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Selg C, Gordić V, Krajnović T, Buzharevski A, Laube M, Kazimir A, Lönnecke P, Wolniewicz M, Sárosi MB, Schädlich J, Pietzsch J, Mijatović S, Maksimović-Ivanić D, Hey-Hawkins E. Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential. Sci Rep 2024; 14:30488. [PMID: 39681576 DOI: 10.1038/s41598-024-81414-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
In this study, we investigated a novel anti-cancer drug design approach by revisiting diclofenac-based carborane-substituted prodrugs. The redesigned compounds combine the robust carborane scaffold with the oxindole framework, resulting in four carborane-derivatized oxindoles and a unique zwitterionic amidine featuring a nido-cluster. We tested the anti-cancer potential of these prodrugs against murine colon adenocarcinoma (MC38), human colorectal carcinoma (HCT116), and human colorectal adenocarcinoma (HT29). The tests showed that diclofenac and the carborane-substituted oxindoles exhibited no cytotoxicity, the dichlorophenyl-substituted oxindole had moderate anti-cancer activity, while with the amidine this effect was strongly potentiated with activity mapping within low micromolar range. Compound 3 abolished the viability of selected colon cancer cell line MC38 preferentially through strong inhibition of cell division and moderate apoptosis accompanied by ROS/RNS depletion. Our findings suggest that carborane-based prodrugs could be a promising direction for new anti-cancer therapies. Inhibition assays for COX-1 and COX-2 revealed that while diclofenac had strong COX inhibition, the re-engineered carborane compounds demonstrated a varied range of anti-cancer effects, probably owing to both, COX inhibition and COX-independent pathways.
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Affiliation(s)
- Christoph Selg
- Department of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig University, Deutscher Platz 5, 04103, Leipzig, Germany
| | - Vuk Gordić
- Department of Immunology, Institute for Biological Research "Siniša Stanković" - National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, Belgrade, 11108, Serbia
| | - Tamara Krajnović
- Department of Immunology, Institute for Biological Research "Siniša Stanković" - National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, Belgrade, 11108, Serbia
| | - Antonio Buzharevski
- Department of Chemistry and Mineralogy, Institute of Inorganic Chemistry, Leipzig University, Johannisallee 29, 04103, Leipzig, Germany
| | - Markus Laube
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
| | - Aleksandr Kazimir
- Institute for Drug Discovery, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany
| | - Peter Lönnecke
- Department of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig University, Deutscher Platz 5, 04103, Leipzig, Germany
| | - Mara Wolniewicz
- Department of Chemistry and Mineralogy, Institute of Organic Chemistry, Leipzig University, Johannisallee 29, 04103, Leipzig, Germany
| | - Menyhárt B Sárosi
- Department of Chemistry and Mineralogy, Institute of Inorganic Chemistry, Leipzig University, Johannisallee 29, 04103, Leipzig, Germany
| | - Jonas Schädlich
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstraße 4, 01069, Dresden, Germany
| | - Jens Pietzsch
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstraße 4, 01069, Dresden, Germany
| | - Sanja Mijatović
- Department of Immunology, Institute for Biological Research "Siniša Stanković" - National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, Belgrade, 11108, Serbia
| | - Danijela Maksimović-Ivanić
- Department of Immunology, Institute for Biological Research "Siniša Stanković" - National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, Belgrade, 11108, Serbia
| | - Evamarie Hey-Hawkins
- Department of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig University, Deutscher Platz 5, 04103, Leipzig, Germany.
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Uddin MJ, Lo JHJ, Oltman CG, Crews BC, Huda T, Liu J, Kingsley PJ, Lin S, Milad M, Aleem AM, Asaduzzaman A, McIntyre JO, Duvall CL, Marnett LJ. Discovery of a Redox-Activatable Chemical Probe for Detection of Cyclooxygenase-2 in Cells and Animals. ACS Chem Biol 2022; 17:1714-1722. [PMID: 35786843 PMCID: PMC10464600 DOI: 10.1021/acschembio.1c00961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Cyclooxygenase-2 (COX-2) expression is up-regulated in inflammatory tissues and many premalignant and malignant tumors. Assessment of COX-2 protein in vivo, therefore, promises to be a powerful strategy to distinguish pathologic cells from normal cells in a complex disease setting. Herein, we report the first redox-activatable COX-2 probe, fluorocoxib Q (FQ), for in vivo molecular imaging of pathogenesis. FQ inhibits COX-2 selectively in purified enzyme and cell-based assays. FQ exhibits extremely low fluorescence and displays time- and concentration-dependent fluorescence enhancement upon exposure to a redox environment. FQ enters the cells freely and binds to the COX-2 enzyme. FQ exhibits high circulation half-life and metabolic stability sufficient for target site accumulation and demonstrates COX-2-targeted uptake and retention in cancer cells and pathologic tissues. Once taken up, it undergoes redox-mediated transformation into a fluorescent compound fluorocoxib Q-H that results in high signal-to-noise contrast and differentiates pathologic tissues from non-pathologic tissues for real-time in vivo imaging.
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Affiliation(s)
- Md. Jashim Uddin
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Justin Han-Je Lo
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 USA
| | - Connor G. Oltman
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Brenda C. Crews
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Tamanna Huda
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Justin Liu
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
- Department of Neuroscience, Columbia University, New York City, New York, 10027 USA
| | - Philip J. Kingsley
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Shuyang Lin
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Mathew Milad
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Ansari M. Aleem
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Abu Asaduzzaman
- Department of Electrical Engineering and Computer Science, Wichita State University, Wichita, Kansas 67260 USA
| | - J. Oliver McIntyre
- Departments of Radiology and Radiological Sciences, and Pharmacology, Vanderbilt Institute of Imaging Science, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 USA
| | - Craig L. Duvall
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37232 USA
| | - Lawrence J. Marnett
- Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 USA
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Ji XK, Madhurapantula SV, He G, Wang KY, Song CH, Zhang JY, Wang KJ. Genetic variant of cyclooxygenase-2 in gastric cancer: More inflammation and susceptibility. World J Gastroenterol 2021; 27:4653-4666. [PMID: 34366627 PMCID: PMC8326261 DOI: 10.3748/wjg.v27.i28.4653] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/17/2021] [Accepted: 07/02/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer accounts for the majority cancer-related deaths worldwide. Although various methods have considerably improved the screening, diagnosis, and treatment of gastric cancer, its incidence is still high in Asia, and the 5-year survival rate of advanced gastric cancer patients is only 10%-20%. Therefore, more effective drugs and better screening strategies are needed for reducing the incidence and mortality of gastric cancer. Cyclooxygenase-2 (COX-2) is considered to be the key inducible enzyme in prostaglandins (PGs) synthesis, which is involved in multiple pathways in the inflammatory response. For example, inflammatory cytokines stimulate innate immune responses via Toll-like receptors and nuclear factor-kappa B to induce COX-2/PGE2 pathway. In these processes, the production of an inflammatory microenvironment promotes the occurrence of gastric cancer. Epidemiological studies have also indicated that non-steroidal anti-inflammatory drugs can reduce the risk of malignant tumors of the digestive system by blocking the effect of COX-2. However, clinical use of COX-2 inhibitors to prevent or treat gastric cancer may be limited because of potential side effects, especially in the cardiovascular system. Given these side effects and low treatment efficacy, new therapeutic approaches and early screening strategies are urgently needed. Some studies have shown that genetic variation in COX-2 also play an important role in carcinogenesis. However, the genetic variation analysis in these studies is incomplete and isolated, pointing out only a few single nucleotide polymorphisms (SNPs) and the risk of gastric cancer, and no comprehensive study covering the whole gene region has been carried out. In addition, copy number variation (CNV) is not mentioned. In this review, we summarize the SNPs in the whole COX-2 gene sequence, including exons, introns, and both the 5' and 3' untranslated regions. Results suggest that COX-2 does not increase its expression through the CNV and the SNPs in COX-2 may serve as the potential marker to establish risk stratification in the general population. This review synthesizes emerging insights of COX-2 as a biomarker in multiple studies, summarizes the association between whole COX-2 sequence variation and susceptibility to gastric cancer, and discusses the future prospect of therapeutic intervention, which will be helpful for early screening and further research to find new approaches to gastric cancer treatment.
