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Wang T, Huang Y, Jiang P, Yuan X, Long Q, Yan X, Huang Y, Wang Z, Li C. Research progress on anti-inflammatory drugs for preventing colitis-associated colorectal cancer. Int Immunopharmacol 2025; 144:113583. [PMID: 39580861 DOI: 10.1016/j.intimp.2024.113583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 11/04/2024] [Accepted: 11/05/2024] [Indexed: 11/26/2024]
Abstract
Colorectal cancer (CRC) is the third most prevalent malignancy worldwide. Inflammatory bowel diseases (IBD) encompass a group of chronic intestinal inflammatory disorders, including ulcerative colitis (UC) and Crohn's disease (CD). As a chronic inflammatory bowel disease, UC may persist and elevate the risk of malignancy, thereby contributing to the development of colorectal cancer, known as colitis-associated colorectal cancer (CAC). Chronic intestinal inflammation is a significant risk factor for colorectal cancer, and the incidence of colitis-associated colorectal cancer continues to rise. Current studies indicate that therapeutic agents targeting inflammation and key molecules or signaling pathways involved in the inflammatory process may effectively prevent and treat CAC. Mechanistically, drugs with anti-inflammatory or modulatory effects on inflammation-related pathways may exert preventive or therapeutic roles in CAC through multiple molecules or signaling pathways implicated in tumor development. Moreover, the development or discovery of novel drugs with anti-inflammatory properties to prevent or delay CAC progression is becoming an emerging field in fighting against CRC. Therefore, this review aims to summarize drugs that prevent or delay CAC through modulating anti-inflammatory pathways. First, we categorize the published studies exploring the role of anti-inflammatory in CAC prevention. Second, we highlight the specific molecular mechanisms underlying the anti-inflammatory effect of the above-mentioned drugs. Finally, we discuss the potential and challenges associated with clinical application of these drugs. It is hoped that this review offers new insights for further drug development and mechanism exploration.
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Affiliation(s)
- Tong Wang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | | | - Peng Jiang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | - Xin Yuan
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | - Qian Long
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | - Xiaochen Yan
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | - Yuwei Huang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China
| | - Zongkui Wang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China.
| | - Changqing Li
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, Chengdu, Sichuan 610052, PR China.
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Wei X, Liang J, Liu J, Dai Y, Leng X, Cheng Y, Chi L. Anchang Yuyang Decoction inhibits experimental colitis-related carcinogenesis by regulating PPAR signaling pathway and affecting metabolic homeostasis of host and microbiota. JOURNAL OF ETHNOPHARMACOLOGY 2024; 326:117995. [PMID: 38428656 DOI: 10.1016/j.jep.2024.117995] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 02/26/2024] [Indexed: 03/03/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be the driving factor of colitis carcinogenesis. Effective control of inflammation is helpful to prevent and treat colitis-related colorectal cancer (CAC). Anchang Yuyang Decoction (AYD), a traditional Chinese medicine (TCM) formula, is originated from the ancient prescription of TCM for treating colitis and colorectal cancer. AYD has demonstrated efficacy in treating IBD and potential anti-carcinogenic properties. AIM OF THE STUDY This research aims to assess the therapeutic efficacy of AYD in ameliorating experimental colitis-related carcinogenesis induced by AOM/DSS. It further seeks to elucidate its potential mechanisms by integrating multiple omics sequencing approaches. MATERIALS AND METHODS A rat model for colitis-related carcinogenesis was developed using azoxymethane (AOM)/dextran sulfate sodium (DSS). UPLC-MS identified AYD's chemical constituents. Rats were administered varying doses of AYD (18.37, 9.19 and 4.59 g/kg) orally for 53 days, with mesalazine as a positive control. The study evaluated anti-carcinogenic effects by examining adenoma number, adenoma load, abnormal crypt foci (ACF), histopathological damage, and tumor-related protein expression. Anti-inflammatory and reparative effects were assessed through body weight, disease activity index (DAI), colon length, spleen index, inflammatory cytokine levels, and tight junction protein expression. The effects on intestinal microbiota and host metabolism were explored through 16S rRNA sequencing, targeted short-chain fatty acid (SCFA) metabonomics, and non-targeted colon metabolomics. Potential AYD targets were identified through transcriptomic sequencing and validated by qRT-PCR and western blotting. RESULTS AYD significantly reduced adenoma number, adenoma load, neoplasm-associated lesions, ACF, and tumor-related protein expression (e.g., p53, PCNA) in AOM/DSS-induced rats, thus impeding colitis-related carcinogenesis progression. AYD also alleviated histopathological damage and inflammation, promoting intestinal mucosal barrier repair. Furthermore, AYD modulated intestinal flora structure, enhanced SCFA production, and regulated colon metabolites. Transcriptomic sequencing revealed a significant impact on the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Subsequent qRT-PCR and western blotting experiments indicated AYD's influence in up-regulating PPAR-γ and down-regulating PPAR-α, PPAR-β/δ, and related proteins (thrombomodulin [Thbd], fatty acid binding protein 5 [Fabp5], stearoyl-CoA desaturase 2 [Scd2], phospholipid transfer protein [Pltp]). CONCLUSIONS This study demonstrates AYD's ability to inhibit experimental colitis-related carcinogenesis induced by AOM/DSS. Its mechanism likely involves modulation of the PPAR signaling pathway, impacting intestinal microbiota and host metabolic equilibrium.
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Affiliation(s)
- Xiunan Wei
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
| | - Junwei Liang
- Department of Gastroenterology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
| | - Jiahui Liu
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
| | - Yonggang Dai
- Department of Clinical Laboratory Medicine, Shandong Provincial Third Hospital, Jinan, 250014, China.
| | - Xiaohui Leng
- Department of Cardiovascular Medicine, Weifang Traditional Chinese Hospital, Weifang, 261000, China.
| | - Yan Cheng
- Department of Gastroenterology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
| | - Lili Chi
- Department of Gastroenterology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
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Hajjar R, Oliero M, Fragoso G, Ajayi AS, Alaoui AA, Vennin Rendos H, Calvé A, Cuisiniere T, Gerkins C, Thérien S, Taleb N, Dagbert F, Sebajang H, Loungnarath R, Schwenter F, Ratelle R, Wassef R, De Broux E, Richard C, Santos MM. Modulating Gut Microbiota Prevents Anastomotic Leak to Reduce Local Implantation and Dissemination of Colorectal Cancer Cells after Surgery. Clin Cancer Res 2024; 30:616-628. [PMID: 38010363 DOI: 10.1158/1078-0432.ccr-23-1601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/10/2023] [Accepted: 11/21/2023] [Indexed: 11/29/2023]
Abstract
PURPOSE Anastomotic leak (AL) is a major complication in colorectal cancer surgery and consists of the leakage of intestinal content through a poorly healed colonic wound. Colorectal cancer recurrence after surgery is a major determinant of survival. We hypothesize that AL may allow cancer cells to escape the gut and lead to cancer recurrence and that improving anastomotic healing may prevent local implantation and metastatic dissemination of cancer cells. EXPERIMENTAL DESIGN We investigated the association between AL and postoperative outcomes in patients with colorectal cancer. Using mouse models of poor anastomotic healing, we assessed the processes of local implantation and dissemination of cancer cells. The effect of dietary supplementation with inulin and 5-aminosalicylate (5-ASA), which activate PPAR-γ in the gut, on local anastomotic tumors was assessed in mice undergoing colonic surgery. Inulin and 5-ASA were also assessed in a mouse model of liver metastasis. RESULTS Patients experiencing AL displayed lower overall and oncologic survival than non-AL patients. Poor anastomotic healing in mice led to larger anastomotic and peritoneal tumors. The microbiota of patients with AL displays a lower capacity to activate the antineoplastic PPAR-γ in the gut. Modulation of gut microbiota using dietary inulin and 5-ASA reinforced the gut barrier and prevented anastomotic tumors and metastatic spread in mice. CONCLUSIONS Our findings reinforce the hypothesis that preventing AL is paramount to improving oncologic outcomes after colorectal cancer surgery. Furthermore, they pave the way toward dietary targeting of PPAR-γ as a novel way to enhance healing and diminish cancer recurrence.
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Affiliation(s)
- Roy Hajjar
- Nutrition and Microbiome Laboratory, Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Manon Oliero
- Nutrition and Microbiome Laboratory, Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Gabriela Fragoso
- Nutrition and Microbiome Laboratory, Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Ayodeji Samuel Ajayi
- Nutrition and Microbiome Laboratory, Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Ahmed Amine Alaoui
- Nutrition and Microbiome Laboratory, Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Hervé Vennin Rendos
- Nutrition and Microbiome Laboratory, Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Annie Calvé
- Nutrition and Microbiome Laboratory, Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Thibault Cuisiniere
- Nutrition and Microbiome Laboratory, Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Claire Gerkins
- Nutrition and Microbiome Laboratory, Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Sophie Thérien
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
| | - Nassima Taleb
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
| | - François Dagbert
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Herawaty Sebajang
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Rasmy Loungnarath
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Frank Schwenter
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Richard Ratelle
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Ramses Wassef
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Eric De Broux
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Carole Richard
- Digestive Surgery Service, Department of Surgery, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Manuela M Santos
- Nutrition and Microbiome Laboratory, Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Canada
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Liang J, Yang C, Li P, Zhang M, Xie X, Xie X, Chen Y, Wang Q, Zhou L, Luo X. Astragaloside IV inhibits AOM/DSS-induced colitis-associated tumorigenesis via activation of PPARγ signaling in mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 121:155116. [PMID: 37776619 DOI: 10.1016/j.phymed.2023.155116] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/15/2023] [Accepted: 09/21/2023] [Indexed: 10/02/2023]
Abstract
BACKGROUND Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD), resulting from long-term inflammation in the intestines. The primary cause of CAC is the imbalance of oxidative metabolism in intestinal cells, triggered by excessive reactive oxygen (ROS) and nitrogen (NO) species production due to prolonged intestinal inflammation. This imbalance leads to genomic instability caused by DNA damage, eventually resulting in the development of intestinal cancer. Previous studies have demonstrated that astragaloside IV is effective in treating dextran sulfate sodium salt (DSS)-induced colitis, but there is currently no relevant research on its efficacy in treating CAC. METHODS To investigate the effect of astragaloside IV against CAC and the underlying mechanism, C57 mice were treated with (20, 40, 80 mg/kg) astragaloside IV while CAC was induced by intraperitoneal injection of 10 mg/kg azoxymethane (AOM) and ad libitum consumption of 2% dextran sulfate sodium salt (DSS). We re-verified the activating effects of astragaloside IV on PPARγ signaling in IEC-6 cells, which were reversed by GW9662 (the PPARγ inhibitor). RESULTS Our results showed that astragaloside IV significantly improved AOM/DSS-induced CAC mice by inhibiting colonic shortening, preventing intestinal mucosal damage, reducing the number of tumors and, the expression of Ki67 protein. In addition, astragaloside IV could activate PPARγ signaling, which not only promoted the expression of Nrf2 and HO-1, restored the level of SOD, CAT and GSH, but also inhibited the expression of iNOS and reduced the production of NO in the intestine and IEC-6 cells. And this effect could be reversed by GW9662 in vitro. Astragaloside IV thus decreased the level of ROS and NO in the intestinal tract of mice, as well as reduced the damage of DNA, and therefore inhibited the occurrence of CAC. CONCLUSION Astragaloside IV can activate PPARγ signaling in intestinal epithelial cells and reduces DNA damage caused by intestinal inflammation, thereby inhibiting colon tumourigenesis. The novelty of this study is to use PPARγ as the target to inhibit DNA damage to prevent the occurrence of CAC.
