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Salihi A, Al-Naqshabandi MA, Khudhur ZO, Housein Z, Hama HA, Abdullah RM, Hussen BM, Alkasalias T. Gasotransmitters in the tumor microenvironment: Impacts on cancer chemotherapy (Review). Mol Med Rep 2022; 26:233. [PMID: 35616143 PMCID: PMC9178674 DOI: 10.3892/mmr.2022.12749] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/07/2022] [Indexed: 11/23/2022] Open
Abstract
Nitric oxide, carbon monoxide and hydrogen sulfide are three endogenous gasotransmitters that serve a role in regulating normal and pathological cellular activities. They can stimulate or inhibit cancer cell proliferation and invasion, as well as interfere with cancer cell responses to drug treatments. Understanding the molecular pathways governing the interactions between these gases and the tumor microenvironment can be utilized for the identification of a novel technique to disrupt cancer cell interactions and may contribute to the conception of effective and safe cancer therapy strategies. The present review discusses the effects of these gases in modulating the action of chemotherapies, as well as prospective pharmacological and therapeutic interfering approaches. A deeper knowledge of the mechanisms that underpin the cellular and pharmacological effects, as well as interactions, of each of the three gases could pave the way for therapeutic treatments and translational research.
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Affiliation(s)
- Abbas Salihi
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region 44001, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region 44002, Iraq
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-17165 Stockholm, Sweden
| | - Mohammed A. Al-Naqshabandi
- Department of Clinical Biochemistry, College of Health Sciences, Hawler Medical University, Erbil, Kurdistan Region 44001, Iraq
| | - Zhikal Omar Khudhur
- Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Erbil, Kurdistan Region 44001, Iraq
| | - Zjwan Housein
- Department of Medical Laboratory Technology, Technical Health and Medical College, Erbil Polytechnique University, Erbil, Kurdistan Region 44002, Iraq
| | - Harmand A. Hama
- Department of Biology, Faculty of Education, Tishk International University, Erbil, Kurdistan Region 44002, Iraq
| | - Ramyar M. Abdullah
- College of Medicine, Hawler Medical University, Erbil, Kurdistan Region 44002, Iraq
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region 44002, Iraq
| | - Twana Alkasalias
- General Directorate of Scientific Research Center, Salahaddin University-Erbil, Erbil, Kurdistan Region 44002, Iraq
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, SE-17176 Stockholm, Sweden
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Oxidative Stress Markers Are Associated with a Poor Prognosis in Patients with Pancreatic Cancer. Antioxidants (Basel) 2022; 11:antiox11040759. [PMID: 35453444 PMCID: PMC9029757 DOI: 10.3390/antiox11040759] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/04/2022] [Accepted: 04/07/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic cancer is a malignancy of rising prevalence, especially in developed countries where dietary patterns and sedentariness favor its onset. This malady ranks seventh in cancer-related deaths in the world, although it is expected to rank second in the coming years, behind lung cancer. The low survival rate is due to the asymptomatic course of the early stages, which in many cases leads to metastases when becoming evident in advanced stages. In this context, molecular pathology is on the way towards finding new approaches with biomarkers that allow a better prognosis and monitoring of patients. So the present study aims to evaluate a series of molecular biomarkers, PARP1, NOX1, NOX2, eNOS and iNOS, as promising candidates for prognosis and survival by using immunohistochemistry. The analysis performed in 41 patients with pancreatic cancer showed a correlation between a high expression of all these components with a low survival rate, with high statistical power for all. In addition, a 60-month longitudinal surveillance program was managed, accompanied by several clinical parameters. The derivative Kaplan–Meier curves indicated a low cumulative survival rate as well. Ultimately, our research emphasized the value of these molecules as survival-associated biomarkers in pancreatic cancer, offering new gates for clinical management.
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Protein Phosphorylation in Cancer: Role of Nitric Oxide Signaling Pathway. Biomolecules 2021; 11:biom11071009. [PMID: 34356634 PMCID: PMC8301900 DOI: 10.3390/biom11071009] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 12/16/2022] Open
Abstract
Nitric oxide (NO), a free radical, plays a critical role in a wide range of physiological and pathological processes. Due to its pleiotropic function, it has been widely investigated in various types of cancers and is strongly associated with cancer development. Mounting pieces of evidence show that NO regulates various cancer-related events, which mainly depends on phosphorylating the key proteins in several signaling pathways. However, phosphorylation of proteins modulated by NO signaling pathway may lead to different effects in different types of cancer, which is complex and remains unclear. Therefore, in this review, we focus on the effect of protein phosphorylation modulated by NO signaling pathway in different types of cancers including breast cancer, lung cancer, prostate cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, and neuroblastoma. Phosphorylation of key proteins, including p38 MAPK, ERK, PI3K, STAT3, and p53, modified by NO in various signaling pathways affects different cancer-related processes including cell apoptosis, proliferation, angiogenesis, metastasis, and several cancer therapies. Our review links the NO signaling pathway to protein phosphorylation in cancer development and provides new insight into potential targets and cancer therapy.