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Affiliation(s)
- Xuan-Ke Ji
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Sailaja Vatsalya Madhurapantula
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Gui He
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Kun-Yan Wang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Chun-Hua Song
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Jian-Ying Zhang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Kai-Juan Wang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou University, Zhengzhou 450001, Henan Province, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, Henan Province, China
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Sameni HR, Yosefi S, Alipour M, Pakdel A, Torabizadeh N, Semnani V, Bandegi AR. Co-administration of 5FU and propolis on AOM/DSS induced colorectal cancer in BALB-c mice. Life Sci 2021; 276:119390. [PMID: 33794252 DOI: 10.1016/j.lfs.2021.119390] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 03/10/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023]
Abstract
AIMS Currently, the main problems with chemotherapy are its side effects, toxicity, and drug resistance. Propolis has biological activities, such as anti-inflammatory and anti-cancer properties. This study aims to examine the combined effects of 5-fluorouracil (5FU) and propolis on colorectal cancer (CRC) in mouse models. MATERIALS AND METHODS The chemical composition of ethanolic extract of propolis was determined by gas chromatography-mass spectrometry (GC-MS). In this study, 49 male Balb/c mice (16-20 g) were divided in seven groups as a control group and experimental groups (treated and untreated CRC model [azoxymethane + dextran sodium sulfate]). This study was conducted in 8 weeks. To examine the anti-cancer effects of propolis, the number of aberrant crypt foci (ACF) was counted and the pathological lesions in the distal colonic epithelial tissue were diagnosed. In this study, the expression of beta-catenin (β-catenin), induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2) proteins, which play a major role in the incidence and progression of cancer, were determined. KEY FINDINGS GC-MS analysis of propolis showed the presence of hydrocarbons, alcohols, ketones, terpenes, phenols, and flavonoids. Administering propolis in combination with 5FU reduced the number of ACFs and pathological lesions in comparison with cancer control groups (p < 0.0001) and 5FU-alone treatment (p < 0.05). The propolis combined with 5FU reduced the expression of Cox-2, iNOS, and β-catenin proteins. SIGNIFICANCE The results showed that propolis increased the efficiency of 5FU and could be taken into account as the adjunct therapy for colorectal cancer.
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Affiliation(s)
- Hamid Reza Sameni
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Sedighe Yosefi
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Marzieh Alipour
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Abbas Pakdel
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Najmeh Torabizadeh
- Laboratory of Food Sciences, Administration of Standards Khorasan Razavi, Mashhad, Iran
| | - Vahid Semnani
- Department of Pathology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Ahmad Reza Bandegi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
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Zhang Y, Pu W, Bousquenaud M, Cattin S, Zaric J, Sun LK, Rüegg C. Emodin Inhibits Inflammation, Carcinogenesis, and Cancer Progression in the AOM/DSS Model of Colitis-Associated Intestinal Tumorigenesis. Front Oncol 2021; 10:564674. [PMID: 33489875 PMCID: PMC7821392 DOI: 10.3389/fonc.2020.564674] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 11/18/2020] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancer worldwide. Chronic inflammation contributes to CRC development and progression. Emodin, is a natural anthraquinone derivative with anti-oxidant, anti-inflammatory, and anti-tumor activities. We used the AOM/DSS model of colitis-associated intestinal tumorigenesis to characterize the effect of Emodin on inflammation and tumorigenesis at weeks 3, 5, and 14 after initiation with AOM. At all three time points, Emodin (50 mg/kg) reduced inflammatory cell (i.e. CD11b+ and F4/80+) recruitment, cytokine (i.e. TNFα, IL1α/β, IL6, CCL2, CXCL5) and pro-inflammatory enzymes (i.e. COX-2, NOS2) expression in the tumor microenvironment, while promoting recruitment of CD3+ T lymphocytes at 14 weeks. Emodin decreased the incidence of premalignant lesions (adenoma) at week 3, the incidence of dysplastic lesions and carcinomas at week 5, and the incidence, size and the invasiveness of carcinomas at week 14. Emodin also reduced the acute clinical intestinal symptoms (i.e. bleeding and diarrhea) during DSS treatment. In vitro, Emodin inhibited the expression of pro-inflammatory mediators by LPS-stimulated RAW 264.7 macrophages, and reduced viability, adhesion, migration, and fibroblasts-induced invasion of SW620 and HCT116 colon cancer cells. In conclusion, this work demonstrates that Emodin suppresses carcinogenesis-associated intestinal inflammation and prevents AOM/DSS-induced intestinal tumorigenesis and progression. These results instigate further studies on Emodin as a natural agent for the prevention or treatment of colorectal cancer.
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Affiliation(s)
- Yunsha Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Pathology Unit, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Weiling Pu
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mélanie Bousquenaud
- Pathology Unit, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Sarah Cattin
- Pathology Unit, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Jelena Zaric
- Pathology Unit, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Li-Kang Sun
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Curzio Rüegg
- Pathology Unit, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
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Abbaoui B, Lucas CR, Riedl KM, Clinton SK, Mortazavi A. Cruciferous Vegetables, Isothiocyanates, and Bladder Cancer Prevention. Mol Nutr Food Res 2018; 62:e1800079. [PMID: 30079608 DOI: 10.1002/mnfr.201800079] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 06/11/2018] [Indexed: 12/16/2022]
Abstract
Bladder cancer is a significant health burden due to its high prevalence, risk of mortality, morbidity, and high cost of medical care. Epidemiologic evidence suggests that diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk. Phytochemicals in cruciferous vegetables, such as glucosinolates, which are enzymatically hydrolyzed to bioactive isothiocyanates, are possible mediators of an anticancer effect. In vitro studies have shown inhibition of bladder cancer cell lines, cell cycle arrest, and induction of apoptosis by these isothiocyanates, in particular sulforaphane and erucin. Although not yet completely understood, many mechanisms of anticancer activity at the steps of cancer initiation, promotion, and progression have been attributed to these isothiocyanates. They target multiple pathways including the adaptive stress response, phase I/II enzyme modulation, pro-growth, pro-survival, pro-inflammatory signaling, angiogenesis, and even epigenetic modulation. Multiple in vivo studies have shown the bioavailability of isothiocyanates and their antitumoral effects. Although human studies are limited, they support oral bioavailability with reasonable plasma and urine concentrations achieved. Overall, both cell and animal studies support a potential role for isothiocyanates in bladder cancer prevention and treatment. Future studies are necessary to examine clinically relevant outcomes and define guidelines on ameliorating the bladder cancer burden.