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Affiliation(s)
- Junjie Liang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China; Affiliated Dongguan Hospital, Southern Medical University (Dongguan People's Hospital)
| | - Caiyi Yang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Pengcheng Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Meiling Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Xueqian Xie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Xuting Xie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Yunliang Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Qing Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Lian Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China.
| | - Xia Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China.
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Lin Q, Li Z, Lu L, Xu H, Lou E, Chen A, Sun D, Zhang W, Zhu W, Yee EU, Sears PS, Chen X, Kelly CP. Budesonide, an anti-inflammatory drug, exacerbate clostridioides difficile colitis in mice. Biomed Pharmacother 2023; 167:115489. [PMID: 37713991 DOI: 10.1016/j.biopha.2023.115489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/17/2023] Open
Abstract
BACKGROUND AND AIMS Clostridioides difficile infection (CDI) induces intense acute inflammatory responses through toxin release. A combination of antibiotic and anti-inflammatory agents is sometimes recommended in severe, non-responsive cases, although clinical trials have been inconclusive, raising concerns about potential complications. This study aims to investigate the effect of budesonide and mesalamine in the treatment of CDI in a murine model, by evaluating the combination of fidaxomicin and these anti-inflammatory drugs. METHOD C57BL/6 J female mice pretreated with an antimicrobial mixture were challenged with C. difficile VPI 10463 or culture media by gavage. After the challenge, mice received placebo, fidaxomicin alone (20 mg/kg), or fidaxomicin combined with mesalamine (200, 400 mg/kg) or budesonide (0.2, 1, 10 mg/kg) for 5 days. The mice were monitored for 7 days with weight and survival. Colon and cecum tissues were harvested for histological assessment. RESULTS CDI of mice caused 80% mortality. Fidaxomicin completely protected against CDI in all parameters (weight, survival and pathscores). Mortality rates were up to 90%, 70% in budesonide(10 mg/kg) and mesalamine (400 mg/kg) treatment group, respectively. Budesonide (0.02,0.1 and 1 mg/kg) adjunction to fidaxomicin worsened the disease outcome according to all tested parameters. While mesalamine in combination with fidaxomicin (200, 400 mg/kg) did not lead to any deaths during CDI treatment, it did not provide additional benefits. CONCLUSIONS Anti-inflammatory drugs including corticosteroid therapy may worsen the incidence and severity of CDI in this mouse model. These studies may have important clinical implications for understanding the role of anti-inflammatory/ corticosteroid therapy in CDI and inflammatory bowel disease management.
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Affiliation(s)
- Qianyun Lin
- Department of Gastroenterology, Beijing Friendship Hospital, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Capital Medical University, Beijing, China; Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Zitong Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Lu
- Section of Neonatology, Department of Paediatrics and Medicine, the University of Chicago, Chicago, IL, USA
| | - Hua Xu
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Eddie Lou
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Alyssa Chen
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Dustin Sun
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Wuyi Zhang
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Weishu Zhu
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Eric U Yee
- Department of Pathology, Beth Israel Deaconess Medical Centre, Boston, MA, USA; Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | | | - Xinhua Chen
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA.
| | - Ciaran P Kelly
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA.
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Dan WY, Zhou GZ, Peng LH, Pan F. Update and latest advances in mechanisms and management of colitis-associated colorectal cancer. World J Gastrointest Oncol 2023; 15:1317-1331. [PMID: 37663937 PMCID: PMC10473934 DOI: 10.4251/wjgo.v15.i8.1317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/03/2023] [Accepted: 07/25/2023] [Indexed: 08/10/2023] Open
Abstract
Colitis-associated colorectal cancer (CAC) is defined as a specific cluster of colorectal cancers that develop as a result of prolonged colitis in patients with inflammatory bowel disease (IBD). Patients with IBD, including ulcerative colitis and Crohn's disease, are known to have an increased risk of developing CAC. Although the incidence of CAC has significantly decreased over the past few decades, individuals with CAC have increased mortality compared to individuals with sporadic colorectal cancer, and the incidence of CAC increases with duration. Chronic inflammation is generally recognized as a major contributor to the pathogenesis of CAC. CAC has been shown to progress from colitis to dysplasia and finally to carcinoma. Accumulating evidence suggests that multiple immune-mediated pathways, DNA damage pathways, and pathogens are involved in the pathogenesis of CAC. Over the past decade, there has been an increasing effort to develop clinical approaches that could help improve outcomes for CAC patients. Colonoscopic surveillance plays an important role in reducing the risk of advanced and interval cancers. It is generally recommended that CAC patients undergo endoscopic removal or colectomy. This review summarizes the current understanding of CAC, particularly its epidemiology, mechanisms, and management. It focuses on the mechanisms that contribute to the development of CAC, covering advances in genomics, immunology, and the microbiome; presents evidence for management strategies, including endoscopy and colectomy; and discusses new strategies to interfere with the process and development of CAC. These scientific findings will pave the way for the management of CAC in the near future.
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Affiliation(s)
- Wan-Yue Dan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
- Medical School, Nankai University, Tianjin 300071, China
| | - Guan-Zhou Zhou
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
- Medical School, Nankai University, Tianjin 300071, China
| | - Li-Hua Peng
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Fei Pan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
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7
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Chang WCL, Ghosh J, Cooper HS, Vanderveer L, Schultz B, Zhou Y, Harvey KN, Kaunga E, Devarajan K, Li Y, Jelinek J, Fragoso MF, Sapienza C, Clapper ML. Folic Acid Supplementation Promotes Hypomethylation in Both the Inflamed Colonic Mucosa and Colitis-Associated Dysplasia. Cancers (Basel) 2023; 15:2949. [PMID: 37296911 PMCID: PMC10252136 DOI: 10.3390/cancers15112949] [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: 05/05/2023] [Revised: 05/22/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
PURPOSE The purpose of this study was to assess the effect of folic acid (FA) supplementation on colitis-associated colorectal cancer (CRC) using the azoxymethane/dextran sulfate sodium (AOM/DSS) model. METHODS Mice were fed a chow containing 2 mg/kg FA at baseline and randomized after the first DSS treatment to receive 0, 2, or 8 mg/kg FA chow for 16 weeks. Colon tissue was collected for histopathological evaluation, genome-wide methylation analyses (Digital Restriction Enzyme Assay of Methylation), and gene expression profiling (RNA-Seq). RESULTS A dose-dependent increase in the multiplicity of colonic dysplasias was observed, with the multiplicity of total and polypoid dysplasias higher (64% and 225%, respectively) in the 8 mg FA vs. the 0 mg FA group (p < 0.001). Polypoid dysplasias were hypomethylated, as compared to the non-neoplastic colonic mucosa (p < 0.05), irrespective of FA treatment. The colonic mucosa of the 8 mg FA group was markedly hypomethylated as compared to the 0 mg FA group. Differential methylation of genes involved in Wnt/β-catenin and MAPK signaling resulted in corresponding alterations in gene expression within the colonic mucosa. CONCLUSIONS High-dose FA created an altered epigenetic field effect within the non-neoplastic colonic mucosa. The observed decrease in site-specific DNA methylation altered oncogenic pathways and promoted colitis-associated CRC.
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Affiliation(s)
- Wen-Chi L. Chang
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA (L.V.); (E.K.)
| | - Jayashri Ghosh
- Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA; (J.G.); (B.S.)
| | - Harry S. Cooper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA (L.V.); (E.K.)
- Department of Pathology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - Lisa Vanderveer
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA (L.V.); (E.K.)
| | - Bryant Schultz
- Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA; (J.G.); (B.S.)
| | - Yan Zhou
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - Kristen N. Harvey
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA (L.V.); (E.K.)
| | - Esther Kaunga
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA (L.V.); (E.K.)
| | - Karthik Devarajan
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - Yuesheng Li
- DNA Sequencing and Genomic Core Facility, National Heart, Lung, and Blood Institute, NIH, 10 Center Drive, Bethesda, MD 20892, USA
| | - Jaroslav Jelinek
- Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA; (J.G.); (B.S.)
| | - Mariana F. Fragoso
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA (L.V.); (E.K.)
| | - Carmen Sapienza
- Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA; (J.G.); (B.S.)
| | - Margie L. Clapper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA (L.V.); (E.K.)
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Fermented Glutinous Rice Extract Mitigates DSS-Induced Ulcerative Colitis by Alleviating Intestinal Barrier Function and Improving Gut Microbiota and Inflammation. Antioxidants (Basel) 2023; 12:antiox12020336. [PMID: 36829894 PMCID: PMC9951866 DOI: 10.3390/antiox12020336] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/19/2023] [Accepted: 01/30/2023] [Indexed: 02/04/2023] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease caused by various factors, including intestinal inflammation and barrier dysfunction. Herein, we determined the effects of fermented glutinous rice (FGR) on the expression of tight junction proteins and levels of inflammation and apoptosis in the dextran sodium sulfate (DSS)-induced acute colitis model. FGR was orally administered once per day to C57BL/6J mice with colitis induced by 5% DSS in drinking water. FGR administration recovered DSS-induced body weight loss and irregularly short colon lengths. FGR inhibited the DSS-induced decrease in FITC-dextran (FD)-4 permeability and myeloperoxidase activity. Moreover, FGR treatment repaired the reduction of zonula occluden-1 (ZO-1) and occludin expression and the increase in claudin-2 expression in colonic tissue relative to that following DSS administration. FGR treatment significantly recovered expression of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, in serum or respective mRNA expression in colonic tissue relative to that following DSS administration. FGR regulated levels of oxidative stress-related factors, such as malondialdehyde and glutathione, and the activity of catalase and superoxide dismutase in the colon tissue of the DSS-induced acute colitis mice model. Furthermore, FGR treatment inhibited apoptosis by reducing the activity of caspase-3 and the ratio of Bcl-2 associated X (Bax)/B-cell lymphoma 2 (Bcl-2). Collectively, FGR treatment protected the intestinal barrier from dysfunction and inhibited inflammation and apoptosis in DSS-induced colitis. Therefore, FGR may decrease the inflammatory response and be a candidate for treating and prevention inflammatory bowel disease by protecting the intestinal integrity.
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9
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Cellular Carcinogenesis: Role of Polarized Macrophages in Cancer Initiation. Cancers (Basel) 2022; 14:cancers14112811. [PMID: 35681791 PMCID: PMC9179569 DOI: 10.3390/cancers14112811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/26/2022] [Accepted: 06/02/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Inflammation is a hallmark of many cancers. Macrophages are key participants in innate immunity and important drivers of inflammation. When chronically polarized beyond normal homeostatic responses to infection, injury, or aging, macrophages can express several pro-carcinogenic phenotypes. In this review, evidence supporting polarized macrophages as endogenous sources of carcinogenesis is discussed. In addition, the depletion or modulation of macrophages by small molecule inhibitors and probiotics are reviewed as emerging strategies in cancer prevention. Abstract Inflammation is an essential hallmark of cancer. Macrophages are key innate immune effector cells in chronic inflammation, parainflammation, and inflammaging. Parainflammation is a form of subclinical inflammation associated with a persistent DNA damage response. Inflammaging represents low-grade inflammation due to the dysregulation of innate and adaptive immune responses that occur with aging. Whether induced by infection, injury, or aging, immune dysregulation and chronic macrophage polarization contributes to cancer initiation through the production of proinflammatory chemokines/cytokines and genotoxins and by modulating immune surveillance. This review presents pre-clinical and clinical evidence for polarized macrophages as endogenous cellular carcinogens in the context of chronic inflammation, parainflammation, and inflammaging. Emerging strategies for cancer prevention, including small molecule inhibitors and probiotic approaches, that target macrophage function and phenotype are also discussed.