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Garcia CB, Fernandes PC, Micheli DC, Pereira AHM, Murta EFC, Tavares-Murta BM. Effect of Treatment on Mononuclear Cell Migration in Cervical Cancer Patients. TUMORI JOURNAL 2018; 94:712-7. [DOI: 10.1177/030089160809400512] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims and background Our aim was to evaluate the effect of treatment on the in vitro migration of circulating mononuclear cells in cervical cancer patients at different stages. Methods We prospectively investigated 24 patients with cervical neoplasia, without prior treatment, submitted to surgery or chemotherapy as therapeutic conduct. Controls were healthy volunteer women (n = 23). Mononuclear cells were isolated from peripheral venous blood before and after treatment, and their migration capacity was evaluated in a microchemotaxis chamber assay towards the chemotactic stimuli fMLP, MCP-1 and RANTES, compared to basal migration. Serum levels of nitric oxide metabolites were assayed by the Griess reaction. Results Increased mononuclear cell migration in response to the chemotactic stimuli, compared to basal migration, was observed in controls and patients, without differences between them. After treatment (n = 14), mononuclear cell migration in response to MCP-1 and RANTES was increased compared to pre-treatment. Serum levels of nitric oxide metabolites were more elevated in patients (n = 19) than in controls (n = 17), but decreased after treatment (n = 15). Conclusions The results suggest that the production of soluble circulating factors by tumor cells could interfere with the functional activity of blood mononuclear cells.
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Affiliation(s)
| | - Paulo Cesar Fernandes
- Discipline of Gynecology and Obstetrics/Research Institute of Oncology (IPON), Federal University of Triângulo Mineiro, Uberaba, MG, Brazil
| | - Douglas Côbo Micheli
- Department of Biological Sciences, Federal University of Triângulo Mineiro, Uberaba, MG, Brazil
| | | | - Eddie Fernando Candido Murta
- Discipline of Gynecology and Obstetrics/Research Institute of Oncology (IPON), Federal University of Triângulo Mineiro, Uberaba, MG, Brazil
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Wang J, He P, Gaida M, Yang S, Schetter AJ, Gaedcke J, Ghadimi BM, Ried T, Yfantis H, Lee D, Weiss JM, Stauffer J, Hanna N, Alexander HR, Hussain SP. Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer. Oncotarget 2018; 7:52993-53004. [PMID: 27367029 PMCID: PMC5288163 DOI: 10.18632/oncotarget.10323] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 06/12/2016] [Indexed: 12/30/2022] Open
Abstract
Pancreatic cancer is one of the most lethal malignancies and is refractory to the available treatments. Pancreatic ductal adenocarcinoma (PDAC) expresses high level of inducible nitric oxide synthase (NOS2), which causes sustained production of nitric oxide (NO). We tested the hypothesis that an aberrantly increased NO-release enhances the development and progression of PDAC. Enhanced NOS2 expression in tumors significantly associated with poor survival in PDAC patients (N = 107) with validation in independent cohorts. We then genetically targeted NOS2 in an autochthonous mouse model of PDAC to examine the effect of NOS2-deficiency on disease progression and survival. Genetic ablation of NOS2 significantly prolonged survival and reduced tumor severity in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice. Primary tumor cells isolated from NOS2-deficient KPC (NKPC) mice showed decreased proliferation and invasiveness as compared to those from KPC mice. Furthermore, NKPC tumors showed reduced expression of pERK, a diminished inactivation of Forkhead box transcription factor O (FOXO3), a tumor suppressor, and a decrease in the expression of oncomir-21, when compared with tumors in KPC mice. Taken together, these findings showed that NOS2 is a predictor of prognosis in early stage, resected PDAC patients, and provide proof-of-principle that targeting NOS2 may have potential therapeutic value in this lethal malignancy.