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Affiliation(s)
- Besma Abbaoui
- Foods for Health Discovery Theme, The College of Food, Agricultural and Environmental Sciences, The Ohio State University, Columbus, OH, 43210.,Department of Food Science and Technology, The College of Food, Agricultural, and Environmental Sciences, The Ohio State University, Columbus, OH, 43210.,Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, OH, 43210
| | - Christopher R Lucas
- Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, OH, 43210.,Department of Mechanical and Aerospace Engineering, The College of Engineering, The Ohio State University, Columbus, OH, 43210.,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210
| | - Ken M Riedl
- Department of Food Science and Technology, The College of Food, Agricultural, and Environmental Sciences, The Ohio State University, Columbus, OH, 43210.,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210
| | - Steven K Clinton
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210.,Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, 43210
| | - Amir Mortazavi
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210.,Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, 43210
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Punganuru SR, Madala HR, Mikelis CM, Dixit A, Arutla V, Srivenugopal KS. Conception, synthesis, and characterization of a rofecoxib-combretastatin hybrid drug with potent cyclooxygenase-2 (COX-2) inhibiting and microtubule disrupting activities in colon cancer cell culture and xenograft models. Oncotarget 2018; 9:26109-26129. [PMID: 29899846 PMCID: PMC5995258 DOI: 10.18632/oncotarget.25450] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 05/03/2018] [Indexed: 12/28/2022] Open
Abstract
Tumor heterogeneity and drug resistance pose severe limitations to chemotherapy of colorectal cancers (CRCs) necessitating innovative approaches to trigger multiple cytocidal events for increased efficacy. Here, we developed a hybrid drug called KSS19 by combining the COX-2 selective NSAID rofecoxib with the cis-stilbene found in combretastatin A4 (CA4), a problematic, but potent antimicrotubule and anti-angiogenesis agent. The structural design of KSS19 completely prevented the isomerization of CA4 its biologically inactive trans-form. Molecular modeling showed that KSS19 bound avidly to the COX-2 active site and colchicine -binding site of tubulin, with similar docking scores of rofecoxib and CA4 respectively. KSS-19 showed potent anti-proliferative activity against a panel of colon cancer cell lines; HT29 cells, which are resistant to CA4 were 100 times more sensitive to KSS19. The hybrid drug potently inhibited the tubulin polymerization in vitro and in cells inducing a G2/M arrest and aberrant mitotic spindles. Both the basal and LPS-activated levels of COX-2 in colon cancer cells were highly suppressed by the KSS-19. The cancer cell migration/invasion was inhibited and accompanied by increased E-cadherin levels and activated NF-kB/Snail pathways in KSS19-treated cells. The drug also curtailed the formation of endothelial tubes in three-dimensional cultures of the HUVE cells at 250 nM, indicating strong anti-angiogenic properties. In subcutaneous HT29 colon cancer xenografts, KSS19, as a single agent (25 mg/kg/day) significantly inhibited the tumor growth and downregulated the intratumoral COX-2, Ki-67, the angiogenesis marker CD31, however, the cleaved caspase-3 was elevated. Collectively, KSS19 represents a rational hybrid drug with clinical relevance to CRC.
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Affiliation(s)
- Surendra R Punganuru
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Hanumantha Rao Madala
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Constantinos M Mikelis
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Anshuman Dixit
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India
| | - Viswanath Arutla
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Kalkunte S Srivenugopal
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
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Juan TK, Liu KC, Kuo CL, Yang MD, Chu YL, Yang JL, Wu PP, Huang YP, Lai KC, Chung JG. Tetrandrine suppresses adhesion, migration and invasion of human colon cancer SW620 cells via inhibition of nuclear factor-κB, matrix metalloproteinase-2 and matrix metalloproteinase-9 signaling pathways. Oncol Lett 2018; 15:7716-7724. [PMID: 29731901 PMCID: PMC5921181 DOI: 10.3892/ol.2018.8286] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 10/20/2017] [Indexed: 01/02/2023] Open
Abstract
Tetrandrine (TET) exhibits biological activities, including anticancer activity. In Chinese medicine, TET has been used to treat hypertensive and arrhythmic conditions and has been demonstrated to induce cytotoxic effects on human cancer cell lines. However, to the best of the author's knowledge, no previous studies have revealed that TET affects cell metastasis in SW620 human colon cancer cells. The present study demonstrated that TET decreased the cell number and inhibited cell adhesion and mobility of SW620 cells. Furthermore, a wound healing assay was performed to demonstrate that TET suppressed cell movement, and Transwell chamber assays were used to reveal that TET suppressed the cell migration and invasion of SW620 cells. Western blotting demonstrated that TET significantly reduced protein expression levels of SOS Ras/Rac guanine nucleotide exchange factor 1, phosphatidylinositol 3-kinase, growth factor receptor bound protein 2, phosphorylated (p)-c Jun N-terminal kinase 1/2, p-p38, p38, 14-3-3, Rho A, β-catenin, nuclear factor-κB p65, signal transducer and activator of transcription-1 and cyclooxygenase-2, in comparison with untreated SW620 cells. Overall, the results of the present study suggested that TET may be used as a novel anti-metastasis agent for the treatment of human colon cancer in the future.
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Affiliation(s)
- Ta-Kuo Juan
- Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, R.O.C
| | - Kuo-Ching Liu
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan, R.O.C
| | - Chao-Lin Kuo
- Chinese Medicine Resources, China Medical University, Taichung 404, Taiwan, R.O.C
| | - Mei-Due Yang
- Department of Surgery, China Medical University Hospital, Taichung 404, Taiwan, R.O.C
| | - Yung-Lin Chu
- International Master's Degree Program in Food Science, International College, National Pingtung University of Science and Technology, Pingtung 912, Taiwan, R.O.C
| | - Jiun-Long Yang
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan, R.O.C
| | - Ping-Ping Wu
- School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C
| | - Yi-Ping Huang
- Department of Physiology, China Medical University, Taichung 404, Taiwan, R.O.C
| | - Kuang-Chi Lai
- School of Medicine, China Medical University, Taichung 404, Taiwan, R.O.C.,Department of Medical Laboratory Science and Biotechnology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, Tainan 717, Taiwan, R.O.C.,Department of Surgery, China Medical University Beigang Hospital, Beigang, Yunlin 651, Taiwan, R.O.C
| | - Jing-Gung Chung
- Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, R.O.C.,Department of Biotechnology, Asia University, Wufeng, Taichung 413, Taiwan, R.O.C
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9
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González-Montoya M, Hernández-Ledesma B, Silván JM, Mora-Escobedo R, Martínez-Villaluenga C. Peptides derived from in vitro gastrointestinal digestion of germinated soybean proteins inhibit human colon cancer cells proliferation and inflammation. Food Chem 2018; 242:75-82. [PMID: 29037738 DOI: 10.1016/j.foodchem.2017.09.035] [Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 07/25/2017] [Accepted: 09/07/2017] [Indexed: 01/07/2023]
Abstract
The aim was to investigate the potential of germinated soybean proteins asa source of peptides with anticancer and anti-inflammatory activities produced after simulated gastrointestinal digestion. Protein concentrate from germinated soybean was hydrolysed with pepsin/pancreatin and fractionated by ultrafiltration. Whole digest and fractions>10, 5-10, and<5kDa caused cytotoxicity to Caco-2, HT-29, HCT-116 human colon cancer cells, and reduced inflammatory response caused by lipopolysaccharide in macrophages RAW 264.7. Antiproliferative and anti-inflammatory effects were generally higher in 5-10kDa fractions. This fraction was further purified by semi-preparative chromatography and characterised by HPLC-MS/MS. The most potent fraction was mainly composed of β-conglycinin and glycinin fragments rich in glutamine. This is the first report on the anti-cancer and anti-inflammatory effects of newly isolated and identified peptides from germinated soybean released during gastrointestinal digestion. These findings highlight the potential of germination as a process to obtain functional foods or nutraceuticals for colon cancer prevention.