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Tang S, Liu W, Zhao Q, Li K, Zhu J, Yao W, Gao X. Combination of polysaccharides from Astragalus membranaceus and Codonopsis pilosula ameliorated mice colitis and underlying mechanisms. JOURNAL OF ETHNOPHARMACOLOGY 2021; 264:113280. [PMID: 32822821 DOI: 10.1016/j.jep.2020.113280] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 06/02/2020] [Accepted: 08/11/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Astragalus membranaceus and Codonopsis pilosula which are two Chinese medicinal herbs are often combinedly used as monarch drugs in Traditional Chinese Medicine (TCM) prescriptions to treat ulcerative colitis (UC). However, the exact mechanisms and effective constituents of the two herbs remain unclear. AIM OF THE STUDY Polysaccharides are the main active ingredients of the two medicinal herbs and some specific polysaccharides extracted from the two medicinal herbs have been proven effective in relieving colitis. Hence, we speculated that polysaccharides of the two medicinal herbs may be the material basis for compatibility in TCM prescriptions to treat UC. In the research, total polysaccharides of A. membranaceus and C. pilosula extractum, named AERP and CERP respectively, were administrated to 2.5% dextran sulfate sodium (DSS)-induced acute colitis mice by dosing alone and in combination to test this hypothesis. MATERIALS AND METHODS 5-aminosalicylic acid (5-ASA, 100 mg/kg/d) was selected as the positive drug. The basic indexes of colitis mice including body weight, stool bleeding, stool consistency and colon lengths were recorded. In addition, tissue inflammatory factors, mucosa-associated proteins, fecal short chain fatty acids (SCFAs) and gut microbiota were also analyzed. RESULTS The co-administration of AERP and CERP at specific doses could improve the clinical symptoms, reestablish the immune balance, and alleviate colonic mucosal injury in colitis mice. The unique efficacy of co-administration relied on activation of the aryl hydrocarbon receptor (AhR) and up-regulation of isovaleric acid and butyrate. In addition, the structure of intestinal flora was recovered in the co-administration group. CONCLUSION Our research proved the efficacy after co-administration of total polysaccharides from A. membranaceus and C. pilosula on colitis mice which provided a theoretical basis for their compatibility in TCM prescriptions to treat UC.
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Affiliation(s)
- Shuai Tang
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China
| | - Wei Liu
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China
| | - Qianqian Zhao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China
| | - Kaidong Li
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China
| | - Jingyi Zhu
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China
| | - Wenbing Yao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China.
| | - Xiangdong Gao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China.
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11
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Montrose DC, Makino T, Basu S, Ito N, Dannenberg AJ. Induction of colitis-associated neoplasia in mice using azoxymethane and dextran sodium sulfate. Methods Cell Biol 2020; 163:123-135. [PMID: 33785161 DOI: 10.1016/bs.mcb.2020.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Long-standing inflammatory bowel diseases (IBD) increase the risk for the development of colorectal cancer (CRC). This increase is due in large part to chronic intestinal inflammation which exposes the epithelium to pro-carcinogenic factors. Moreover, enhanced mucosal proliferation associated with repetitive wound healing events following an inflammatory episode, further enhance this pro-tumorigenic environment. Although multiple factors involved in IBD pathogenesis and its associated neoplasia have been identified, more work is needed to develop and improve therapies to ameliorate disease and thus reduce CRC risk. Murine models have served as useful tools to identify factors involved in the pathogenesis of colitis-associated neoplasia and test therapies. These include both chemically-induced and genetic engineering approaches, resulting in chronic inflammation and tumor development. Here, we present a step-by-step method of inducing inflammation-associated colon neoplasia by combining administration of azoxymethane and dextran sodium sulfate in mice. A detailed description of this methodology will facilitate its use in the scientific community with the goals of further elucidating the mechanisms underlying colitis-associated tumorigenesis and developing risk reducing interventions.
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Affiliation(s)
- David C Montrose
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States; Stony Brook Cancer Center, Stony Brook, NY, United States.
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Srijani Basu
- Department of Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Naotake Ito
- Department of Medicine, Weill Cornell Medicine, New York, NY, United States
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12
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Effect of Long-Term Mesalamine Therapy on Cancer-Associated Gene Expression in Colonic Mucosa of Patients with Ulcerative Colitis. Dig Dis Sci 2019; 64:740-750. [PMID: 30478770 DOI: 10.1007/s10620-018-5378-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 11/13/2018] [Indexed: 01/20/2023]
Abstract
BACKGROUND The role of 5-aminosalicylic acid (5-ASA or mesalamine) in the prevention of colorectal cancer in ulcerative colitis (UC) patients was reported, but the effect on molecular targets in UC colon mucosa is unknown. AIM This observational study evaluates gene expression levels of 5-ASA targets using serial colon biopsy specimens from UC patients undergoing long-term 5-ASA therapy. METHODS Transcript levels were compared between colonoscopic biopsy specimens collected from 62 patients at initial and final follow-up colonoscopy at 2-6 years. All patients had mild-to-moderate UC and were undergoing long-term 5-ASA maintenance. Stepwise multiple linear regression analyses were performed to correlate changes in transcript levels with therapeutic response (Mayo clinical score endoscopy and DAI and/or Nancy histopathology score) and nonclinical variables. RESULTS The transcript levels of colorectal carcinogenesis-associated known 5-ASA target genes were significantly reduced after prolonged 5-ASA therapy (P < 0.005-0.03). Multiple linear regression models predicted significant association between transcript levels of Ki-67, NF-kB (p65), PPARγ, COX-2 and IL-8, CDC25A, and CXCL10 with duration of drug (5-ASA) exposure (P ≤ 0.05). Ki-67, NF-kB (p65), and CXCL10 transcripts were also correlated with reduced endoscopy sub-score (P ≤ 0.05). COX-2, IL-8, CDC25A, and TNF transcripts strongly correlated with DAI sub-scores (P ≤ 0.05). Only COX-2 and IL-8 transcript levels correlated (P ≤ 0.05) with Nancy histological score. CONCLUSION This study provides molecular evidence of changes in carcinogenesis-related targets/pathways in colon tissue during long-term 5-ASA maintenance therapy that may contribute to the observed chemopreventive effects of 5-ASA in UC patients.
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Casado-Bedmar M, Heil SDS, Myrelid P, Söderholm JD, Keita ÅV. Upregulation of intestinal mucosal mast cells expressing VPAC1 in close proximity to vasoactive intestinal polypeptide in inflammatory bowel disease and murine colitis. Neurogastroenterol Motil 2019; 31:e13503. [PMID: 30407703 DOI: 10.1111/nmo.13503] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 09/24/2018] [Accepted: 10/07/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND Mast cells (MCs) and vasoactive intestinal polypeptide (VIP) have been proposed as regulators of the intestinal barrier and inflammation. Our aim was to map the distribution in inflammatory bowel disease (IBD) and murine colitis. METHODS MCs, VIP, and VIP-receptors (VPACs) were quantified by immunofluorescence and enzyme-immunoassay (EIA) in ileal tissues (villus epithelium (VE) and adjacent VE, ie, VE next to the follicle-associated epithelium, (FAE)) from Crohn's disease (CD; n = 16) and non-IBD patients, and in colonic specimens of ulcerative colitis (UC; n = 12) and healthy controls (HCs). In addition, VIP levels were measured in plasma from HCs, non-IBD, and IBD in remission (CD n = 30; UC n = 30). Colon, ileum, and plasma from mice with dextran sulfate sodium (DSS)-induced colitis and control mice were analyzed likewise. KEY RESULTS FAE-adjacent VE in ileum of CD possessed more MCs (P < 0.05) and MCs expressing VPAC1 (P < 0.05), but not VPAC2, compared to controls. Both adjacent and regular VE of CD had more MCs co-localizing/in close proximity to VIP (P < 0.05). In UC colon, more MCs (P < 0.0005), MCs close to VIP (P < 0.0005), and MCs expressing VPAC1 (P < 0.05) were found compared to controls. VIP levels were elevated in plasma from CD and UC compared to controls (P < 0.0005). Colon of DSS mice showed more MCs and MCs close to VIP (P < 0.05) compared to control mice. In vitro experiments revealed MCs expressing VPACs and internalized VIP after 120 minutes of VIP-stimulation. CONCLUSIONS AND INFERENCES Communication between MCs and VIP is upregulated during IBD and mice colitis. In CD patients, the epithelium next to FAE seems to be more involved than the surrounding VE, suggesting increased MC-VIP-interactions in this intestinal region.
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Affiliation(s)
- Maite Casado-Bedmar
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Linköping University, Linköping, Sweden
| | - Stéphanie D S Heil
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Linköping University, Linköping, Sweden
| | - Pär Myrelid
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Linköping University, Linköping, Sweden
- Department of Surgery, County Council of Östergötland, Linköping, Sweden
| | - Johan D Söderholm
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Linköping University, Linköping, Sweden
- Department of Surgery, County Council of Östergötland, Linköping, Sweden
| | - Åsa V Keita
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Linköping University, Linköping, Sweden
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Xu H, Li J, Chen H, Ghishan FK. NHE8 Deficiency Promotes Colitis-Associated Cancer in Mice via Expansion of Lgr5-Expressing Cells. Cell Mol Gastroenterol Hepatol 2018; 7:19-31. [PMID: 30465020 PMCID: PMC6240644 DOI: 10.1016/j.jcmgh.2018.08.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/16/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Lgr5 overexpression has been detected in colorectal cancers (CRCs), including some cases of colitis-associated CRCs. In colitis-associated CRCs, chronic inflammation is a contributing factor in carcinogenesis. We recently reported that intestinal Na+/H+ exchanger isoform 8 (NHE8) plays an important role in intestinal mucosal protection and that loss of NHE8 expression results in an ulcerative colitis-like condition. Therefore, we hypothesized that NHE8 may be involved in the development of intestinal tumors. METHODS We assessed NHE8 expression in human CRCs by immunohistochemistry and studied tumor burden in NHE8 knockout (KO) mice using an azoxymethane/dextran sodium sulfate colon cancer model. We also evaluated cell proliferation in HT29NHE8KO cells and assessed tumor growth in NOD scid gamma (NSG) mice xenografted with HT29NHE8KO cells. To verify if a relationship exists between Lgr5 and NHE8 expression, we analyzed Lgr5 expression in NHE8KO mice by polymerase chain reaction and in situ hybridization. Lgr5 expression and cell proliferation in the absence of NHE8 were confirmed in colonic organoid cultures. The expression of β-catenin and c-Myc also were analyzed to evaluate Wnt/β-catenin activation. RESULTS NHE8 was undetectable in human CRC tissues. Although only 9% of NHE8 wild-type mice showed tumorigenesis in the azoxymethane/dextran sodium sulfate colon cancer model, almost 10 times more NHE8KO mice (89%) developed tumors. In the absence of NHE8, a higher colony formation unit was discovered in HT29NHE8KO cells. In NSG mice, larger tumors developed at the site where HT29NHE8KO cells were injected compared with HT29NHE8 wild type cells. Furthermore, NHE8 deficiency resulted in increased Lgr5 expression in the colon, in HT29-derived tumors, and in colonoids. The absence of NHE8 also increased Wnt/β-catenin activation. CONCLUSIONS NHE8 might be an intrinsic factor that regulates Wnt/β-catenin in the intestine.