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Affiliation(s)
- Jian Wang
- Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD, USA
| | - Peijun He
- Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD, USA
| | - Matthias Gaida
- Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Shouhui Yang
- Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD, USA
| | | | - Jochen Gaedcke
- Department of General, Visceral and Pediatric Surgery, University Medicine, Göttingen, Germany
| | - B Michael Ghadimi
- Department of General, Visceral and Pediatric Surgery, University Medicine, Göttingen, Germany
| | - Thomas Ried
- Genetics Branch, CCR, NCI, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA
| | - Harris Yfantis
- Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA
| | - Dong Lee
- Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA
| | | | - Jimmy Stauffer
- Laboratory of Cell and Developmental Signaling, NCI Frederick, MD, USA
| | - Nader Hanna
- Division of Surgical Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - H Richard Alexander
- Division of Surgical Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - S Perwez Hussain
- Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD, USA
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Akram M, Kim KA, Kim ES, Syed AS, Kim CY, Lee JS, Bae ON. Potent Anti-inflammatory and Analgesic Actions of the Chloroform Extract of Dendropanax morbifera Mediated by the Nrf2/HO-1 Pathway. Biol Pharm Bull 2017; 39:728-36. [PMID: 27150144 DOI: 10.1248/bpb.b15-00823] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Dendropanax morbifera LEVEILLE (DP) has been used in traditional Korean medicines to treat a variety of inflammatory diseases. Although the in vitro anti-inflammatory potential of this plant is understood, its in vivo efficacy and underlying molecular mechanism of anti-inflammatory effects are largely unknown. We elucidated the anti-inflammatory and analgesic activities and the underlying molecular mechanisms of DP using in vitro and in vivo models. Lipopolysaccharide (LPS)-stimulated murine macrophages were used to analyze the in vitro anti-inflammatory potential of DP extract and to elucidate the underlying mechanisms. In vivo animal models of phorbol 12-myristate 13-acetate (TPA)-induced ear edema and acetic acid-induced writhing response tests were used to analyze the in vivo anti-inflammatory effects and anti-nociceptive effects of DP extract, respectively. Methanolic extract of DP (DPME) significantly inhibited the release of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-activated macrophages. Among the five sub-fractions, the chloroform fraction (DP-C) showed the most potent suppressive effects against pro-inflammatory mediators and cytokines in LPS-stimulated macrophages. These effects were attributed to inhibition of nuclear factor-κB (NF-κB) nuclear translocation and c-Jun N terminal kinase (JNK) 1/2 phosphorylation and to activation of NF-E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling. DP-C exhibited strong protective in vivo effects in TPA-induced ear edema mouse model and acetic acid-induced writhing response test. Our data suggest that DP-C has potent anti-inflammatory and analgesic activities and may be a promising treatment against a variety of inflammatory diseases.
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Affiliation(s)
- Muhammad Akram
- College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University
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Newman SJ, Mrkonjich L. Cyclooxygenase-2 Expression in Feline Pancreatic Adenocarcinomas. J Vet Diagn Invest 2016; 18:590-3. [PMID: 17121089 DOI: 10.1177/104063870601800612] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Cyclooxygenase-2 (COX-II) is an inducible enzyme that is responsible for the production of prostaglandin E2 (PGE2), which is often upregulated in neoplastic conditions. Expression of COX-II is documented in the majority of human pancreatic adenocarcinomas and in many epithelial neoplasms in humans and animals. The purpose of this study was to assess a series of feline pancreatic adenocarcinomas for the expression of COX-II. Eight feline pancreatic adenocarcinomas (5 poorly differentiated ductular variants and 3 well-differentiated acinar variants) were included. Immunohistochemical staining showed that COX-II was expressed in 2 (both poorly differentiated ductular variants) of the 8 neoplasms (25%). Approximately 10% of the epithelial cells from these 2 neoplasms expressed intense cytoplasmic staining. However, because feline pancreatic adenocarcinoma does not appear to consistently express COX-II, it is not a useful prognostic indicator for this group of feline neoplasma. In addition, COX-II inhibitors are not likely to be effective therapeutics for cats with this neoplasm.