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Affiliation(s)
- Marcela González-Montoya
- Escuela Nacional de Ciencias Biológicas-Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, Wilfrido Massieu s/n., 07738 Ciudad de México, Mexico
| | - Blanca Hernández-Ledesma
- Instituto de Investigación en Ciencias de la Alimentación (CIAL, CSIC-UAM, CEI UAM+CSIC), Nicolás Cabrera, 9, 28049 Madrid, Spain
| | - Jose Manuel Silván
- Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
| | - Rosalva Mora-Escobedo
- Escuela Nacional de Ciencias Biológicas-Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, Wilfrido Massieu s/n., 07738 Ciudad de México, Mexico
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10
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Ovadje P, Ammar S, Guerrero JA, Arnason JT, Pandey S. Dandelion root extract affects colorectal cancer proliferation and survival through the activation of multiple death signalling pathways. Oncotarget 2018; 7:73080-73100. [PMID: 27564258 PMCID: PMC5341965 DOI: 10.18632/oncotarget.11485] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 07/26/2016] [Indexed: 12/18/2022] Open
Abstract
Dandelion extracts have been studied extensively in recent years for its anti-depressant and anti-inflammatory activity. Recent work from our lab, with in-vitro systems, shows the anti-cancer potential of an aqueous dandelion root extract (DRE) in several cancer cell models, with no toxicity to non-cancer cells. In this study, we examined the cancer cell-killing effectiveness of an aqueous DRE in colon cancer cell models. Aqueous DRE induced programmed cell death (PCD) selectively in > 95% of colon cancer cells, irrespective of their p53 status, by 48 hours of treatment. The anti-cancer efficacy of this extract was confirmed in in-vivo studies, as the oral administration of DRE retarded the growth of human colon xenograft models by more than 90%. We found the activation of multiple death pathways in cancer cells by DRE treatment, as revealed by gene expression analyses showing the expression of genes implicated in programmed cell death. Phytochemical analyses of the extract showed complex multi-component composition of the DRE, including some known bioactive phytochemicals such as α-amyrin, β-amyrin, lupeol and taraxasterol. This suggested that this natural extract could engage and effectively target multiple vulnerabilities of cancer cells. Therefore, DRE could be a non-toxic and effective anti-cancer alternative, instrumental for reducing the occurrence of cancer cells drug-resistance.
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Affiliation(s)
- Pamela Ovadje
- Department of Chemistry & Biochemistry, University of Windsor, Windsor ON, Canada
| | - Saleem Ammar
- Department of Biology, University of Ottawa, Ottawa ON, Canada
| | - Jose-Antonio Guerrero
- Department of Biology, University of Ottawa, Ottawa ON, Canada.,Red de Estudios Moleculares Avanzados, Instituto de Ecología A.C. Xalapa, Veracruz, México
| | | | - Siyaram Pandey
- Department of Chemistry & Biochemistry, University of Windsor, Windsor ON, Canada
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11
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Applegate CC, Lane MA. Role of retinoids in the prevention and treatment of colorectal cancer. World J Gastrointest Oncol 2015; 7:184-203. [PMID: 26483874 PMCID: PMC4606174 DOI: 10.4251/wjgo.v7.i10.184] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 07/10/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
Vitamin A and its derivatives, retinoids, have been widely studied for their use as cancer chemotherapeutic agents. With respect to colorectal cancer (CRC), several critical mutations dysregulate pathways implicated in progression and metastasis, resulting in aberrant Wnt/β-catenin signaling, gain-of-function mutations in K-ras and phosphatidylinositol-3-kinase/Akt, cyclooxygenase-2 over-expression, reduction of peroxisome proliferator-activated receptor γ activation, and loss of p53 function. Dysregulation leads to increased cellular proliferation and invasion and decreased cell-cell interaction and differentiation. Retinoids affect these pathways by various mechanisms, many involving retinoic acid receptors (RAR). RAR bind to all-trans-retinoic acid (ATRA) to induce the transcription of genes responsible for cellular differentiation. Although most research concerning the chemotherapeutic efficacy of retinoids focuses on the ability of ATRA to decrease cancer cell proliferation, increase differentiation, or promote apoptosis; as CRC progresses, RAR expression is often lost, rendering treatment of CRCs with ATRA ineffective. Our laboratory focuses on the ability of dietary vitamin A to decrease CRC cell proliferation and invasion via RAR-independent pathways. This review discusses our research and others concerning the ability of retinoids to ameliorate the defective signaling pathways listed above and decrease tumor cell proliferation and invasion through both RAR-dependent and RAR-independent mechanisms.
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12
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Wu WK, Wang XJ, Cheng AS, Luo MX, Ng SS, To KF, Chan FK, Cho CH, Sung JJ, Yu J. Dysregulation and crosstalk of cellular signaling pathways in colon carcinogenesis. Crit Rev Oncol Hematol 2013; 86:251-77. [PMID: 23287077 DOI: 10.1016/j.critrevonc.2012.11.009] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Revised: 11/07/2012] [Accepted: 11/27/2012] [Indexed: 02/06/2023] Open
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13
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Nwose EU, Cann N. Whole blood viscosity issues VI: Association with blood salicylate level and gastrointestinal bleeding. NORTH AMERICAN JOURNAL OF MEDICAL SCIENCES 2012; 2:457-60. [PMID: 22558547 PMCID: PMC3339107 DOI: 10.4297/najms.2010.2457] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background: This series on whole blood viscosity issues has been trying to elucidate the sensitivity, specificity and usefulness of the laboratory parameter in clinical practice. The postulation has been that since antiplatelet is used in the management of stasis, of which blood viscosity is an index, the latter would be useful laboratory indication and/or contraindication. Aim: The aim of this study was to observe whether blood level of acetylsalicylic acid differs with the level of whole blood viscosity. Patients and Methods: Out of the ten years database, 538 cases that were concomitantly tested for haematocrit, total proteins and blood level of salicylate were selected for this study. A separate nine cases of positive faecal occult blood tests were audited for blood viscosity and reviewed. Results: A statistically significant difference is observed with lower blood viscosity being associated with higher salicylate level in comparison of the former between the highest vs. lowest quartiles (p < 0.002). This observation demonstrates the effect of aspirin in lowering blood stasis. Reviewing the positive faecal occult blood cases indicate that gastrointestinal bleeding is characterized by relative hypoviscosity and that hyperviscosity is not present during bleeding complications. Conclusion: The findings affirm that whole blood viscosity is a valid clinical laboratory parameter for evidence-based contraindication, indication and monitoring of antiplatelet medication. It calls for better appreciation and clinical utility of whole blood viscosity, which (in the absence of viscometer) can now be extrapolated from haematocrit and total proteins.