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Key Words
- AOM, azoxymethane
- CRC, colorectal cancer
- CRISPR/Cas9, clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9
- Colorectal Tumor
- DMEM, Dulbecco's modified Eagle medium
- DSS, dextran sodium sulfate
- EGFP, enhanced green fluorescent protein
- EdU, 5-ethynyl-2’-deoxyuridine
- FACS, fluorescence-activated cell sorter
- KO, knockout
- Lgr5
- NHE, Na+/H+ exchanger
- NHE8
- NSG, NOD scid gamma
- PCR, polymerase chain reaction
- UC, ulcerative colitis
- WT, wild type
- mRNA, messenger RNA
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Affiliation(s)
- Hua Xu
- Department of Pediatrics, University of Arizona Health Sciences Center, Tucson, Arizona
| | - Jing Li
- Department of Pediatrics, University of Arizona Health Sciences Center, Tucson, Arizona
| | - Hao Chen
- Department of Pathology, University of Arizona Health Sciences Center, Tucson, Arizona
| | - Fayez K. Ghishan
- Department of Pediatrics, University of Arizona Health Sciences Center, Tucson, Arizona,Correspondence Address correspondence to: Fayez K. Ghishan, MD, Department of Pediatrics, Steele Children’s Research Center, 1501 North Campbell Avenue, Tucson, Arizona 85724. fax: (520) 626-4141.
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15
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Alabi QK, Akomolafe RO, Omole JG, Adefisayo MA, Ogundipe OL, Aturamu A, Sanya JO. Polyphenol-rich extract of Ocimum gratissimum leaves ameliorates colitis via attenuating colonic mucosa injury and regulating pro-inflammatory cytokines production and oxidative stress. Biomed Pharmacother 2018; 103:812-822. [PMID: 29684860 DOI: 10.1016/j.biopha.2018.04.071] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/09/2018] [Accepted: 04/09/2018] [Indexed: 12/13/2022] Open
Abstract
Colitis is a chronic inflammation and ulcer on the inner lining of the large intestine. For many centuries Ocimum gratissimum (OG) leaves have been used in folk medicine in Nigeria to treat inflammatory bowel diseases, however, to date, the anti-colitis effects of OG have not been scientifically proven. In this study we investigated the effects of polyphenol rich extract of Ocimum gratissimum (PREOG) leaf on colonic mucosa injury in colitis, its mechanisms, initial administration time and dosage. Dextran sodium sulfate (DSS)-induced rat colitis models was used. PREOG administration was initiated at 3 and 7 d after the model was established at doses of 200, 400 and 800 mg/kg for 7 d. 5-aminosalicylic acid (5-ASA) was used as a reference drug. The disease activity index (DAI), vascular permeability, markers of oxidative stress, granulocyte infiltration, inflammation and histopathological alteration were evaluated. Obvious colonic inflammation and mucosa injuries were observed in DSS-induced colitis groups. PREOG administration promoted repair of colonic mucosa injuries, attenuated inflammation, and decreased DAI scores in rats with colitis. PREOG also decreased the plasma concentrations of Interleukin-(IL)-6 and tumor necrosis factor (TNF)-α, and concentrations of myeloperoxidase, nitric oxide, cyclooxygenase-2 and malondialdehyde in the colon, and increased the plasma concentrations of IL-4 and IL-10 as well as the concentration of superoxide dismutase, catalase and reduced glutathione in the colon. The efficacy of PREOG was dosage dependent. In conclusion, OG repairs colonic mucosa injury in experimental colitis through its ant-inflammatory and ant-oxidant. Its efficacy related to initial administration time and dose.
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Affiliation(s)
- Quadri K Alabi
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria; Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria.
| | - Rufus O Akomolafe
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Joseph G Omole
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Modinat A Adefisayo
- Department of Physiology, Faculty of Basic Medical Sciences, University of Medical Sciences,Ondo State, Nigeria
| | - Olaofe L Ogundipe
- Department of Public Health and Community Medicine, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria
| | - Ayodeji Aturamu
- Health Center College of Education, Ikere Ekiti, Ekiti State, Nigeria
| | - Joseph O Sanya
- Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria
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Da Silva S, Keita ÅV, Mohlin S, Påhlman S, Theodorou V, Påhlman I, Mattson JP, Söderholm JD. A Novel Topical PPARγ Agonist Induces PPARγ Activity in Ulcerative Colitis Mucosa and Prevents and Reverses Inflammation in Induced Colitis Models. Inflamm Bowel Dis 2018. [PMID: 29529198 DOI: 10.1093/ibd/izx079] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPARγ agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis. METHODS Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPARγ-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay). AS002 absorption was determined in the colonic mucosa of UC patients. DSS-colitis mice received PPARγ agonists or vehicle daily by intrarectal administration starting 2 days before induction of colitis (preventive) or from days 3 to 8 (curative). Myeloperoxidase (MPO) and cytokine levels in colonic mucosa were determined. In addition, AS002 effects were studied in TNBS colitis. RESULTS AS002 displayed an absorption pattern of a lipophilic drug totally metabolized in the mucosa. AS002 and rosiglitazone increased ADIPOPHILIN mRNA expression (3-fold) and decreased TNF-α, IL-1β, and IL-13 levels in human UC biopsies. In DSS, in both preventive and curative treatment and in TNBS colitis, AS002 protected against macroscopic and histological damage and lowered MPO and TNF-α, IL-1β, and IL-13 levels. CONCLUSIONS AS002 triggers anti-inflammatory PPARγ activity in the human colonic mucosa of UC patients and prevents and reverses colitis in mice. Our data suggest that AS002 has potential for topical maintenance treatment of UC, which warrants further studies in vivo in patients.
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Affiliation(s)
- Stéphanie Da Silva
- Department of Surgery and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Åsa V Keita
- Department of Surgery and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Sofie Mohlin
- Translational Cancer Research, Cancer Center at Medicon Village, Lund University, Lund, Sweden
| | - Sven Påhlman
- Translational Cancer Research, Cancer Center at Medicon Village, Lund University, Lund, Sweden
| | - Vassilia Theodorou
- Toxalim UMR 1331 INRA/INP/UPS Neuro-Gastroenterology and Nutrition Unit, Toulouse, France
| | | | - Jan P Mattson
- Albireo AB, Arvid Wallgrens Backe, Gothenburg, Sweden
| | - Johan D Söderholm
- Department of Surgery and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
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17
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Osman J, Savari S, Chandrashekar NK, Bellamkonda K, Douglas D, Sjölander A. Cysteinyl leukotriene receptor 1 facilitates tumorigenesis in a mouse model of colitis-associated colon cancer. Oncotarget 2018; 8:34773-34786. [PMID: 28410235 PMCID: PMC5471010 DOI: 10.18632/oncotarget.16718] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 03/20/2017] [Indexed: 12/19/2022] Open
Abstract
Cysteinyl leukotriene receptor 1 (CysLT1R) has been shown to be up-regulated in the adenocarcinomas of colorectal cancer patients, which is associated with a poor prognosis. In a spontaneous model of colon cancer, CysLT1R disruption was associated with a reduced tumor burden in double-mutant female mice (ApcMin/+/Cysltr1-/-) compared to ApcMin/+ littermates. In the current study, we utilized a genetic approach to investigate the effect of CysLT1R in the induced azoxymethane/dextran sulfate sodium (AOM/DSS) model of colitis-associated colon cancer. We found that AOM/DSS female mice with a global disruption of the Cysltr1 gene (Cysltr1-/-) had a higher relative body weight, a more normal weight/length colon ratio and smaller-sized colonic polyps compared to AOM/DSS wild-type counterparts. The Cysltr1-/- colonic polyps exhibited low-grade dysplasia, while wild-type polyps had an adenoma-like phenotype. The Cysltr1-/- colonic polyps exhibited significant decreases in nuclear β-catenin and COX-2 protein expression, while the normal crypts surrounding the polyps exhibited increased Mucin 2 expression. Furthermore, Cysltr1-/- mice exhibited an overall reduction in inflammation, with a significant decrease in proinflammatory cytokines, polyp 5-LOX expression and infiltration of CD45 leukocytes and F4/80 macrophages. In conclusion, the present genetic approach in an AOM/DSS model further supports an important role for CysLT1R in colon tumorigenesis.
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Affiliation(s)
- Janina Osman
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Sayeh Savari
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Naveen Kumar Chandrashekar
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Kishan Bellamkonda
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Desiree Douglas
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Anita Sjölander
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
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18
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Dai YC, Zheng L, Zhang YL, Chen X, Chen DL, Wang LJ, Tang ZP. Jianpi Qingchang decoction regulates intestinal motility of dextran sulfate sodium-induced colitis through reducing autophagy of interstitial cells of Cajal. World J Gastroenterol 2017; 23:4724-4734. [PMID: 28765693 PMCID: PMC5514637 DOI: 10.3748/wjg.v23.i26.4724] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 04/30/2017] [Accepted: 06/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the underlying effect of Jianpi Qingchang decoction (JQD) regulating intestinal motility of dextran sulfate sodium (DSS)-induced colitis in mice. METHODS C57BL/6 mice were randomly divided into four groups: the control group, the DSS group, the JQD group, and the 5-aminosalicylic acid group. Except for the control group, colitis was induced in other groups by giving distilled water containing 5% DSS. Seven days after modeling, the mice were administered corresponding drugs intragastrically. The mice were sacrificed on the 15th day. The disease activity index, macroscopic and histopathologic lesions, and ultrastructure of colon interstitial cells of Cajal (ICC) were observed. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-10 and interferon gamma (IFN-γ), the expression of nuclear factor-kappa B (NF-κB) p65, c-kit, microtubule-associated protein 1 light chain 3 (LC3-II) and Beclin-l mRNA, and the colonic smooth muscle tension were assessed. RESULTS Acute inflammation occurred in the mice administered DSS. Compared with the control group, the levels of IL-1β, TNF-α, IL-10 and IFN-γ, the expression of LC3-II, Beclin-1 and NF-κB p65 mRNA, and the contractile frequency increased (P < 0.05), the expression of c-kit mRNA and the colonic smooth muscle contractile amplitude decreased in the DSS group (P < 0.05). Compared with the DSS group, the levels of IL-10 and IFN-γ, the expression of c-kit mRNA, and the colonic smooth muscle contractile amplitude increased (P < 0.05), the levels of TNF-α and IL-1β, the expression of LC3-II, Beclin-1 and NF-κB p65 mRNA, and the contractile frequency decreased in the JQD group (P < 0.05). CONCLUSION JQD can regulate the intestinal motility of DSS-induced colitis in mice through suppressing intestinal inflammatory cascade reaction, reducing autophagy of ICC, and regulating the network path of ICC/smooth muscle cells.