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Affiliation(s)
- Shelley Joy Newman
- Department of Pathology, University of Tennessee, College of Veterinary Medicine, Knoxville, TN 37996-4542, USA
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Bhattacharya I, Domínguez AP, Drägert K, Humar R, Haas E, Battegay EJ. Hypoxia potentiates tumor necrosis factor-α induced expression of inducible nitric oxide synthase and cyclooxygenase-2 in white and brown adipocytes. Biochem Biophys Res Commun 2015; 461:287-92. [DOI: 10.1016/j.bbrc.2015.04.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/03/2015] [Indexed: 01/04/2023]
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Kim HK. Role of ERK/MAPK signalling pathway in anti-inflammatory effects of Ecklonia cava in activated human mast cell line-1 cells. ASIAN PAC J TROP MED 2014. [DOI: 10.1016/s1995-7645(14)60120-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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Pomianowska E, Schjølberg AR, Clausen OPF, Gladhaug IP. COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favourable prognosis. BMC Cancer 2014; 14:458. [PMID: 24950702 PMCID: PMC4230243 DOI: 10.1186/1471-2407-14-458] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 06/11/2014] [Indexed: 12/16/2022] Open
Abstract
Background Overexpression of cyclooxygenase-2 (COX-2) has been implicated in oncogenesis and progression of adenocarcinomas of the pancreatic head. The data on the prognostic importance of COX expression in these tumours is inconsistent and conflicting. We evaluated how COX-2 overexpression affected overall postoperative survival in pancreatic head adenocarcinomas. Methods The study included 230 consecutive pancreatoduodenectomies for pancreatic cancer (PC, n = 92), ampullary cancer (AC, n = 62) and distal bile duct cancer (DBC, n = 76). COX-2 expression was assessed by immunohistochemistry. Associations between COX-2 expression and histopathologic variables including degree of differentiation, histopathologic type of differentiation (pancreatobiliary vs. intestinal) and lymph node ratio (LNR) were evaluated. Unadjusted and adjusted survival analysis was performed. Results COX-2 staining was positive in 71% of PC, 77% in AC and 72% in DBC. Irrespective of tumour origin, overall patient survival was more favourable in patients with COX-2 positive tumours than COX-2 negative (p = 0.043 in PC, p = 0.011 in AC, p = 0.06 in DBC). In tumours of pancreatobiliary type of histopathological differentiation, COX-2 expression did not significantly affect overall patient survival. In AC with intestinal differentiation COX-2 expression significantly predicted favourable survival (p = 0.003). In PC, COX-2 expression was significantly associated with high degree of differentiation (p = 0.002). COX-2 and LNR independently predicted good prognosis in a multivariate model. Conclusions COX-2 is overexpressed in pancreatic cancer, ampullary cancer and distal bile duct cancer and confers a survival benefit in all three cancer types. In pancreatic cancer, COX-2 overexpression is significantly associated with the degree of differentiation and independently predicts a favourable prognosis.
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Affiliation(s)
- Ewa Pomianowska
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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Pomianowska E, Sandnes D, Grzyb K, Schjølberg AR, Aasrum M, Tveteraas IH, Tjomsland V, Christoffersen T, Gladhaug IP. Inhibitory effects of prostaglandin E2 on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma. BMC Cancer 2014; 14:413. [PMID: 24912820 PMCID: PMC4084579 DOI: 10.1186/1471-2407-14-413] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 05/20/2014] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Several studies have described an increased cyclooxygenase-2 (COX-2) expression in pancreatic cancer, but the role of COX-2 in tumour development and progression is not clear. The aim of the present study was to examine expression of COX-2 in cancer cells and stromal cells in pancreatic cancer specimens, and to explore the role of PGE2 in pancreatic stellate cell proliferation and collagen synthesis. METHODS Immunohistochemistry and immunofluorescence was performed on slides from whole sections of tissue blocks using antibodies against COX-2 and α-smooth muscle actin (αSMA). Pancreatic stellate cells (PSC) were isolated from surgically resected tumour tissue by the outgrowth method. Cells were used between passages 4 and 8. Collagen synthesis was determined by [(3)H]-proline incorporation, or by enzyme immunoassay measurement of collagen C-peptide. DNA synthesis was measured by incorporation of [(3)H]-thymidine in DNA. Cyclic AMP (cAMP) was determined by radioimmunoassay. Collagen 1A1 mRNA was determined by RT-qPCR. RESULTS Immunohistochemistry staining showed COX-2 in pancreatic carcinoma cells, but not in stromal cells. All tumours showed positive staining for αSMA in the fibrotic stroma. Cultured PSC expressed COX-2, which could be further induced by interleukin-1β (IL-1β), epidermal growth factor (EGF), thrombin, and PGE2, but not by transforming growth factor-β1 (TGFβ). Indirect coculture with the adenocarcinoma cell line BxPC-3, but not HPAFII or Panc-1, induced COX-2 expression in PSC. Treatment of PSC with PGE2 strongly stimulated cAMP accumulation, mediated by EP2 receptors, and also stimulated phosphorylation of extracellular signal-regulated kinase (ERK). Treatment of PSC with PGE2 or forskolin suppressed both TGFβ-stimulated collagen synthesis and PDGF-stimulated DNA synthesis. CONCLUSIONS The present results show that COX-2 is mainly produced in carcinoma cells and suggest that the cancer cells are the main source of PGE2 in pancreatic tumours. PGE2 exerts a suppressive effect on proliferation and fibrogenesis in pancreatic stellate cells. These effects of PGE2 are mediated by the cAMP pathway and suggest a role of EP2 receptors.