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Affiliation(s)
- Ezekiel Uba Nwose
- Western Pathology Cluster - NSW Health, South West Pathology Service; 590 Smollett Street Albury, NSW, Australia
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14
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Paduch R, Kandefer-Szerszeń M. Nitric Oxide (NO) and Cyclooxygenase-2 (COX-2) Cross-Talk in Co-Cultures of Tumor Spheroids with Normal Cells. CANCER MICROENVIRONMENT 2011; 4:187-98. [PMID: 21909878 PMCID: PMC3170423 DOI: 10.1007/s12307-011-0063-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Accepted: 02/09/2011] [Indexed: 12/20/2022]
Abstract
Cyclooxygenases (COX), prostaglandin E2 (PGE2) and nitric oxide (NO) are believed to be some of the most important factors related to colon cancer growth and metastasis. In this study, we aimed to investigate the associations between COX-2, PGE2 and NO in co-cultures of human colon cancer spheroids obtained from different tumor grades with normal human colonic epithelium and myofibroblast monolayers. L-arginine (2 mM), a substrate for nitric oxide synthases (NOS), decreased COX-2 and PGE2 levels, while NG-nitro-L-arginine methyl ester (L-NAME) (2 mM), a NOS inhibitor, had no influence on COX-2 and PGE2 levels but limited tumor cell motility. NS398 (75 μM), a selective COX-2 inhibitor, had no significant influence on NO level but decreased motility of tumor cells. COX-2, PGE2 and NO levels depended on the tumor grade of the cells, being the highest in Duke’s stage III colon carcinoma. Summing up, we showed that addition of L-arginine at doses which did not stimulate NO level caused a significant decrease in COX-2 and PGE2 amounts in co-cultures of colon tumor spheroids with normal epithelial cells and myofibroblasts. Any imbalances in NO level caused by exogenous factors influence COX-2 and PGE2 amounts depending on the kind of cells, their reciprocal interactions and the local microenvironmental conditions. The knowledge of these effects may be useful in limiting colon carcinoma progression and invasion.
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Affiliation(s)
- Roman Paduch
- Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033, Lublin, Poland,
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15
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Uckun FM, Dibirdik I. Chemoprevention of Colorectal Cancer by Targeting Janus Kinase 3 With a Rationally Designed Small Molecule Inhibitor. Nutr Cancer 2010; 62:968-72. [DOI: 10.1080/01635581.2010.513471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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16
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Singh P, Bhardwaj A. Mono-, Di-, and Triaryl Substituted Tetrahydropyrans as Cyclooxygenase-2 and Tumor Growth Inhibitors. Synthesis and Biological Evaluation. J Med Chem 2010; 53:3707-17. [DOI: 10.1021/jm1001327] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Palwinder Singh
- Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, India
| | - Atul Bhardwaj
- Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, India
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17
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Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms. Cancer Lett 2010; 295:7-16. [PMID: 20381235 DOI: 10.1016/j.canlet.2010.03.015] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2010] [Revised: 03/18/2010] [Accepted: 03/22/2010] [Indexed: 12/20/2022]
Abstract
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risks for esophageal, gastric and colon cancers as well as other solid tumors. The antitumor effect of NSAIDs is mediated through cyclooxygenase-2 (COX-2)-dependent and -independent regulation of oncogenic and tumor-suppressive pathways. Recent discoveries have shed new light on the regulation of COX-2 at the molecular level in these cancers. Moreover, prostaglandin E(2) (PGE(2)), a COX-2-derived eicosanoid, has been found to affect numerous tumorigenic processes. In this connection, PGE(2) activates multiple intracellular signaling pathways, including (1) transactivation of epidermal growth factor receptor (EGFR); (2) protein kinase C-dependent, EGFR-independent activation of extracellular signal-regulated kinase (ERK) and the transcription factors activator protein-1 and c-Myc; (3) G-protein-mediated activation of beta-catenin/TCF-dependent transcription. Activation of these signaling pathways by PGE(2) is mediated by EP receptors whose inhibitors suppress gastrointestinal carcinogenesis. Taken together, COX-2 expression is dysregulated in many types of cancer and COX-2-derived PGE(2) elicits multiple oncogenic signals to promote carcinogenesis. Targeting PGE(2) signaling by EP receptor antagonists holds promise for the development of targeted therapy for the treatment of cancer.
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18
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Abstract
Several studies illustrated considerably elevated levels of cyclooxygenase-2 (COX-2) protein in various types of human cancer including malignant melanoma. Recently, it was reported that COX-2 is strongly expressed in malignant melanoma and may be correlated with the development and progression of disease. In contrast, other groups did not detect COX-2 protein in primary melanoma cells but did in infiltrating inflammatory cells or metastases. However, there are no reports about patterns or alterations of COX-2 expression in melanoma cells during disease progression or of a correlation between COX-2 expression and overall survival. The aim of this study was to investigate whether there is a correlation between expression of COX-2 protein and disease prognosis in malignant melanoma. We therefore analyzed the expression of COX-2 protein by immunohistochemistry in 101 primary malignant melanomas and 28 metastases and correlated our data with Breslow tumor thickness, Clark levels, different melanoma subtypes, metastases, and overall survival. We detected a strong COX-2 expression in 95% of all primary melanomas, primarily restricted to melanoma cells as shown by various immunohistochemical methods. Levels of COX-2 expression in primary melanoma and corresponding metastases remained stable. A significant correlation between immunohistochemical staining intensity and tumor thickness was demonstrated. Furthermore, Kaplan-Meier curves illustrated a significant correlation between staining intensity and disease-specific survival. Our findings emphasize that the COX-2 protein might be a novel prognostic marker. Owing to its strong expression in melanoma cells it might also be a reasonable therapeutic target.
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19
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Singh P, Mittal A, Kaur S, Kumar S. 2,3,5-Substituted tetrahydrofurans: COX-2 inhibitory activities of 5-hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols. Eur J Med Chem 2008; 43:2792-9. [DOI: 10.1016/j.ejmech.2007.12.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2007] [Revised: 12/06/2007] [Accepted: 12/11/2007] [Indexed: 11/16/2022]
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20
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Wobst I, Schiffmann S, Birod K, Maier TJ, Schmidt R, Angioni C, Geisslinger G, Grösch S. Dimethylcelecoxib inhibits prostaglandin E2 production. Biochem Pharmacol 2008; 76:62-9. [DOI: 10.1016/j.bcp.2008.04.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2008] [Revised: 04/15/2008] [Accepted: 04/16/2008] [Indexed: 12/11/2022]
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21
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Bai L, Mao GP, Cao CP. Effects of inflammatory cytokines on the recurrence of liver cancer after an apparently curative operation. J Dig Dis 2007; 8:154-9. [PMID: 17650228 DOI: 10.1111/j.1443-9573.2007.00292.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the effects of inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and vascular cell adhesion molecule (VCAM-1), on the recurrence of liver cancer after apparently curative surgical resection of the tumor. METHODS An experimental mouse model of liver cancer metastasis was designed using hepatoma 22(H(22)) inoculated into the subserous layer of spleen of 615 mice. Partial hepatectomy (PH) or sham operation (SH) was performed at various periods of spleen inoculation and metastasic effects were recorded. The expression of inflammatory cytokines as TNF-alpha, IL-1beta, IL-6 and VCAM-1 were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS Compared with SH, a significant augmented metastatic effect was observed in the mice with PH (P < 0.01), and higher mRNA expressions of TNF-alpha, IL-1beta, IL-6 and VCAM-1 were also observed. The peak expressions of IL-1beta, IL-6 and VCAM-1 were found at 48 and 72 h, respectively. Among them, TNF-alpha expression was found immediately increasing after 4 h and kept at a high level till 96 h after PH. The expression of VCAM-1 was found to have two peaks at 4 and 72 h after PH, 3-6 times higher than its level prior to the operation. The expression of TNF-alpha, IL-1beta, IL-6 and VCAM-1 showed a significantly positive correlation with the augmenting effect of liver metastasis in the mice model. CONCLUSION The results indicate that pro-inflammatory cytokines, TNF-alpha, IL-1beta, IL-6 and VCAM-1 might be involved in promoting the enhanced metastasis of liver cancer after surgical operation, especially the PH.
