably transfected single-cell clones were selected, characterized by Southern blotting, sorted into six-well plates, and cultured with or without 5-ASA. Frameshift mutations that shift the enhanced green fluorescence protein into its proper reading frame were quantified by flow cytometry. RESULTS In HCT116, 5-ASA reduced the mutant fraction at (CA)13 by 48.3%, at A10 by 35.6-43.6%, at G10 by 74.9-83.6%, and at (AAAG)17 by 37.6-44.4%. Similar results were observed in hMLH1-proficient HCT116+chr3 cells. Moreover, the presence of 5-ASA significantly reduced mutations in TGFBR2 (A10) and ACVR2 (A8) by 39.9% and 46.2%, respectively. CONCLUSIONS 5-ASA increases replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats and reduces mutations in tumor suppressor genes TGFBR2 and ACVR2, a finding that may provoke in vivo studies for the prevention of colorectal cancer in hereditary nonpolyposis colorectal cancer.
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Affiliation(s)
- Christoph Campregher
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
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Wasan SK, Farraye FA. Do 5-ASAs prevent colorectal neoplasia in patients with ulcerative colitis? Still no answers. Inflamm Bowel Dis 2010; 16:358-60. [PMID: 19685451 DOI: 10.1002/ibd.21065] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Sharmeel K Wasan
- Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA
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Terdiman JP, Johnson LK, Kim YS, Sleisenger MH, Gum JR, Hayes A, Weinberg VK, McQuaid KR. Chemoprevention of colonic polyps with balsalazide: an exploratory, double-blind, placebo-controlled study. Dig Dis Sci 2009; 54:2488-96. [PMID: 19757048 PMCID: PMC2762046 DOI: 10.1007/s10620-009-0966-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2009] [Accepted: 08/20/2009] [Indexed: 01/19/2023]
Abstract
BACKGROUND A number of agents, including aspirin, nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, folic acid, calcium, and vitamins, have been evaluated for their potential in chemoprevention of sporadic colorectal adenomas or cancer. Preclinical data suggest that 5-aminosalicylates also may have a chemopreventive effect. AIM To investigate chemoprevention of colonic polyps with balsalazide, a 5-aminosalicylate prodrug. METHODS In this randomized, double-blind, placebo-controlled study, adults diagnosed with small polyps in the rectosigmoid colon were treated with either balsalazide 3 g/d or placebo for 6 months. Follow-up lower endoscopy was performed, and all polyps were measured and analyzed histologically. The primary endpoint was reduction in mean size of the largest polyp per subject. RESULTS Among 241 participants screened, 86 were randomized to treatment, with 75 subjects evaluable. Balsalazide 3 g/d (n = 38) did not significantly reduce the mean size of the largest colonic polyp or the number of polyps compared with placebo (n = 37). Although not significant, post-hoc analysis revealed that total adenoma burden per subject, calculated as the sum of the volumes of all adenomas in mm3, increased by 55% in the balsalazide group compared with 95% in the placebo group. CONCLUSIONS Although balsalazide did not have significant chemopreventive effects on established colonic polyps, these results can aid in designing future prospective studies.
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Affiliation(s)
- Jonathan P. Terdiman
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA
| | | | - Young S. Kim
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA ,Department of Veterans Affairs Medical Center, San Francisco, CA USA
| | - Marvin H. Sleisenger
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA ,Department of Veterans Affairs Medical Center, San Francisco, CA USA
| | - James R. Gum
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA ,Department of Veterans Affairs Medical Center, San Francisco, CA USA
| | - Ann Hayes
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA ,Department of Veterans Affairs Medical Center, San Francisco, CA USA
| | - Vivian K. Weinberg
- Helen Diller Family Cancer Center Biostatistics Core, University of California, San Francisco, Box 1623, San Francisco, CA 94143 USA
| | - Kenneth R. McQuaid
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA ,Department of Veterans Affairs Medical Center, San Francisco, CA USA
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Daperno M, Sostegni R, Canaparo R, Serpe L, Lavagna A, Crocellà L, Castagno F, Vernetto A, Rigazio C, Ercole E, D'Antico S, Pera A, Zara G, Rocca R. Prospective study of the effects of concomitant medications on thiopurine metabolism in inflammatory bowel disease. Aliment Pharmacol Ther 2009; 30:843-53. [PMID: 19650826 DOI: 10.1111/j.1365-2036.2009.04106.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Thiopurines are increasingly used in the treatment of inflammatory bowel disease (IBD), being the most common immunosuppressive therapy; however, potentially harmful interactions between thiopurines and other drugs (especially 5-aminosalicylic acid, 5-ASA) were described. AIM To explore potential interactions between thiopurines and concomitant medications. METHODS A total of 183 consecutive IBD patients were enrolled. Clinical characteristics and concomitant medications were recorded. Thiopurine metabolism was analysed with thiopurine S-methyl transferase (TPMT) genetic variants and enzyme activity assays. Comparisons were carried out with stratification of patients according to clinical characteristics and active treatments. RESULTS Based on TPMT genetics, 95% IBD patients were wild-type homozygous, the remaining being heterozygous. Median TPMT activity was 24.9 U/Hgb g (IQR 20.7-29.5). No difference in TPMT activity was noted according to 5-ASA exposure. IBD patients on thiopurines had higher TPMT activity levels, but no dose-effect was evident. No difference in TPMT activity was observed in 41 (63%) patients co-treated with 5-ASA. In patients on active thiopurines also, 6-TGN and 6-MMP levels were evaluated and no significant difference was observed based on co-medication. TPMT activity was independently associated only with thiopurines dose (P = 0.016). CONCLUSIONS Our data suggest the absence of significant interactions between thiopurines and 5-ASA.