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Affiliation(s)
- Ewa Pomianowska
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, PO Box 4956, Nydalen 0424 Oslo, Norway
| | - Dagny Sandnes
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Krzysztof Grzyb
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Aasa R Schjølberg
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Monica Aasrum
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Ingun H Tveteraas
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Vegard Tjomsland
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, PO Box 4956, Nydalen 0424 Oslo, Norway
| | - Thoralf Christoffersen
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Ivar P Gladhaug
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, PO Box 4956, Nydalen 0424 Oslo, Norway
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Ling S, Feng T, Jia K, Tian Y, Li Y. Inflammation to cancer: The molecular biology in the pancreas (Review). Oncol Lett 2014; 7:1747-1754. [PMID: 24932227 PMCID: PMC4049733 DOI: 10.3892/ol.2014.2003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 03/11/2014] [Indexed: 02/07/2023] Open
Abstract
Inflammatory responses are known to be correlated with cancer initiation and progression, and exploration of the route from inflammation to cancer makes a great contribution in elucidating the mechanisms underlying cancer development. Pancreatic cancer (PC) is a lethal disease with a low radical-resection rate and a poor prognosis. As chronic pancreatitis is considered to be a significant etiological factor for PC development, the current review aims to describe the molecular pathways from inflammation to pancreatic carcinogenesis, in support of the strategies for the prevention, diagnosis and treatment of PC.
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Affiliation(s)
- Sunbin Ling
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Tingting Feng
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Kaiqi Jia
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Yu Tian
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Yan Li
- Institute of Cancer Stem Cells, Dalian Medical University, Dalian, Liaoning 116044, P.R. China ; College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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Rahat MA, Hemmerlein B. Macrophage-tumor cell interactions regulate the function of nitric oxide. Front Physiol 2013; 4:144. [PMID: 23785333 PMCID: PMC3684767 DOI: 10.3389/fphys.2013.00144] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 05/29/2013] [Indexed: 12/12/2022] Open
Abstract
Tumor cell-macrophage interactions change as the tumor progresses, and the generation of nitric oxide (NO) by the inducible nitric oxide synthase (iNOS) plays a major role in this interplay. In early stages, macrophages employ their killing mechanisms, particularly the generation of high concentrations of NO and its derivative reactive nitrogen species (RNS) to initiate tumor cell apoptosis and destroy emerging transformed cells. If the tumor escapes the immune system and grows, macrophages that infiltrate it are reprogramed in situ by the tumor microenvironment. Low oxygen tensions (hypoxia) and immunosuppressive cytokines inhibit iNOS activity and lead to production of low amounts of NO/RNS, which are pro-angiogenic and support tumor growth and metastasis by inducing growth factors (e.g., VEGF) and matrix metalloproteinases (MMPs). We review here the different roles of NO/RNS in tumor progression and inhibition, and the mechanisms that regulate iNOS expression and NO production, highlighting the role of different subtypes of macrophages and the microenvironment. We finally claim that some tumor cells may become resistant to macrophage-induced death by increasing their expression of microRNA-146a (miR-146a), which leads to inhibition of iNOS translation. This implies that some cooperation between tumor cells and macrophages is required to induce tumor cell death, and that tumor cells may control their fate. Thus, in order to induce susceptibility of tumors cells to macrophage-induced death, we suggest a new therapeutic approach that couples manipulation of miR-146a levels in tumors with macrophage therapy, which relies on ex vivo stimulation of macrophages and their re-introduction to tumors.
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Affiliation(s)
- Michal A Rahat
- Department of Immunology, Immunology Research Unit, Carmel Medical Center and the Ruth and Bruce Rappaport Faculty of Medicine Technion, Haifa, Israel
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Hogendorf P, Durczyński A, Kumor A, Strzelczyk J. Prostaglandin E2 (PGE2) in portal blood in patients with pancreatic tumor--a single institution series. J INVEST SURG 2012; 25:8-13. [PMID: 22272632 DOI: 10.3109/08941939.2011.592569] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cyclooxygenase-2 (COX-2) may play a significant role in the development of pancreatic cancer. One of COX-2 main metabolites is prostaglandin E2 (PGE2), which is involved both in inflammation and carcinogenesis. As PGE2 is inactivated in the lungs and the liver we assumed that the best medium to assess the level of PGE2 is not peripheral but portal blood. PATIENTS AND METHODS Fifty-seven patients with pathologically verified diagnosis of pancreatic ductal adenocarcinoma (PDAC group, n = 38) and chronic pancreatitis (CP group, n = 19) were enrolled in this study. Sample of blood from central line was collected before surgery. Intraoperatively portal vein was identified and sampled. PGE2 levels were determined using ELISA test. All the patients were followed-up for 1-35 months. RESULTS PGE2 portal blood levels in patients with PDAC were higher than in patients with CP (190.55 ± 149.86 versus 120.23 ± 132.60; p = .04). PGE2 concentration at a cut-off value of 94.46 pg/ml had a sensitivity of 91.67%, specificity of 50%, AUC = 0.631 (95% CI, 0.489-0.758). CONCLUSION The PGE2 portal blood levels in PDAC patients are higher than in those with CP. The PGE2 portal concentration cannot be a single marker in diagnosing PDAC due to low specificity.