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Affiliation(s)
- Li Bai
- Department of Gastroenterology, General Air Force Hospital, Beijing, China.
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22
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Singh P, Mittal A, Kumar S. 2,3,5-Substituted tetrahydrofurans as cancer chemopreventives. Part 1: Synthesis and anti-cancer activities of 5-hydroxymethyl-2,3-diaryl-tetrahydro-furan-3-ols. Bioorg Med Chem 2007; 15:3990-6. [PMID: 17446077 DOI: 10.1016/j.bmc.2007.04.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2007] [Revised: 03/31/2007] [Accepted: 04/03/2007] [Indexed: 11/18/2022]
Abstract
The allylation of appropriate benzoin in presence of indium metal followed by m-CPBA mediated cyclization gave 5-hydroxymethyl-2,3-diaryl-tetrahydro-furan-3-ols. Investigations on 59 human tumor cell lines of these compounds identify four compounds exhibiting significant growth inhibition of tumor cells at particular cell lines. Compound 12 is very specific toward CCRF-CEM and SR cell lines of leukemia.
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Affiliation(s)
- Palwinder Singh
- Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India.
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23
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Fernandes GO, Pereira Junior JJ, França MAV, Costa JHG. Polipose adenomatosa familiar atenuada. ACTA ACUST UNITED AC 2007. [DOI: 10.1590/s0101-98802007000200008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A Polipose Adenomatosa Familiar Atenuada(PAFA) é uma síndrome autossômica dominante, de diagnóstico tardio, comparando-se à forma clássica da polipose adenomatosa familiar. Dentre as características da síndrome estão: a)presença de menos de 100 pólipos colorretais; b) curso brando da doença, com idade tardia do diagnóstico e do aparecimento de câncer; c)prevalência maior dos pólipos à direita do cólon; d) reto poupado de lesões, na maioria dos casos. Analisar as características clínicas, tratamento e seguimento de 13 pacientes com diagnóstico de PAFA. Dos pacientes estudados, a média de idade ao diagnóstico foi 55 anos. Cinco pacientes apresentavam história familiar de polipose e/ou neoplasia. Nove (69%) pacientes já tinham câncer no momento do diagnóstico. A maioria dos pacientes possuía pólipos localizados no cólon direito (31%). Do total, 06 pacientes foram submetidos à ressecção cirúrgica, com proctocolectomia ou colectomia. A média de seguimento dos pacientes foi de 26 meses. O controle foi realizado através de colonoscopias e retossigmoidoscopias, de acordo com o tratamento realizado. O diagnóstico de PAFA foi feito em idade tardia em relação à forma clássica da doença, com a maioria dos pólipos localizados no cólon direito. O controle endoscópico dos pacientes deve ser realizado com rigor. A colectomia com anastomose do íleo-reto é uma boa opção cirúrgica no tratamento dos pacientes, com baixa recidiva de pólipos no reto.
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24
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Antunes LMG, de Barros E Lima Bueno R, da Luz Dias F, de Lourdes Pires Bianchi M. Acetylsalicylic acid exhibits anticlastogenic effects on cultured human lymphocytes exposed to doxorubicin. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2007; 626:155-61. [PMID: 17097912 DOI: 10.1016/j.mrgentox.2006.09.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2006] [Revised: 09/20/2006] [Accepted: 09/29/2006] [Indexed: 11/16/2022]
Abstract
Acetylsalicylic acid (ASA) is a non-steroidal anti-inflammatory drug (NSAID) with many pharmacological properties, such as anti-inflammatory, antipyretic and analgesic. Many studies have suggested the possible efficiency of ASA and other NSAIDs in preventing cancer. ASA could also have antimutagenic and antioxidant properties. The aim of this study was to investigate the possible clastogenic and anticlastogenic effects of different concentrations of ASA on doxorubicin-induced chromosomal aberrations in human lymphocytes. Human blood samples were obtained from six healthy, non-smoking volunteers; and the chromosomal aberration assay was carried out using conventional techniques. The parameters analyzed were mitotic index, total number of chromosomal aberrations and percentage of aberrant metaphases. The concentrations of ASA (25, 50 or 100 microg/mL) tested in combination with DXR (0.2 microg/mL) were established on the basis of the results of the mitotic index. The treatment with ASA alone was neither cytotoxic nor clastogenic (p>0.01). In lymphocyte cultures treated with different combinations of ASA and DXR, a significant decrease in the total number of chromosome aberrations was observed compared with DXR alone (p<0.01). This protective effect of ASA on DXR-induced chromosomal damage was obtained for all combinations, and it was most evident when ASA was at 25.0 microg/mL. In our experiments, ASA may have acted as an antioxidant and inhibited the chromosomal damage induced by the free radicals generated by DXR. The identification of compounds that could counteract the free radicals produced by doxorubicin could be of possible benefits against the potential harmful effects of anthracyclines. The results of this study show that there is a relevant need for more investigations in order to elucidate the mechanisms underlying the anticlastogenic effect of ASA.
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Affiliation(s)
- Lusânia Maria Greggi Antunes
- Depto de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.
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Popovtzer A, Morgenstein S, Roizman P, Gutman D, Bahar G, Stern Y, Feinmesser R. Cyclooxygenase-2 expression in medullary thyroid carcinoma. Head Neck 2007; 29:559-63. [PMID: 17274057 DOI: 10.1002/hed.20542] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Recent studies have demonstrated that cyclooxygenase-2 (COX-2) expression is associated with the carcinogenesis of numerous neoplasms. The aim of this study was to evaluate the role of COX-2 in medullary thyroid carcinoma (MTC). METHODS Tissue specimens of thyroid neoplasms were obtained from 22 patients with MTC and 15 control subjects with nonmalignant thyroid specimens. RESULTS This immunohistochemical study confirms the presence of COX-2 in a significant number of MTCs. A large area of staining was noted in only 2 patients in the control group (13%) compared with 18 (82%) in the medullary carcinoma group. On a scale of 0 to 3, the average area of positive staining measured 2.35 in the study group and 0.9 in the control group (p < .0001). The average intensity of staining on a scale of 0 to 5 (deep brown) was 2.15 and 0.8 mm, respectively (p < .001). CONCLUSION COX-2 is expressed significantly in MTC including a larger area of staining and greater intensity than in nonmalignant thyroid tissue. These findings may have important treatment implications for the use of COX-2 inhibitors in patients with MTC.
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Affiliation(s)
- Aron Popovtzer
- Department of Otorhinolaryngology, Head and Neck Surgery and Felsenstein Research Medical Center, Rabin Medical Center, Beilinson Campus, Petah Tiqwa, Israel.