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Colussi D, Bazzoli F, Ricciardiello L. Chemoprevention of Colorectal Cancer in High-Risk Patients: from Molecular Targets to Clinical Trials. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0364-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
Optimizing the management of colorectal cancer (CRC) risk in IBD requires a fundamental understanding of the evolutionary process underpinning tumorigenesis. In IBD, clonal evolution begins long before the development of overt neoplasia, and is probably accelerated by the repeated cycles of epithelial wounding and repair that are characteristic of the condition. Here, we review the biological drivers of mutant clone selection in IBD with particular reference to the unique histological architecture of the intestinal epithelium coupled with the inflammatory microenvironment in IBD, and the unique mutation patterns seen in IBD-driven neoplasia when compared with sporadic adenomas and CRC. How these data can be leveraged as evolutionary-based biomarkers to predict cancer risk is discussed, as well as how the efficacy of CRC surveillance programmes and the management of dysplasia can be improved. From a research perspective, the longitudinal surveillance of patients with IBD provides an under-exploited opportunity to investigate the biology of the human gastrointestinal tract over space and time.
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Affiliation(s)
- Chang-Ho R Choi
- Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
- Inflammatory Bowel Disease Unit, Level 4 St Mark's Hospital, Watford Road, London HA1 3UJ, UK
| | - Ibrahim Al Bakir
- Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
- Inflammatory Bowel Disease Unit, Level 4 St Mark's Hospital, Watford Road, London HA1 3UJ, UK
| | - Ailsa L Hart
- Inflammatory Bowel Disease Unit, Level 4 St Mark's Hospital, Watford Road, London HA1 3UJ, UK
| | - Trevor A Graham
- Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
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Chang WCL, Masih S, Thadi A, Patwa V, Joshi A, Cooper HS, Palejwala VA, Clapper ML, Shailubhai K. Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc +/Min-FCCC mice. World J Gastrointest Pharmacol Ther 2017; 8:47-59. [PMID: 28217374 PMCID: PMC5292606 DOI: 10.4292/wjgpt.v8.i1.47] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/30/2016] [Accepted: 10/27/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effect of orally administered plecanatide on colorectal dysplasia in Apc+/Min-FCCC mice with dextran sodium sulfate (DSS)-induced inflammation.
METHODS Inflammation driven colorectal carcinogenesis was induced in Apc+/Min-FCCC mice by administering DSS in their drinking water. Mice were fed a diet supplemented with plecanatide (0-20 ppm) and its effect on the multiplicity of histopathologically confirmed polypoid, flat and indeterminate dysplasia was evaluated. Plecanatide-mediated activation of guanylate cyclase-C (GC-C) signaling was assessed in colon tissues by measuring cyclic guanosine monophosphate (cGMP) by ELISA, protein kinase G-II and vasodilator stimulated phosphoprotein by immunoblotting. Ki-67, c-myc and cyclin D1 were used as markers of proliferation. Cellular levels and localization of β-catenin in colon tissues were assessed by immunoblotting and immunohistochemistry, respectively. Uroguanylin (UG) and GC-C transcript levels were measured by quantitative reverse transcription polymerase chain reaction (RT-PCR). A mouse cytokine array panel was used to detect cytokines in the supernatant of colon explant cultures.
RESULTS Oral treatment of Apc+/MinFCCC mice with plecanatide produced a statistically significant reduction in the formation of inflammation-driven polypoid, flat and indeterminate dysplasias. This anti-carcinogenic activity of plecanatide was accompanied by activation of cGMP/GC-C signaling mediated inhibition of Wnt/β-catenin signaling and reduced proliferation. Plecanatide also decreased secretion of pro-inflammatory cytokines (IL-6, IL1 TNF), chemokines (MIP-1, IP-10) and growth factors (GCSF and GMCSF) from colon explants derived from mice with acute DSS-induced inflammation. The effect of plecanatide-mediated inhibition of inflammation/dysplasia on endogenous expression of UG and GC-C transcripts was measured in intestinal tissues. Although GC-C expression was not altered appreciably, a statistically significant increase in the level of UG transcripts was detected in the proximal small intestine and colon, potentially due to a reduction in intestinal inflammation and/or neoplasia. Taken together, these results suggest that reductions in endogenous UG, accompanied by dysregulation in GC-C signaling, may be an early event in inflammation-promoted colorectal neoplasia; an event that can potentially be ameliorated by prophylactic intervention with plecanatide.
CONCLUSION This study provides the first evidence that orally administered plecanatide reduces the multiplicity of inflammation-driven colonic dysplasia in mice, demonstrating the utility for developing GC-C agonists as chemopreventive agents.
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Duan H, Lü S, Qin H, Gao C, Bai X, Wei Y, Wu X, Liu M, Zhang X, Liu Z. Co-delivery of zinc and 5-aminosalicylic acid from alginate/ N -succinyl-chitosan blend microspheres for synergistic therapy of colitis. Int J Pharm 2017; 516:214-224. [DOI: 10.1016/j.ijpharm.2016.11.036] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/03/2016] [Accepted: 11/12/2016] [Indexed: 01/04/2023]
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Duan H, Lü S, Gao C, Bai X, Qin H, Wei Y, Wu X, Liu M. Mucoadhesive microparticulates based on polysaccharide for target dual drug delivery of 5-aminosalicylic acid and curcumin to inflamed colon. Colloids Surf B Biointerfaces 2016; 145:510-519. [PMID: 27239905 DOI: 10.1016/j.colsurfb.2016.05.038] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 04/18/2016] [Accepted: 05/14/2016] [Indexed: 02/07/2023]
Abstract
In this work, thiolated chitosan/alginate composite microparticulates (CMPs) coated by Eudragit S-100 were developed for colon-specific delivery of 5-aminosalicylic acid (5-ASA) and curcumin (CUR), and the use of it as a multi drug delivery system for the treatment of colitis. The physicochemical properties of the CMPs were evaluated. In vitro release was performed in gradually pH-changing medium simulating the conditions of different parts of GIT, and the results showed that the Eudragit S-100 coating has a pH-sensitive release property, which can avoid drug being released at a pH lower than 7. An everted sac method was used to evaluate the mucoadhesion of CMPs. Ex vivo mucoadhesive tests showed CMPs have excellent mucosa adhesion for the colonic mucosa of rats. In vivo treatment effect of enteric microparticulates systems was evaluated in colitis rats. The results showed superior therapeutic efficiency of this drug delivery system for the colitis rats induced by TNBS. Therefore, the enteric microparticulates systems combined the properties of pH dependent delivery, mucoadhesive, and control release, and could be an available tool for the treatment of human inflammatory bowel disease.
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Affiliation(s)
- Haogang Duan
- Department of Chemistry, Lanzhou University, Lanzhou 730000, PR China; Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, PR China
| | - Shaoyu Lü
- Department of Chemistry, Lanzhou University, Lanzhou 730000, PR China
| | - Chunmei Gao
- Department of Chemistry, Lanzhou University, Lanzhou 730000, PR China
| | - Xiao Bai
- Department of Chemistry, Lanzhou University, Lanzhou 730000, PR China
| | - Hongyan Qin
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, PR China
| | - Yuhui Wei
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, PR China
| | - Xin'an Wu
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, PR China
| | - Mingzhu Liu
- Department of Chemistry, Lanzhou University, Lanzhou 730000, PR China.
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Saber MM, Galal MA, Ain-Shoka AA, Shouman SA. Combination of metformin and 5-aminosalicylic acid cooperates to decrease proliferation and induce apoptosis in colorectal cancer cell lines. BMC Cancer 2016; 16:126. [PMID: 26896068 PMCID: PMC4759732 DOI: 10.1186/s12885-016-2157-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 02/10/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The link between inflammation and cancer has been confirmed by the use of anti-inflammatory therapies in cancer prevention and treatment. 5-aminosalicylic acid (5-ASA) was shown to decrease the growth and survival of colorectal cancer (CRC) cells. Studies also revealed that metformin induced apoptosis in several cancer cell lines. METHODS We investigated the combinatory effect of 5-ASA and metformin on HCT-116 and Caco-2 CRC cell lines. Apoptotic markers were determined using western blotting. Expression of pro-inflammatory cytokines was determined by RT-PCR. Inflammatory transcription factors and metastatic markers were measured by ELISA. RESULTS Metformin enhanced CRC cell death induced by 5-ASA through significant increase in oxidative stress and activation of apoptotic machinery. Moreover, metformin enhanced the anti-inflammatory effect of 5-ASA by decreasing the gene expression of IL-1β, IL-6, COX-2 and TNF-α and its receptors; TNF-R1 and TNF-R2. Significant inhibition of activation of NF-κB and STAT3 transcription factors, and their downstream targets was also observed. Metformin also enhanced the inhibitory effect of 5-ASA on MMP-2 and MMP-9 enzyme activity, indicating a decrease in metastasis. CONCLUSION The current data demonstrate that metformin potentiates the antitumor effect of 5-ASA on CRC cells suggesting their potential use as an adjuvant treatment in CRC.
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Affiliation(s)
- Mona M Saber
- Pharmacology and Toxicolgy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| | - May A Galal
- Pharmacology and Toxicolgy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| | - Afaf A Ain-Shoka
- Pharmacology and Toxicolgy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| | - Samia A Shouman
- Parmacology Unit,Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11796, Egypt.
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25
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Lupeol inhibits LPS-induced NF-kappa B signaling in intestinal epithelial cells and macrophages, and attenuates acute and chronic murine colitis. Life Sci 2016; 146:100-8. [DOI: 10.1016/j.lfs.2016.01.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Revised: 12/17/2015] [Accepted: 01/02/2016] [Indexed: 12/31/2022]
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26
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Giner E, Recio MC, Ríos JL, Cerdá-Nicolás JM, Giner RM. Chemopreventive effect of oleuropein in colitis-associated colorectal cancer in c57bl/6 mice. Mol Nutr Food Res 2015; 60:242-55. [DOI: 10.1002/mnfr.201500605] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 09/09/2015] [Accepted: 09/16/2015] [Indexed: 01/03/2023]
Affiliation(s)
- Elisa Giner
- Departament de Farmacologia; Facultat de Farmàcia; Universitat de València; Burjassot Spain
| | - M. Carmen Recio
- Departament de Farmacologia; Facultat de Farmàcia; Universitat de València; Burjassot Spain
| | - José Luis Ríos
- Departament de Farmacologia; Facultat de Farmàcia; Universitat de València; Burjassot Spain
| | | | - Rosa María Giner
- Departament de Farmacologia; Facultat de Farmàcia; Universitat de València; Burjassot Spain
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Golovko D, Kedrin D, Yilmaz ÖH, Roper J. Colorectal cancer models for novel drug discovery. Expert Opin Drug Discov 2015; 10:1217-29. [PMID: 26295972 DOI: 10.1517/17460441.2015.1079618] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Despite increased screening rates and advances in targeted therapy, colorectal cancer (CRC) remains the third leading cause of cancer-related mortality. CRC models that recapitulate key features of human disease are essential to the development of novel and effective therapeutics. Classic methods of modeling CRC such as human cell lines and xenograft mice, while useful for many applications, carry significant limitations. Recently developed in vitro and in vivo models overcome some of these deficiencies and thus can be utilized to better model CRC for mechanistic and translational research. AREAS COVERED The authors review established models of in vitro cell culture and describe advances in organoid culture for studying normal and malignant intestine. They also discuss key features of classic xenograft models and describe other approaches for in vivo CRC research, including patient-derived xenograft, carcinogen-induced, orthotopic transplantation and transgenic mouse models. We also describe mouse models of metastatic CRC. EXPERT OPINION No single model is optimal for drug discovery in CRC. Genetically engineered models overcome many limitations of xenograft models. Three-dimensional organoids can be efficiently derived from both normal and malignant tissue for large-scale in vitro and in vivo (transplantation) studies and are thus a significant advance in CRC drug discovery.