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Affiliation(s)
- Piotr Hogendorf
- Department of General and Transplant Surgery, Norbert Barlicki Memorial Teaching Hospital, Medical University of Łódź, Poland.
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Kim SJ, Jeong HJ, Yi BJ, Kang TH, An NH, Lee EH, Yang DC, Kim HM, Hong SH, Um JY. TransgenicPanax ginsengInhibits the Production of TNF-α, IL-6, and IL-8 as well as COX-2 Expression in Human Mast Cells. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2012; 35:329-39. [PMID: 17436372 DOI: 10.1142/s0192415x07004850] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The most well-known medicinal plant, Panax ginseng (P. ginseng), contains various phytosterols and bioactive triterpene saponins (ginsenosides). Squalene synthase is a key regulatory enzyme for triterpene biosynthesis and overexpression of the squalene synthase confers the hyper-production of triterpene saponins to form transgenic ginseng. In this study, we have investigated whether and how transgenic P. ginseng modulates an inflammatory reaction in a stimulated human mast cell line, HMC-1. It was found that transgenic P. ginseng inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and the expression of cyclooxygenase-2 in phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187 (PMACI)-stimulated HMC-1. Additionally, we have shown that transgenic P. ginseng suppressed the intracellular calcium level induced by PMACI. These results provide new insights into the pharmacological actions of transgenic P. ginseng as a potential molecule for use in therapy in mast cell-mediated inflammatory diseases.
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Affiliation(s)
- Su-Jin Kim
- Department of Pharmacology, College of Oriental Medicine, Institute of Oriental Medicine, Kyung Hee University, 1 Hoegi-Dong, Dongdaemun-Gu, Seoul, 130-701, Republic of Korea
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Abstract
Resveratrol, a natural polyphenol abundantly found in grape skins and red wine, possesses diverse biochemical and physiological actions, including anti-inflammatory, anti-oxidation, anti-proliferation and promotion of differentiation, and chemopreventive effects. Recently, it is attracting increased attention due to its health benefits, especially in common age-related diseases such as cardiovascular disease, cancer, type 2 diabetes, and neurological conditions. In this review, we discuss the latest cellular and molecular findings that account for the beneficial actions of resveratrol.
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Affiliation(s)
- Wei Yu
- Department of Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, People's Republic of China
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17
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Multhoff G, Molls M, Radons J. Chronic inflammation in cancer development. Front Immunol 2012; 2:98. [PMID: 22566887 PMCID: PMC3342348 DOI: 10.3389/fimmu.2011.00098] [Citation(s) in RCA: 326] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Accepted: 12/28/2011] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammatory mediators exert pleiotropic effects in the development of cancer. On the one hand, inflammation favors carcinogenesis, malignant transformation, tumor growth, invasion, and metastatic spread; on the other hand inflammation can stimulate immune effector mechanisms that might limit tumor growth. The link between cancer and inflammation depends on intrinsic and extrinsic pathways. Both pathways result in the activation of transcription factors such as NF-κB, STAT-3, and HIF-1 and in accumulation of tumorigenic factors in tumor and microenvironment. STAT-3 and NF-κB interact at multiple levels and thereby boost tumor-associated inflammation which can suppress anti-tumor immune responses. These factors also promote tumor growth, progression, and metastatic spread. IL-1, IL-6, TNF, and PGHS-2 are key mediators of an inflammatory milieu by modulating the expression of tumor-promoting factors. In this review we concentrate on the crucial role of pro-inflammatory mediators in inflammation-driven carcinogenesis and outline molecular mechanisms of IL-1 signaling in tumors. In addition, we elucidate the dual roles of stress proteins as danger signals in the development of anti-cancer immunity and anti-apoptotic functions.
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Affiliation(s)
- Gabriele Multhoff
- Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München Munich, Germany.
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18
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Park B, Prasad S, Yadav V, Sung B, Aggarwal BB. Boswellic acid suppresses growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model through modulation of multiple targets. PLoS One 2011; 6:e26943. [PMID: 22066019 PMCID: PMC3204996 DOI: 10.1371/journal.pone.0026943] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Accepted: 10/06/2011] [Indexed: 01/30/2023] Open
Abstract
Pancreatic cancer (PaCa) is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA), an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation). These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg) significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets.