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Jin DZ, Yin LL, Ji XQ, Zhu XZ. Cryptotanshinone inhibits cyclooxygenase-2 enzyme activity but not its expression. Eur J Pharmacol 2006; 549:166-72. [PMID: 16989810 DOI: 10.1016/j.ejphar.2006.07.055] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2006] [Accepted: 07/26/2006] [Indexed: 11/19/2022]
Abstract
Cyclooxygenase-2 (COX-2) is a key enzyme that catalyzes the biosynthesis of prostaglandins from arachidonic acid and plays a critical role in some pathologies including inflammation, neurodegenerative diseases and cancer. Cryptotanshinone is a major constituent of tanshinones, which are extracted from the medicinal herb Salvia miltiorrhiza Bunge, and has well-documented antioxidative and anti-inflammatory effects. This study confirmed the remarkable anti-inflammatory effect of cryptotanshinone in the carrageenan-induced rat paw edema model. Since the action of cryptotanshinone on COX-2 has not been previously described, in the present study, we further examined the effect of cryptotanshinone on cyclooxygenase activity in the exogenous arachidonic acid-stimulated insect sf-9 cells, which highly express human COX-2 or human COX-1, and on cyclooxygenases expression in human U937 promonocytes stimulated by lipopolysaccharide (LPS) plus phorbolmyristate acetate (PMA). Cryptotanshinone reduced prostaglandin E2 synthesis and reactive oxygen species generation catalyzed by COX-2, without influencing COX-1 activity in cloned sf-9 cells. In PMA plus LPS-stimulated U937 cells, cryptotanshinone had negligible effects on the expression of COX-1 and COX-2, at either a mRNA or protein level. These results demonstrate that the anti-inflammatory effect of cryptotanshinone is directed against enzymatic activity of COX-2, not against the transcription or translation of the enzyme.
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Affiliation(s)
- Dao-Zhong Jin
- Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
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Grösch S, Maier TJ, Schiffmann S, Geisslinger G. Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst 2006; 98:736-47. [PMID: 16757698 DOI: 10.1093/jnci/djj206] [Citation(s) in RCA: 354] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Nonsteroidal antiinflammatory drugs (NSAIDs) appear to reduce the risk of developing cancer. One mechanism through which NSAIDs act to reduce carcinogenesis is to inhibit the activity of cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in various cancer tissues. Overexpression of COX-2 increases cell proliferation and inhibits apoptosis. However, selective COX-2 inhibitors can also act through COX-independent mechanisms. In this review, we describe the COX-2-independent molecular targets of these COX-2 inhibitors and discuss how these targets may be involved in the anticarcinogenic activities of these selective COX-2 inhibitors. We also compare the concentrations of these inhibitors used in in vitro and in vivo experiments and discuss the implications of the in vitro studies for clinical management of cancer with these drugs.
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Affiliation(s)
- Sabine Grösch
- Pharmazentrum Frankfurt, ZAFES, Institut für klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe, Universität Frankfurt, Theodor Stern Kai 7, Frankfurt/Main, Germany.
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Itagaki S, Gopal E, Zhuang L, Fei YJ, Miyauchi S, Prasad PD, Ganapathy V. Interaction of ibuprofen and other structurally related NSAIDs with the sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8). Pharm Res 2006; 23:1209-16. [PMID: 16729224 DOI: 10.1007/s11095-006-0023-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2005] [Accepted: 01/18/2006] [Indexed: 12/24/2022]
Abstract
PURPOSE Sodium-coupled monocarboxylate transporter 1 (SMCT1) is a Na+-coupled transporter for monocarboxylates. Many nonsteroidal anti-inflammatory drugs (NSAIDs) are monocarboxylates. Therefore, we investigated the interaction of these drugs with human SMCT1 (hSMCT1). METHODS We expressed hSMCT1 in a mammalian cell line and in Xenopus laevis oocytes and used the uptake of nicotinate and propionate-induced currents to monitor its transport function, respectively. We also used [14C]-nicotinate and [3H]-ibuprofen for direct measurements of uptake in oocytes. RESULTS In mammalian cells, hSMCT1-mediated nicotinate uptake was inhibited by ibuprofen and other structurally related NSAIDs. The inhibition was Na+ dependent. With ibuprofen, the concentration necessary for 50% inhibition was 64 +/- 16 microM. In oocytes, the transport function of hSMCT1 was associated with inward currents in the presence of propionate. Under identical conditions, ibuprofen and other structurally related NSAIDs failed to induce inward currents. However, these compounds blocked propionate-induced currents. With ibuprofen, the blockade was dose dependent, Na+ dependent, and competitive. However, there was no uptake of [3H]-ibuprofen into oocytes expressing hSMCT1, although the uptake of [14C]-nicotinate was demonstrable under identical conditions. CONCLUSIONS Ibuprofen and other structurally related NSAIDs interact with hSMCT1 as blockers of its transport function rather than as its transportable substrates.
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Affiliation(s)
- Shirou Itagaki
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912, USA
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Konturek PC, Rembiasz K, Burnat G, Konturek SJ, Tusinela M, Bielanski W, Rehfeld J, Karcz D, Hahn E. Effects of cyclooxygenase-2 inhibition on serum and tumor gastrins and expression of apoptosis-related proteins in colorectal cancer. Dig Dis Sci 2006; 51:779-87. [PMID: 16615003 DOI: 10.1007/s10620-006-3206-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2005] [Accepted: 07/07/2005] [Indexed: 02/06/2023]
Abstract
The objective of the present study was to determine the influence of cyclooxygenase-2 (COX-2) inhibition by Celecoxib (CLX) in humans with distal colorectal adenocarcinoma (CRC) on serum and tumor levels of progastrin and gastrin and serum levels of proinflammatory cytokines (IL-8, TNF-alpha). In addition, the effects of this CLX treatment on tumor and adjacent mucosa expression of gastrin, its receptors (CCK2), and COX-1 and COX-2, as well as protein expression of the active form of nuclear factor kappa B (NFkappa B) and the apoptotic-related proteins Bcl-2 and survivin, have been examined. Ten distal CRC patients were examined twice, once before and then after 14-day treatment with CLX (200 mg bid). Large biopsy samples were taken from the tumor and intact mucosa 10 cm above the tumor. For comparison, 20 age- and sex-matched healthy controls were enrolled and treated with CLX as CRC patients. Serum levels of IL-8 and TNF-alpha were measured by enzyme-linked immunosorbent assay, and serum levels of amidated gastrins and progastrin, by specific radioimmunoassay. The gene or protein expressions of progastrin, gastrin, CCK2, COX-1, COX-2, Bcl-2, and survivin as well as NFkappa B were determined by RT-PCR or Western blot in biopsy samples of tumor and intact mucosa of CRC patients. Serum IL-8 and TNF-alpha values were severalfold higher in CRC patients than in controls. The increase in serum proinflammatory cytokines was accompanied by increased expression of the active form of NFkappa B. Serum progastrin levels were also found to be significantly higher in CRC than in controls. Treatment of CRC with CLX resulted in a significant decrease in serum levels of progastrin and this was accompanied by an increment in tumor expression of COX-2 with a concomitant reduction in gastrin, Bcl-2, survivin, and NFkappa B expression. We conclude that (1) distal CRC patients show significantly higher serum progastrin levels than matched healthy controls, confirming that this hormone may be implicated in rectal carcinogenesis; (2) CRC patients exhibit significantly higher serum levels of IL-8 and TNF-alpha than healthy controls, probably reflecting more widespread inflammatory reaction in the colonic mucosa in CRC; (3) gastrin, COX-2, Bcl-2, survivin, and NFkappa B were overexpressed in CRC tumor compared to intact mucosa, but treatment with CLX significantly reduced serum levels of progastrin and IL-8 and TNF-alpha, which could mediate the up-regulation of COX-2 in CRC; and (4) CLX also enhanced expression of COX-2, while inhibiting the expression of gastrin, Bcl-2, survivin, and NFkappa B, suggesting that COX-2 inhibition might be useful in chemoprevention against CRC, possibly due to suppression of the antiapoptotic proteins and reduction in progastrin-induced and NFkappa B-promoted tumor growth.