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Affiliation(s)
- Daniel Golovko
- a 1 Tufts Medical Center, Division of Gastroenterology and Molecular Oncology Research Institute , Boston, MA 02111, USA
| | - Dmitriy Kedrin
- b 2 MIT, The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology , Cambridge, MA 02139, USA.,c 3 Massachusetts General Hospital and Harvard Medical School, Division of Gastroenterology , Boston, MA 02114, USA
| | - Ömer H Yilmaz
- b 2 MIT, The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology , Cambridge, MA 02139, USA.,d 4 Massachusetts General Hospital and Harvard Medical School, Department of Pathology , Boston, MA 02114, USA
| | - Jatin Roper
- a 1 Tufts Medical Center, Division of Gastroenterology and Molecular Oncology Research Institute , Boston, MA 02111, USA .,b 2 MIT, The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology , Cambridge, MA 02139, USA
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28
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Gordon-Weeks AN, Lim SY, Yuzhalin AE, Jones K, Muschel R. Macrophage migration inhibitory factor: a key cytokine and therapeutic target in colon cancer. Cytokine Growth Factor Rev 2015; 26:451-61. [PMID: 25882738 DOI: 10.1016/j.cytogfr.2015.03.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 03/25/2015] [Indexed: 02/07/2023]
Abstract
Macrophage migration inhibitory factor (MIF) was one of the first cytokines to be discovered, over 40 years ago. Since that time a burgeoning interest has developed in the role that MIF plays in both the regulation of normal physiology and the response to pathology. MIF is a pleotropic cytokine that functions to promote inflammation, drive cellular proliferation, inhibit apoptosis and regulate the migration and activation state of immune cells. These functions are particularly relevant for the development of cancer and it is notable that various solid tumours over express MIF. This includes tumours of the gastrointestinal tract and MIF appears to play a particularly prominent role in the development and progression of colonic adenocarcinoma. Here we review the role that MIF plays in colonic carcinogenesis through the promotion of colonic inflammation, as well as the progression of primary and metastatic colon cancer. The recent development of various antagonists and antibodies that inhibit MIF activity indicates that we may soon be able to classify MIF as a therapeutic target in colon cancer patients.
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Affiliation(s)
- A N Gordon-Weeks
- CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK.
| | - S Y Lim
- CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK
| | - A E Yuzhalin
- CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK
| | - K Jones
- CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK
| | - R Muschel
- CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK
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29
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Peroxisome proliferator-activated receptor-γ is downregulated in ulcerative colitis and is involved in experimental colitis-associated neoplasia. Oncol Lett 2015; 10:1259-1266. [PMID: 26622660 DOI: 10.3892/ol.2015.3397] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 03/12/2015] [Indexed: 01/04/2023] Open
Abstract
The aim of the present study was to evaluate the expression of peroxisome proliferator-activated receptor (PPAR)-γ in inflammatory bowel disease (IBD), and to also identify the association between PPAR-γ and the clinical features of patients with IBD. An azoxymethane (AOM)/dextran sodium sulfate (DSS) animal model of colitis-associated neoplasia was established to investigate the protective effect of 5-aminosalicylic acid (5-ASA) and to explore the changes in the expression of PPAR-γ during this process. A total of 66 specimens of colorectal tissue obtained from biopsy performed on IBD patients and 30 healthy control individuals were immunohistochemically stained for PPAR-γ. An AOM/DSS animal model of colitis-associated neoplasia was then established. Reverse transcription quantitative polymerase chain reaction was conducted and it was found that, compared with the control group and patients with Crohn's disease (CD), the expression of PPAR-γ in the intestinal tissue of patients with ulcerative colitis (UC) was significantly decreased (P=0.027 and 0.046, respectively). The expression of PPAR-γ was found to be negatively associated with the disease activity of UC and was not associated with the severity of disease, site of lesions or CD characteristics. Administration of 5-ASA decreased the colitis and tumor burden of colons. The expression level of PPAR-γ in the intestinal tissue was also increased in the AOM/DSS/5-ASA group compared with AOM/DSS group (P<0.001). PPAR-γ is an important factor in the pathogenesis of UC and colitis-associated cancer. The present study found that 5-ASA significantly alleviates the colitis and tumor burden in a mouse model of AOM/DSS-induced colitis-associated neoplasia, and promotes the expression of PPAR-γ in the intestinal tract.
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30
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KAG-308, a newly-identified EP4-selective agonist shows efficacy for treating ulcerative colitis and can bring about lower risk of colorectal carcinogenesis by oral administration. Eur J Pharmacol 2015; 754:179-89. [DOI: 10.1016/j.ejphar.2015.02.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 02/10/2015] [Accepted: 02/11/2015] [Indexed: 12/21/2022]
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31
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Five-aminosalicylic Acid: an update for the reappraisal of an old drug. Gastroenterol Res Pract 2015; 2015:456895. [PMID: 25685145 PMCID: PMC4320793 DOI: 10.1155/2015/456895] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 12/29/2014] [Indexed: 12/17/2022] Open
Abstract
Inflammatory bowel disease (IBD) comprises several conditions with chronic or recurring immune response and inflammation of the gastrointestinal apparatus, of which ulcerative colitis and Crohn's disease are the commonest forms. This disease has a significant prevalence and it is of an unknown aethiology. Five-aminosalicylic acid (5-ASA) and its derivatives are among the oldest drugs approved for the treatment of the IBD. In this review we reapprise aspects of 5-ASA mechanism of action, safety, and efficacy that in our opinion make it a valuable drug that can be fruitfully tailored in personalised treatments as a therapeutic option alongside other immune-modifying agents.
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Pal S, Bhattacharjee A, Ali A, Mandal NC, Mandal SC, Pal M. Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism. JOURNAL OF INFLAMMATION-LONDON 2014; 11:23. [PMID: 25152696 PMCID: PMC4142057 DOI: 10.1186/1476-9255-11-23] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 06/28/2014] [Indexed: 12/13/2022]
Abstract
Activation of nuclear factor-kappa B (NF- κB) as a mechanism of host defense against infection and stress is the central mediator of inflammatory responses. A normal (acute) inflammatory response is activated on urgent basis and is auto-regulated. Chronic inflammation that results due to failure in the regulatory mechanism, however, is largely considered as a critical determinant in the initiation and progression of various forms of cancer. Mechanistically, NF- κB favors this process by inducing various genes responsible for cell survival, proliferation, migration, invasion while at the same time antagonizing growth regulators including tumor suppressor p53. It has been shown by various independent investigations that a down regulation of NF- κB activity directly, or indirectly through the activation of the p53 pathway reduces tumor growth substantially. Therefore, there is a huge effort driven by many laboratories to understand the NF- κB signaling pathways to intervene the function of this crucial player in inflammation and tumorigenesis in order to find an effective inhibitor directly, or through the p53 tumor suppressor. We discuss here on the role of NF- κB in chronic inflammation and cancer, highlighting mutual antagonism between NF- κB and p53 pathways in the process. We also discuss prospective pharmacological modulators of these two pathways, including those that were already tested to affect this mutual antagonism.
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Affiliation(s)
- Srabani Pal
- Pharmacognosy and Phytotherapy laboratory, Division of Pharmacognosy, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Ashish Bhattacharjee
- Department of Biotechnology, National Institute of Technology, Durgapur-713209, India
| | - Asif Ali
- Division of Molecular Medicine, Bose Institute, Kolkata 700054, India
| | | | - Subhash C Mandal
- Pharmacognosy and Phytotherapy laboratory, Division of Pharmacognosy, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Mahadeb Pal
- Division of Molecular Medicine, Bose Institute, Kolkata 700054, India
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Lu L, Chan RLY, Luo XM, Wu WKK, Shin VY, Cho CH. Animal models of gastrointestinal inflammation and cancer. Life Sci 2014; 108:1-6. [PMID: 24825611 DOI: 10.1016/j.lfs.2014.04.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/20/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023]
Abstract
Inflammation and cancer are the two major disorders in the gastrointestinal tract. They are causally related in their pathogenesis. It is important to study animal models' causal relationship and, in particular, to discover new therapeutic agents for such diseases. There are several criteria for these models in order to make them useful in better understanding the etiology and treatment of the said diseases in humans. In this regard, animal models should be similar as possible to human diseases and also be easy to produce and reproducible and also economic to allow a continuous replication in different laboratories. In this review, we summarize the various animal models for inflammatory and cancerous disorders in the upper and lower gastrointestinal tract. Experimental approaches are as simple as by giving a single oral dose of alcohol or other noxious agents or by injections of multiple dosages of ulcer inducing agents or by parenteral administration or in drinking water of carcinogens or by modifying the genetic makeups of animals to produce relatively long-term pathological changes in particular organs. With these methods they could induce consistent inflammatory responses or tumorigenesis in the gastrointestinal mucosa. These animal models are widely used in laboratories in understanding the pathogenesis as well as the mechanisms of action for therapeutic agents in the treatment of gastrointestinal inflammation and cancer.
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Affiliation(s)
- L Lu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Ruby L Y Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - X M Luo
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - William K K Wu
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Vivian Y Shin
- Department of Surgery, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - C H Cho
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
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Stolfi C, De Simone V, Pallone F, Monteleone G. Mechanisms of action of non-steroidal anti-inflammatory drugs (NSAIDs) and mesalazine in the chemoprevention of colorectal cancer. Int J Mol Sci 2013; 14:17972-85. [PMID: 24005861 PMCID: PMC3794763 DOI: 10.3390/ijms140917972] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 08/19/2013] [Accepted: 08/23/2013] [Indexed: 12/21/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide. Although conclusive evidence is still lacking, epidemiologic studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has chemopreventive properties against CRC. Similarly, regular consumption of mesalazine, a drug structurally related to NSAIDs, seems to reduce the risk of CRC in patients with ulcerative colitis. These observations are supported by a large body of experimental data showing the ability of such drugs to inhibit multiple pathways that sustain colon carcinogenesis. This review summarizes the current information on the molecular mechanisms by which NSAIDs and mesalazine could interfere with CRC cell growth and survival.
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Affiliation(s)
- Carmine Stolfi
- Authors to whom correspondence should be addressed; E-Mails: (C.S.); (G.M.); Tel.: +39-06-7259-6158 (C.S. & G.M.); Fax: +39-06-7259-6391 (C.S. & G.M.)
| | | | | | - Giovanni Monteleone
- Authors to whom correspondence should be addressed; E-Mails: (C.S.); (G.M.); Tel.: +39-06-7259-6158 (C.S. & G.M.); Fax: +39-06-7259-6391 (C.S. & G.M.)
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Stolfi C, De Simone V, Pallone F, Monteleone G. Mechanisms of action of non-steroidal anti-inflammatory drugs (NSAIDs) and mesalazine in the chemoprevention of colorectal cancer. Int J Mol Sci 2013. [PMID: 24005861 DOI: 10.3390/jims140917972] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide. Although conclusive evidence is still lacking, epidemiologic studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has chemopreventive properties against CRC. Similarly, regular consumption of mesalazine, a drug structurally related to NSAIDs, seems to reduce the risk of CRC in patients with ulcerative colitis. These observations are supported by a large body of experimental data showing the ability of such drugs to inhibit multiple pathways that sustain colon carcinogenesis. This review summarizes the current information on the molecular mechanisms by which NSAIDs and mesalazine could interfere with CRC cell growth and survival.