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Affiliation(s)
- Byoungduck Park
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Sahdeo Prasad
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Vivek Yadav
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Bokyung Sung
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Bharat B. Aggarwal
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- * E-mail:
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Ansari D, Rosendahl A, Elebro J, Andersson R. Systematic review of immunohistochemical biomarkers to identify prognostic subgroups of patients with pancreatic cancer. Br J Surg 2011; 98:1041-55. [PMID: 21644238 DOI: 10.1002/bjs.7574] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis. There is a need to identify prognostic subtypes of PDAC to predict clinical and therapeutic outcomes accurately, and define novel therapeutic targets. The purpose of this review was to provide a systematic summary and review of available data on immunohistochemical (IHC) prognostic and predictive markers in patients with PDAC. METHODS Relevant articles in English published between January 1990 and June 2010 were obtained from PubMed searches. Other articles identified from cross-checking references and additional sources were reviewed. The inclusion was limited to studies evaluating IHC markers in a multivariable setting. RESULTS Database searches identified 76 independent prognostic and predictive molecular markers implicated in pancreatic tumour growth, apoptosis, angiogenesis, invasion and resistance to chemotherapy. Of these, 11 markers (Ki-67, p27, p53, transforming growth factor β1, Bcl-2, survivin, vascular endothelial growth factor, cyclo-oxygenase 2, CD34, S100A4 and human equilibrative nucleoside transporter 1) provided independent prognostic or predictive information in two or more separate studies. CONCLUSION None of the molecular markers described can be recommended for routine clinical use as they were identified in small cohorts and there were inconsistencies between studies. Their prognostic and predictive values need to be validated further in prospective multicentre studies in larger patient populations. A panel of molecular markers may become useful in predicting individual patient outcome and directing novel types of intervention.
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Affiliation(s)
- D Ansari
- Department of Surgery, Lund University and Skåne University Hospital Lund, Lund, Sweden
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EGCG downregulates IL-1RI expression and suppresses IL-1-induced tumorigenic factors in human pancreatic adenocarcinoma cells. Biochem Pharmacol 2011; 82:1153-62. [PMID: 21787753 DOI: 10.1016/j.bcp.2011.07.063] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 07/07/2011] [Accepted: 07/08/2011] [Indexed: 11/20/2022]
Abstract
Human pancreatic cancer is currently one of the fifth-leading causes of cancer-related mortality with a 5-year survival rate of less than 5%. Since pancreatic carcinoma is largely refractory to conventional therapies, there is a strong medical need for the development of novel and innovative therapeutic strategies. Increasing evidence suggests an association of carcinogenesis and chronic inflammation. Because IL-1 plays a crucial role in inflammation-associated carcinogenesis, we analyzed the biological effects of IL-1 and its modulation by the chemopreventive green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in the human pancreatic adenocarcinoma cell line Colo357. Proinflammatory IL-6 and PGHS-2 as well as proangiogenic IL-8 and VEGF were induced by IL-1, whereas the secretion of invasion-promoting MMP-2 remained unaffected. IL-1 responsiveness and constitutive MMP-2 release in Colo357 were downregulated by EGCG in a dose- and time-dependent manner. Moreover, EGCG reduced cell viability via induction of apoptosis in Colo357. Since EGCG effects on cytokine production precede reduction in cell viability, we hypothesize that these findings are not only a result of cell death but also depend on alterations in the IL-1 signaling cascade. In this context, we found for the first time an EGCG-induced downregulation of the IL-1RI expression possibly being caused by NF-κB inhibition and causative for its inhibitory action on the production of tumorigenic factors. Thus, our data might have future clinical implications with respect to the development of novel approaches as an adjuvant therapy in high-risk patients with human pancreatic carcinoma.
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Takahashi M, Hori M, Mutoh M, Wakabayashi K, Nakagama H. Experimental animal models of pancreatic carcinogenesis for prevention studies and their relevance to human disease. Cancers (Basel) 2011; 3:582-602. [PMID: 24212630 PMCID: PMC3756378 DOI: 10.3390/cancers3010582] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 12/29/2010] [Accepted: 01/26/2011] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer is difficult to cure, so its prevention is very important. For this purpose, animal model studies are necessary to develop effective methods. Injection of N-nitrosobis(2-oxopropyl)amine (BOP) into Syrian golden hamsters is known to induce pancreatic ductal adenocarcinomas, the histology of which is similar to human tumors. Moreover, K-ras activation by point mutations and p16 inactivation by aberrant methylation of 5' CpG islands or by homozygous deletions have been frequently observed in common in both the hamster and humans. Thus, this chemical carcinogenesis model has an advantage of histopathological and genetic similarity to human pancreatic cancer, and it is useful to study promotive and suppressive factors. Syrian golden hamsters are in a hyperlipidemic state even under normal dietary conditions, and a ligand of peroxizome proliferator-activated receptor gamma was found to improve the hyperlipidemia and suppress pancreatic carcinogenesis. Chronic inflammation is a known important risk factor, and selective inhibitors of inducible nitric oxide synthase and cyclooxygenase-2 also have protective effects against pancreatic cancer development. Anti-inflammatory and anti-hyperlipidemic agents can thus be considered candidate chemopreventive agents deserving more attention.