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Affiliation(s)
- Peter C Konturek
- Department of Medicine, University Erlangen-Nuremberg, Erlangen, Germany.
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Vaughan TL, Dong LM, Blount PL, Ayub K, Odze RD, Sanchez CA, Rabinovitch PS, Reid BJ. Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett's oesophagus: a prospective study. Lancet Oncol 2005; 6:945-52. [PMID: 16321762 DOI: 10.1016/s1470-2045(05)70431-9] [Citation(s) in RCA: 159] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Aspirin and other non-steroidal anti-inflammatory drugs (NSAID) probably decrease the risk of colorectal neoplasia; however their effect on development of oesophageal adenocarcinoma is less clear. We aimed to assess the role of NSAID in the development of oesophageal adenocarcinoma and precursor lesions in people with Barrett's oesophagus--a metaplastic disorder that confers a high risk of oesophageal adenocarcinoma. METHODS We did a prospective study of the relation between duration, frequency, and recency of NSAID use and the risk of oesophageal adenocarcinoma, aneuploidy, and tetraploidy in a cohort of 350 people with Barrett's oesophagus followed for 20,770 person-months. We used proportional-hazards regression to calculate hazard ratios (HR) adjusted for age, sex, cigarette use, and anthropometric measurements. FINDINGS Median follow-up was 65.5 months (range 3.1-106.9). Compared with never users, HR for oesophageal adenocarcinoma (n=37 cases) in current NSAID users was 0.32 (95% CI 0.14-0.76), and in former users was 0.70 (0.31-1.58). 5-year cumulative incidence of oesophageal adenocarcinoma was 14.3% (95% CI 9.3-21.6) for never users, 9.7% (4.5-20.5) for former users, and 6.6% (3.1-13.6) for current NSAID users. When changes in NSAID use during follow up were taken into account, the associations were strengthened: HR for oesophageal adenocarcinoma for current users at baseline or afterwards was 0.20 (95% CI 0.10-0.41) compared with never users. Compared with never users, current NSAID users (at baseline and follow-up) had less aneuploidy (n=35 cases; 0.25 [0.12-0.54]) and tetraploidy (n=45 cases; 0.44 [0.22-0.87]). INTERPRETATION NSAID use might be an effective chemopreventive strategy, reducing the risk of neoplastic progression in Barrett's oesophagus.
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Affiliation(s)
- Thomas L Vaughan
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, WA 98109, USA.
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Maia H, Correia T, Freitas LA, Athayde C, Coutinho E. Cyclooxygenase-2 expression in endometrial polyps during menopause. Gynecol Endocrinol 2005; 21:336-9. [PMID: 16390782 DOI: 10.1080/09513590500441739] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
OBJECTIVE To determine whether cyclooxygenase-2 (COX-2) is expressed in endometrial polyps during menopause and how previous hormone use may affect this expression. PATIENTS AND METHODS Fifty-two postmenopausal patients with endometrial polyps were enrolled for this study. Eighteen patients had no history of previous hormone use, while the remaining patients had used vaginal conjugated estrogens for short periods of time (n = 25) or were long-term users of tibolone (n = 5) or tamoxifen (n = 4). The endometrial polyps were removed by hysteroscopy, and COX-2 and Ki-67 expression were measured in tissue samples by immunohistochemistry. RESULTS Endometrial polyps expressed COX-2 in the glandular epithelium and this expression was not significantly greater in patients who had previously used tibolone, tamoxifen or vaginal estrogens. However, Ki-67 expression was greater in the group using vaginal estrogens compared with the group of non-users; while in the other two treatment groups Ki-67 expression was less than in hormone never-users. CONCLUSION COX-2 expression is present in endometrial polyps during menopause and may play a role in their growth regulation.
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Affiliation(s)
- Hugo Maia
- Centro de Pesquisa e Assistência em Reprodução Humana (CEPARH), Salvador, Bahia, Brazil.
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Mayo JC, Sainz RM, Tan DX, Hardeland R, Leon J, Rodriguez C, Reiter RJ. Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol 2005; 165:139-49. [PMID: 15975667 DOI: 10.1016/j.jneuroim.2005.05.002] [Citation(s) in RCA: 228] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2005] [Accepted: 05/04/2005] [Indexed: 10/25/2022]
Abstract
Inflammation is a complex phenomenon involving multiple cellular and molecular interactions which must be tightly regulated. Cyclooxygenase-2 (COX) is the key enzyme that catalyzes the two sequential steps in the biosynthesis of PGs from arachidonic acid. The inducible isoform of COX, namely COX-2, plays a critical role in the inflammatory response and its over-expression has been associated with several pathologies including neurodegenerative diseases and cancer. Melatonin is the main product of the pineal gland with well documented antioxidant and immuno-modulatory effects. Since the action of the indole on COX-2 has not been previously described, the goal of the present report was to test the effect of melatonin on the activities of COX-2 and inducible nitric oxide synthase (iNOS), using lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as a model. Melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), prevented COX-2 activation induced by LPS, without affecting COX-1 protein levels. The structurally related compound 6-methoxy-melatonin only partially prevented the increase in COX-2 protein levels induced by the toxin. Likewise melatonin prevented iNOS activation and reduced the concentration of products from both enzymes, PGE(2) and nitric oxide. Another endogenous antioxidant like N-acetyl-cysteine (NAC) did not reduced COX-2 significantly. The current finding corroborates a role of melatonin as an anti-inflammatory agent and, for the first time, COX-2 and iNOS as molecular targets for either melatonin or its metabolites AFMK and AMK. These anti-inflammatory actions seem not to be exclusively mediated by the free radical scavenging properties of melatonin. As a consequence, the present work suggests these substances as a new class of potential anti-inflammatory agents without the classical side effects due to COX-1 inhibition.
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Affiliation(s)
- Juan C Mayo
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, Asturias, España.
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Ferguson LR, Zhu ST, Harris PJ. Antioxidant and antigenotoxic effects of plant cell wall hydroxycinnamic acids in cultured HT-29 cells. Mol Nutr Food Res 2005; 49:585-93. [PMID: 15841493 DOI: 10.1002/mnfr.200500014] [Citation(s) in RCA: 169] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
We demonstrate that two hydroxycinnamic acids, (E )-ferulic acid and (E )-p-coumaric acid, have the ability to protect against oxidative stress and genotoxicity in cultured mammalian cells. They also show the ability to reduce the activity of the xenobiotic metabolising enzyme, cytochrome P450 1A, and downregulate the expression of the cyclooxygenase-2 enzyme. At equitoxic doses, their activities are equal to or superior to that of the known anticarcinogen, curcumin. The hydroxycinnamic acids are both important components of plant cell walls in certain plant foods. It is known that the action of microbial hydroxycinnamoyl esterases can lead to the release of hydroxycinnamic acids from ester-linkages to cell wall polysaccharides into the human colon. Thus, providing they can reach effective levels in the colon, they could provide an important mechanism by which dietary fibres of food plants, such as spinach or cereal, protect against colon cancer.
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Affiliation(s)
- Lynnette R Ferguson
- Discipline of Nutrition, Faculty of Medicine and Health Sciences. The University of Auckland, Auckland, New Zealand.
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