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Affiliation(s)
- Carmine Stolfi
- Department of Systems Medicine, University of Tor Vergata, Via Montpellier 1, Rome 00133, Italy.
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Fahrer J, Kaina B. O6-methylguanine-DNA methyltransferase in the defense against N-nitroso compounds and colorectal cancer. Carcinogenesis 2013; 34:2435-42. [PMID: 23929436 DOI: 10.1093/carcin/bgt275] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is among the leading causes of cancer death worldwide, involving multiple dietary and non-dietary risk factors. A growing body of evidence suggests that N-nitroso compounds (NOC) play a pivotal role in the etiology of CRC. NOC are present in food and are also formed endogenously in the large intestine. Upon metabolic activation and also spontaneously, they form electrophilic species that methylate the DNA, producing N-methylated purines and O(6)-methylguanine, the latter of which bears high mutagenic and carcinogenic potential. Methylated DNA bases are removed by base excision repair initiated by the alkyladenine-DNA glycosylase, the family of AlkB homologs proteins, and the suicide enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), which is the main focus of this review. We present animal models with a deficiency of MGMT that display a tremendously enhanced sensitivity toward alkylation-induced colorectal carcinogenesis, highlighting its role in the protection against the cytotoxic and mutagenic effects of alkylating agents. In line with these studies, MGMT was linked to the formation of human sporadic CRC. Colorectal tumors and precursor lesions frequently display epigenetic inactivation of MGMT resulting from promoter hypermethylation, which is tightly associated with the occurrence of G:C to A:T transition mutations in the KRAS oncogene. We also discuss clinical data, which identified the MGMT status of CRC patients as promising parameter for the treatment of metastasized CRC using alkylating anticancer drugs such as temozolomide.
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Affiliation(s)
- Jörg Fahrer
- Department of Toxicology, University Medical Center Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany
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Oroxylin A inhibits colitis-associated carcinogenesis through modulating the IL-6/STAT3 signaling pathway. Inflamm Bowel Dis 2013; 19:1990-2000. [PMID: 23823704 DOI: 10.1097/mib.0b013e318293c5e0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Patients with inflammatory bowel disease, which includes ulcerative colitis and Crohn's disease, are at a significantly increased risk of developing colorectal cancer, and aberrant interleukin (IL)-6/STAT3 signaling pathway exists in both inflammatory bowel disease and inflammation-related gastrointestinal cancers. We have previously found that oroxylin A inhibited the NF-κB signaling in human colon tumor HCT-116 cells. However, whether oroxylin A could inhibit the colitis-associated carcinogenesis remains to be determined. METHODS HCT-116 cells were treated with various concentrations of oroxylin A. Expression of relative proteins of IL-6/STAT3 signaling pathway was assayed by Western blot and immunofluorescence analysis. Mouse model for colitis-associated colorectal cancer was induced by a combined treatment with 10 mg/kg azoxymethane (AOM) followed by 3 cycles of 2.5% dextran sodium sulfate in C57BL/6 mice. IL-6 and IL-1β gene expression were analyzed by quantitative real-time PCR. Expression of relative proteins was examined by immunohistochemistry and Western blot. RESULTS Oroxylin A effectively inhibited IL-6/STAT3 pathway in human HCT-116 cells, and the effect of oroxylin A was reversible. Dietary administration of oroxylin A throughout the experimental period significantly reduced the tumor burden, inhibited cell proliferation, and induced apoptosis in colon carcinomas. The expression of inflammatory cytokines IL-6 and IL-1β decreased in tumors in oroxylin A-treated mice. The IL-6/STAT3 signaling pathway was attenuated in oroxylin A-treated mice. CONCLUSIONS Our results demonstrated that oroxylin A inhibits colitis-associated carcinogenesis through modulating IL-6/STAT3 pathway in AOM/dextran sodium sulfate mouse model and in HCT-116 cells.
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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: 26] [Impact Index Per Article: 2.2] [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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Chang WCL, Zenser TV, Cooper HS, Clapper ML. Differential response of flat and polypoid colitis-associated colorectal neoplasias to chemopreventive agents and heterocyclic amines. Cancer Lett 2013; 334:62-8. [PMID: 23415736 DOI: 10.1016/j.canlet.2013.02.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 02/06/2013] [Accepted: 02/06/2013] [Indexed: 02/09/2023]
Abstract
Individuals with ulcerative colitis face an increased risk of developing colorectal cancer and would benefit from early chemopreventive intervention. Results from preclinical studies in the mouse model of dextran sulfate sodium-induced colitis demonstrate that flat and polypoid colitis-associated dysplasias arise via distinct genetic pathways, impacted by the allelic status of p53. Furthermore, flat and polypoid dysplasias vary in their response to induction by the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and inhibition by 5-aminosalicylic acid, a common therapy for the maintenance of colitis patients. These data suggest that use of combination therapy is essential for the optimal inhibition of colitis-associated colorectal cancer.
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Affiliation(s)
- Wen-Chi L Chang
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, United States
| | - Terry V Zenser
- Department of Internal Medicine, St. Louis University, St. Louis, MO 63103, United States
| | - Harry S Cooper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, United States; Department of Pathology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, United States
| | - Margie L Clapper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, United States.
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Navath S, Rao V, Woodford RMT, Midura-Kiela MT, Ahad AM, Alleti R, Kiela PR, Mash EA. Design, Synthesis, and Testing of a Molecular Truck for Colonic Delivery of 5-Aminosalicylic Acid. ACS Med Chem Lett 2012; 3:710-714. [PMID: 23029601 DOI: 10.1021/ml300086c] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
A molecular scaffold bearing eight terminal alkyne groups was synthesized from sucrose. Eight copies of an azide-terminated, azo-linked precursor to 5-aminosalicylic acid were attached to the scaffold via copper(I)-catalyzed azide-alkyne cycloaddition. The resulting compound was evaluated in a DSS model of colitis in BALB/c mice against sulfasalazine as a control. Two independent studies verified that the novel pro-drug, administered in a dose calculated to result in an equimolar 5-ASA yield, outperformed sulfasalazine in terms of protection from mucosal inflammation and T cell activation. A separate study established that 5-ASA appeared in feces produced 24-48 hours following administration of the pro-drug. Thus, a new, orally administered pro-drug form of 5-aminosalicylic acid has been developed and successfully demonstrated.
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Affiliation(s)
- Suryakiran Navath
- Department
of Chemistry and
Biochemistry, University of Arizona, Tucson,
Arizona 85721, United States
| | - Venkataramanarao Rao
- Department
of Chemistry and
Biochemistry, University of Arizona, Tucson,
Arizona 85721, United States
| | - Rita-Marie T. Woodford
- Department of Pediatrics, University of Arizona, Tucson, Arizona 85724, United
States
- School of Dentistry,
Oral Biology
Program, University of North Carolina,
Chapel Hill, North Carolina 27599, United States
| | | | - Ali M. Ahad
- Department
of Chemistry and
Biochemistry, University of Arizona, Tucson,
Arizona 85721, United States
| | - Ramesh Alleti
- Department
of Chemistry and
Biochemistry, University of Arizona, Tucson,
Arizona 85721, United States
| | - Pawel R. Kiela
- Department of Pediatrics, University of Arizona, Tucson, Arizona 85724, United
States
- Department of Immunobiology, University of Arizona, Tucson, Arizona 85724, United
States
| | - Eugene A. Mash
- Department
of Chemistry and
Biochemistry, University of Arizona, Tucson,
Arizona 85721, United States
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Abstract
PURPOSE OF REVIEW Human colitis-associated cancers (CAC) represent a heterogeneous group of conditions in which multiple oncogenic pathways are involved. In this article, we review the latest studies using genetic, chemical, bacterial and innate immune-mediated experimental models of CAC. RECENT FINDINGS Using the azoxymethane-dextran sodium sulfate model, wound healing pathways seem to be required in the development of CAC. There is also an emerging understanding that commensal and/or pathogenic bacteria can promote tumorigenesis, through T cell and TLR-mediated inflammation. Using specific transgenic mice (villin-CD98, T cell SMAD7, villin-TLR4) or specific knockout mice, investigators have determined that derangements in epithelial or innate and adaptive immune pathways can result in CAC. Subtle perturbations in epithelial repair - both too little or too exuberant - can render mice susceptible to tumorigenesis. SUMMARY With the aid of animal models, we have witnessed a rapid expansion of our knowledge of the molecular and immunologic mechanisms underlying inflammatory cancers. Though animal models have contributed a discrete amount of information to our understanding of tumorigenesis in the setting of intestinal inflammation, it is clear that no single animal model will be able to adequately recapitulate the pathogenesis of complex colorectal cancers, but each model gets us one step closer to comprehending the nature of CAC.
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Colorectal cancer chemoprevention by mesalazine and its derivatives. J Biomed Biotechnol 2012; 2012:980458. [PMID: 22701310 PMCID: PMC3373216 DOI: 10.1155/2012/980458] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 04/20/2012] [Indexed: 01/12/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) face an increased lifetime risk of developing colorectal cancer (CRC). Independent factors associated with increased risk include long disease duration, extensive colonic involvement, young age at onset of IBD, severity of inflammation, primary sclerosing cholangitis, backwash ileitis, and a family history of CRC, thus emphasising the role of intestinal inflammation as an underlying mechanism. This notion is also supported by the demonstration that the use of certain drugs used to attenuate the ongoing mucosal inflammation, such as mesalazine, seems to associate with a reduced incidence of colitis-associated CRC. In the last decade, work from many laboratories has contributed to delineate the mechanisms by which mesalazine alters CRC cell behaviour. In this paper, we review the available experimental data supporting the ability of mesalazine and its derivatives to interfere with intracellular signals involved in CRC cell growth.
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Suárez J, Romero-Zerbo Y, Márquez L, Rivera P, Iglesias M, Bermúdez-Silva FJ, Andreu M, de Fonseca FR. Ulcerative colitis impairs the acylethanolamide-based anti-inflammatory system reversal by 5-aminosalicylic acid and glucocorticoids. PLoS One 2012; 7:e37729. [PMID: 22662201 PMCID: PMC3360619 DOI: 10.1371/journal.pone.0037729] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 04/23/2012] [Indexed: 11/18/2022] Open
Abstract
Studies in animal models and humans suggest anti-inflammatory roles on the N-acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE-PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages.