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Affiliation(s)
- M Daperno
- Gastroenterology Division, A.O. Ordine Mauriziano, Torino, Italy.
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GOEL A, MITTAL A, EVSTATIEV R, NEMETH M, KRUIS W, STOLTE M, BOLAND CR, GASCHE C. In vivo effects of mesalazine or E. coli Nissle 1917 on microsatellite instability in ulcerative colitis. Aliment Pharmacol Ther 2009; 30:634-42. [PMID: 19558562 PMCID: PMC2853877 DOI: 10.1111/j.1365-2036.2009.04076.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Microsatellite instability (MSI) occurs in chronically inflamed colorectal tissue and may evolve to colitis-associated cancer. In vitro data suggest that mesalazine (5-ASA) improves MSI. AIM To analyse the changes in MSI in 156 distal colonic biopsies of 39 patients with ulcerative colitis that had been treated within a randomized, double-blind trial comparing 5-ASA with E. coli Nissle (EcN). METHODS Two biopsies had been collected before and after 1 year of treatment. MSI testing was performed using a panel of eight markers, including 3 dinucleotide and 5 mononucleotide repeats. RESULTS No MSI was observed with any of the mono-repeats, and among dinucleotide repeats, only D5S346 (maps to APC) and D17S250 (p53) were consistently informative. Overall, 31/156 (20%) biopsies displayed MSI. After 1 year, 3/11 patients displayed MSI improvement [change to microsatellite stability (MSS); 1 on 5-ASA, 2 on EcN] at D5S346 and 4/11 showed MSI worsening (change from MSS to MSI; all 5-ASA). For D17S250, the corresponding data were for 3/9 patients (2 on 5-ASA, 1 on EcN) and 2/9 (both on 5-ASA), respectively. CONCLUSIONS In the set of biopsies taken from patients treated with 1.5 g 5-ASA for 1 year, there was no improvement in the prevalence of MSI in the distal colon.
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Affiliation(s)
- A. GOEL
- Division of Gastroenterology, Department of Internal Medicine and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA
| | - A. MITTAL
- Division of Gastroenterology, Department of Internal Medicine and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA
| | - R. EVSTATIEV
- Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - M. NEMETH
- Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - W. KRUIS
- Evangelisches Krankenhaus Kalk, Cologne, Germany
| | - M. STOLTE
- Department of Pathology, Klinikum Bayreuth, Germany
| | - C. R. BOLAND
- Division of Gastroenterology, Department of Internal Medicine and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA
| | - C. GASCHE
- Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
,Christian Doppler Laboratory on Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
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Kaufman J, Griffiths TA, Surette MG, Ness S, Rioux KP. Effects of mesalamine (5-aminosalicylic acid) on bacterial gene expression. Inflamm Bowel Dis 2009; 15:985-96. [PMID: 19202572 DOI: 10.1002/ibd.20876] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND 5-Aminosalicylic acid (5-ASA) is a well-established treatment for inflammatory bowel disease (IBD) and may reduce the risk of colon cancer in patients with chronic colitis, but the mechanisms underlying these effects have not been fully elucidated. Although 5-ASA delivery is targeted to the distal gut, little is known about its effects on the luminal bacteria that reside there. Intestinal bacteria are believed play a role in causing or perpetuating IBD, and bioremediation has been studied as a therapeutic strategy. In an effort to better understand the bacteriological effects of 5-ASA, we examined the role of this compound at the level of bacterial gene expression. METHODS 5-ASA was screened for its effects on a random promoter library representing the genome of Salmonella enterica serovar Typhimurium as a model enteric bacterium. Forty-five constructs representing 38 unique promoters were found to be responsive to 5-ASA, and included genes involved in bacterial invasion, cellular metabolism, and stress resistance. Several genes of unknown function were also identified. These effects occurred at 5-ASA concentrations that are relevant to those achieved in the distal intestinal tract in patients with IBD but did not inhibit bacterial growth. RESULTS Bacterial invasiveness was decreased by 5-ASA. Some of the identified genes had homologs among commensal Gram-negative enteric bacteria. CONCLUSIONS This study demonstrates that 5-ASA has potent effects on bacterial gene expression. These novel findings implicate intestinal bacteria as pharmacological targets of 5-ASA, perhaps contributing to the therapeutic action of this important class of IBD drugs.