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Affiliation(s)
- Juan Suárez
- Laboratorio de Medicina Regenerativa, Hospital Carlos Haya, Mediterranean Institute for the Advance of Biotechnology and Health Research Fundación, Málaga, Spain
- El Centro de Investigación Biomédica en Red de Fisiopatología de Obesidad y Nutrición, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Madrid, Spain
| | - Yanina Romero-Zerbo
- Laboratorio de Medicina Regenerativa, Hospital Carlos Haya, Mediterranean Institute for the Advance of Biotechnology and Health Research Fundación, Málaga, Spain
| | - Lucia Márquez
- Department of Gastroenterology, Parc de Salut Mar, Universidad Autónoma, Barcelona, Spain
| | - Patricia Rivera
- Laboratorio de Medicina Regenerativa, Hospital Carlos Haya, Mediterranean Institute for the Advance of Biotechnology and Health Research Fundación, Málaga, Spain
| | - Mar Iglesias
- Department of Pathology, Parc de Salut Mar, Universidad Autónoma, Barcelona, Spain
| | - Francisco J. Bermúdez-Silva
- Laboratorio de Medicina Regenerativa, Hospital Carlos Haya, Mediterranean Institute for the Advance of Biotechnology and Health Research Fundación, Málaga, Spain
- El Centro de Investigación Biomédica en Red de Fisiopatología de Obesidad y Nutrición, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Madrid, Spain
| | - Montserrat Andreu
- Department of Gastroenterology, Parc de Salut Mar, Universidad Autónoma, Barcelona, Spain
- * E-mail: (FRdF); (MA)
| | - Fernando Rodríguez de Fonseca
- Laboratorio de Medicina Regenerativa, Hospital Carlos Haya, Mediterranean Institute for the Advance of Biotechnology and Health Research Fundación, Málaga, Spain
- El Centro de Investigación Biomédica en Red de Fisiopatología de Obesidad y Nutrición, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Madrid, Spain
- * E-mail: (FRdF); (MA)
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Seavey MM, Lu LD, Stump KL, Wallace NH, Hockeimer W, O'Kane TM, Ruggeri BA, Dobrzanski P. Therapeutic Efficacy of CEP-33779, a Novel Selective JAK2 Inhibitor, in a Mouse Model of Colitis-Induced Colorectal Cancer. Mol Cancer Ther 2012; 11:984-93. [PMID: 22334590 DOI: 10.1158/1535-7163.mct-11-0951] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Matthew M Seavey
- Cephalon, Inc., Worldwide Discovery Research, West Chester, PA 19380, USA.
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Kisiel JB, Loftus EV, Harmsen WS, Zinsmeister AR, Sandborn WJ. Outcome of sporadic adenomas and adenoma-like dysplasia in patients with ulcerative colitis undergoing polypectomy. Inflamm Bowel Dis 2012; 18:226-35. [PMID: 21416564 DOI: 10.1002/ibd.21687] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Accepted: 01/20/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) patients are at increased risk of colorectal dysplasia and cancer. Few studies have examined the clinical outcomes of dysplastic polyps resembling sporadic adenomas that are removed with endoscopic polypectomy. METHODS A centralized diagnostic index identified patients evaluated between 1994 and 2004 with UC and polypoid dysplasia who were followed from the time of polypectomy until the most recent colonoscopy. They were stratified into two groups by polyp occurrence, either within (adenoma-like dysplasia) or outside (sporadic adenoma) the most proximal endoscopic or histologic extent of colitis. The endpoints of interest were the development of subsequent colorectal neoplasia, flat dysplasia, or cancer. The cumulative probabilities of these endpoints were estimated using the Kaplan-Meier method, and the association with clinical factors assessed using Cox proportional hazards regression. RESULTS Ninety-five patients were found to have polypoid dysplasia; of these, 77 underwent polypectomy. The cumulative probability of subsequent colorectal neoplasia in polypectomy patients was 18% at 1 year and 69% at 5 years. After polypectomy, cumulative incidence of cancer or flat dysplasia was 2% at 1 year and 13% at 5 years. The proportional hazards models indicated that these outcomes were not significantly associated with polyp type, primary sclerosing cholangitis, family history of colorectal cancer, 5-aminosalicylate use, extent of colitis, or duration of disease. CONCLUSIONS While polypectomy may be safe for the management of adenomas occurring in most UC patients, the 5-year cumulative incidence of a combined endpoint (cancer or flat dysplasia) was 13%. Such patients should be followed closely.
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Affiliation(s)
- John B Kisiel
- Division of Gastroenterology & Hepatology, Rochester, Minnesota 55905, USA
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Li TWH, Yang H, Peng H, Xia M, Mato JM, Lu SC. Effects of S-adenosylmethionine and methylthioadenosine on inflammation-induced colon cancer in mice. Carcinogenesis 2011; 33:427-35. [PMID: 22159228 DOI: 10.1093/carcin/bgr295] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Chronic inflammation is an underlying risk factor for colon cancer. Tumor necrosis factor alpha (TNF-α) plays a critical role in the development of inflammation-induced colon cancer in a mouse model. S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) can inhibit lipopolysaccharide-induced TNF-α expression in macrophages. The aim of this work was to examine whether SAMe and MTA are effective in preventing inflammation-induced colon cancer and if so identify signaling pathways affected. Balb/c mice were treated with azoxymethane (AOM) and dextran sulfate sodium to induce colon cancer. Two days after AOM treatment, mice were divided into three groups: vehicle control, SAMe or MTA. Tumor load, histology, immunohistochemistry, gene and protein expression were determined. SAMe and MTA treatment reduced tumor load by ∼40%. Both treatments raised SAMe and MTA levels but MTA also raised S-adenosylhomocysteine levels. MTA treatment prevented the induction of many genes known to play pathogenetic roles in this model except for TNF-α and inducible nitric oxide synthase (iNOS). SAMe also had no effect on TNF-α or iNOS and was less inhibitory than MTA on the other genes. In vivo, both treatments induced apoptosis but inhibited proliferation, β-catenin, nuclear factor kappa B activation and interleukin (IL) 6 signaling. Effect of SAMe and MTA on IL-6 signaling was examined using Colo 205 colon cancer cells. In these cells, SAMe and MTA inhibited IL-6-induced IL-10 expression. MTA also inhibited IL-10 transcription and signal transducer and activator of transcription 3 activation. In conclusion, SAMe and MTA reduced inflammation-induced colon cancer and inhibited several pathways important in colon carcinogenesis.
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Affiliation(s)
- Tony W H Li
- Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, University of Southern California-University of California, Los Angeles, CA 90033, 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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Thorsteinsdottir S, Gudjonsson T, Nielsen OH, Vainer B, Seidelin JB. Pathogenesis and biomarkers of carcinogenesis in ulcerative colitis. Nat Rev Gastroenterol Hepatol 2011; 8:395-404. [PMID: 21647200 DOI: 10.1038/nrgastro.2011.96] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
One of the most serious complications of ulcerative colitis is the development of colorectal cancer. Screening patients with ulcerative colitis by standard histological examination of random intestinal biopsy samples might be inefficient as a method of cancer surveillance. This Review focuses on the current understanding of the pathogenesis of ulcerative colitis-associated colorectal cancer and how this knowledge can be transferred into patient management to assist clinicians and pathologists in identifying patients with ulcerative colitis who have an increased risk of colorectal cancer. Inflammation-driven mechanisms of DNA damage, including the generation and effects of reactive oxygen species, microsatellite instability, telomere shortening and chromosomal instability, are reviewed, as are the molecular responses to genomic stress. We also discuss how these mechanisms can be translated into usable biomarkers. Although progress has been made in the understanding of inflammation-driven carcinogenesis, markers based on these findings possess insufficient sensitivity or specificity to be usable as reliable biomarkers for risk of colorectal cancer development in patients with ulcerative colitis. However, screening for mutations in p53 could be relevant in the surveillance of patients with ulcerative colitis. Several other new biomarkers, including senescence markers and α-methylacyl-CoA-racemase, might be future candidates for preneoplastic markers in ulcerative colitis.
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Affiliation(s)
- Sigrun Thorsteinsdottir
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, 75 Herlev Ringvej, DK-2730 Herlev, Denmark
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De Robertis M, Massi E, Poeta ML, Carotti S, Morini S, Cecchetelli L, Signori E, Fazio VM. The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies. J Carcinog 2011; 10:9. [PMID: 21483655 PMCID: PMC3072657 DOI: 10.4103/1477-3163.78279] [Citation(s) in RCA: 413] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Accepted: 02/05/2011] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a major health problem in industrialized countries. Although inflammation-linked carcinogenesis is a well accepted concept and is often observed within the gastrointestinal tract, the underlying mechanisms remain to be elucidated. Inflammation can indeed provide initiating and promoting stimuli and mediators, generating a tumour-prone microenvironment. Many murine models of sporadic and inflammation-related colon carcinogenesis have been developed in the last decade, including chemically induced CRC models, genetically engineered mouse models, and xenoplants. Among the chemically induced CRC models, the combination of a single hit of azoxymethane (AOM) with 1 week exposure to the inflammatory agent dextran sodium sulphate (DSS) in rodents has proven to dramatically shorten the latency time for induction of CRC and to rapidly recapitulate the aberrant crypt foci–adenoma–carcinoma sequence that occurs in human CRC. Because of its high reproducibility and potency, as well as the simple and affordable mode of application, the AOM/DSS has become an outstanding model for studying colon carcinogenesis and a powerful platform for chemopreventive intervention studies. In this article we highlight the histopathological and molecular features and describe the principal genetic and epigenetic alterations and inflammatory pathways involved in carcinogenesis in AOM/DSS–treated mice; we also present a general overview of recent experimental applications and preclinical testing of novel therapeutics in the AOM/DSS model.
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Affiliation(s)
- Mariangela De Robertis
- Laboratory of Molecular Medicine and Biotechnology, CIR, Campus Bio-Medico University of Rome, Via Álvaro del Portillo 21 - 00128 Rome, Italy
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Li H, Wu WKK, Li ZJ, Chan KM, Wong CCM, Ye CG, Yu L, Sung JJY, Cho CH, Wang M. 2,3',4,4',5'-Pentamethoxy-trans-stilbene, a resveratrol derivative, inhibits colitis-associated colorectal carcinogenesis in mice. Br J Pharmacol 2010; 160:1352-61. [PMID: 20590626 DOI: 10.1111/j.1476-5381.2010.00785.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND AND PURPOSE Resveratrol, a naturally occurring polyphenolic antioxidant, has been shown to exhibit chemoprophylactic effects on cancer development. Previously, we reported that 2,3',4,4',5'-pentamethoxy-trans-stilbene (PMS), a methoxylated resveratrol derivative, exerted a highly potent anti-proliferative effect on human colon cancer cells as compared with its parent compound. In the present study, the chemopreventive effect of PMS was evaluated in a mouse model of colitis-associated colon carcinogenesis. EXPERIMENTAL APPROACH Seven-week-old Balb/c mice were injected i.p. with 10 mg.kg(-1) azoxymethane (AOM). After 1 week, 3% dextran sodium sulphate (DSS) was administered in the drinking water for 7 days followed by 14 days of tap water for recovery, and this cycle was repeated twice. KEY RESULTS Intragastric administration of PMS (25, 50 mg.kg(-1) body weight) for 16 weeks significantly reduced the multiplicity of colonic neoplasms by 15% and 35% (P < 0.01) respectively. Moreover, PMS at 50 mg.kg(-1) inhibited colon cancer cell proliferation and promoted apoptosis. Such changes were accompanied by reduction of Akt (protein kinase B) phosphorylation, inactivation of beta-catenin and down-regulation of inducible nitric oxide synthase. In parallel, in vitro studies also demonstrated that PMS inhibited proliferation and induced apoptosis in the murine colon adenocarcinoma cell line Colon26 with concomitant inhibition of Akt phosphorylation and inactivation of beta-catenin. CONCLUSIONS AND IMPLICATIONS PMS effectively suppressed colon carcinogenesis in an AOM/DSS animal model and may merit further clinical investigation as a chemoprophylactic agent against colitis-associated colon cancer in humans.
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Affiliation(s)
- Haitao Li
- School of Biological Sciences, The University of Hong Kong, Hong Kong, China
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