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Affiliation(s)
- Jaime Kaufman
- Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada
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Uronis JM, Mühlbauer M, Herfarth HH, Rubinas TC, Jones GS, Jobin C. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One 2009; 4:e6026. [PMID: 19551144 PMCID: PMC2696084 DOI: 10.1371/journal.pone.0006026] [Citation(s) in RCA: 335] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2009] [Accepted: 05/30/2009] [Indexed: 12/12/2022] Open
Abstract
It is well established that the intestinal microbiota plays a key role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) collectively referred to as inflammatory bowel disease (IBD). Epidemiological studies have provided strong evidence that IBD patients bear increased risk for the development of colorectal cancer (CRC). However, the impact of the microbiota on the development of colitis-associated cancer (CAC) remains largely unknown. In this study, we established a new model of CAC using azoxymethane (AOM)-exposed, conventionalized-Il10−/− mice and have explored the contribution of the host intestinal microbiota and MyD88 signaling to the development of CAC. We show that 8/13 (62%) of AOM-Il10−/− mice developed colon tumors compared to only 3/15 (20%) of AOM- wild-type (WT) mice. Conventionalized AOM-Il10−/− mice developed spontaneous colitis and colorectal carcinomas while AOM-WT mice were colitis-free and developed only rare adenomas. Importantly, tumor multiplicity directly correlated with the presence of colitis. Il10−/− mice mono-associated with the mildly colitogenic bacterium Bacteroides vulgatus displayed significantly reduced colitis and colorectal tumor multiplicity compared to Il10−/− mice. Germ-free AOM-treated Il10−/− mice showed normal colon histology and were devoid of tumors. Il10−/−; Myd88−/− mice treated with AOM displayed reduced expression of Il12p40 and Tnfα mRNA and showed no signs of tumor development. We present the first direct demonstration that manipulation of the intestinal microbiota alters the development of CAC. The TLR/MyD88 pathway is essential for microbiota-induced development of CAC. Unlike findings obtained using the AOM/DSS model, we demonstrate that the severity of chronic colitis directly correlates to colorectal tumor development and that bacterial-induced inflammation drives progression from adenoma to invasive carcinoma.
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Affiliation(s)
- Joshua M Uronis
- Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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5-Aminosalicylic acid inhibits TGF-beta1 signalling in colorectal cancer cells. Cancer Lett 2009; 287:82-90. [PMID: 19541409 DOI: 10.1016/j.canlet.2009.05.033] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2009] [Revised: 05/28/2009] [Accepted: 05/29/2009] [Indexed: 01/23/2023]
Abstract
The transforming growth factor-beta (TGF-beta) pathway is an important pathway in the initiation and progression of colorectal cancer. We aimed to determine the effects of 5-aminosalicylic acid (5-ASA) on TGF-beta signalling in colorectal cancer cells in vitro. 5-ASA inhibited TGF-beta1 signalling in HCT116 cells and colonic fibroblasts, as judged by a TGF-beta-specific reporter gene assay, plasminogen activator inhibitor-1 mRNA and protein levels, fibroblast trans-differentiation, Smad3 phosphorylation and nuclear translocation. We conclude that 5-ASA inhibits TGF-beta1 signalling in colorectal cancer cells, and might be a potent adjuvant therapeutic drug, interfering with aberrant TGF-beta signalling in colorectal cancer.
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