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Affiliation(s)
- Mami Takahashi
- Division of Cancer Development System, Carcinogenesis Research Group, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan; E-Mails: (M.H.); (M.M.); (H.N.)
| | - Mika Hori
- Division of Cancer Development System, Carcinogenesis Research Group, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan; E-Mails: (M.H.); (M.M.); (H.N.)
| | - Michihiro Mutoh
- Division of Cancer Development System, Carcinogenesis Research Group, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan; E-Mails: (M.H.); (M.M.); (H.N.)
| | - Keiji Wakabayashi
- Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Yada 52-1, Suruga-ku, Shizuoka 422-8526, Japan; E-Mail:
| | - Hitoshi Nakagama
- Division of Cancer Development System, Carcinogenesis Research Group, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan; E-Mails: (M.H.); (M.M.); (H.N.)
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Abstract
Myocarditis is one of the most commonly cardiovascular diseases in clinical practice, but the treatment is always limited at present. Considering the multifactorial etiology of myocarditis, a novel therapeutic agent with multi-bioactivties should be presented. Red wine has been recognized as a favorable natural medicine against a large number of pathologic conditions. Recent results indicate that red wine could effectively decrease inflammatory factors secretion, reduce the migration of neutrophils, antagonize oxidation, and regulate immunity. By these bioactivities of anti-inflammation, anti-oxidation, and immunomodulation, red wine may be an effective therapeutic candidate to manage the symptoms and prevent the recurrence of myocarditis.
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Affiliation(s)
- Chun-Juan Chen
- Department of Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Peoples' Republic of China
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Nakagawa SA, Lopes A, Lopes de Carvalho A, Rossi BM, Werneck da Cunha I, Soares FA, Chung WT, Alves LA. Nitric oxide synthases, cyclooxygenase-2, nitrotyrosine, and angiogenesis in chondrosarcoma and their relation to prognosis. J Bone Joint Surg Am 2010; 92:1738-46. [PMID: 20660237 DOI: 10.2106/jbjs.h.00717] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND The localization in tumor tissue of various markers by immunohistochemistry can help to establish a diagnosis or predict prognosis. Nitric oxide is associated with tumors and has been studied indirectly by nitrotyrosine analysis and with use of the enzymes nitric oxide synthase (NOS)1, NOS2, and NOS3. Nitric oxide reacts with superoxide anions to yield peroxynitrite, which has toxic effects on genes. Peroxynitrite adds a nitro group to the benzene ring of tyrosine to form nitrotyrosine. The accumulation of nitrotyrosine, a stable product in cells, indicates the formation of peroxynitrite. Nitric oxide stimulates the production of cyclooxygenase-2 (COX-2), which has been associated with angiogenesis in tumors. Neovascularization influences tumor prognosis, as demonstrated by microvessel studies with use of CD34, an immunohistochemical endothelial cell marker. This study examines the expression of these markers in chondrosarcomas and their relation to histological grade and prognosis. METHODS Tissue microarrays composed of formalin-fixed tissue samples from 101 patients with chondrosarcoma were immunohistochemically stained to localize NOS1, NOS2, NOS3, COX-2, nitrotyrosine, and CD34. Five samples of normal cartilage were used as controls. Patient demographics, selected surgical variables, and tumor grade were tabulated, and the associations were analyzed. Analyses of local and overall survival rates were performed with use of the Kaplan-Meier method, and multivariable analyses were performed. RESULTS There was a significant association of nitrotyrosine, COX-2, and CD34 with histological grades (p = 0.022, p = 0.014, and p = 0.028, respectively), but not with overall prognosis (p = 0.064, p = 0.143, and p = 0.581, respectively). The presence of NOS2 was associated with a lower rate of local disease-free survival (p = 0.038), and positive expressions of NOS1 and NOS2 were associated with decreased overall survival rates (p = 0.007 and p < 0.001, respectively). On multivariable analysis, NOS2 expression demonstrated an independent prognostic impact on local disease-free survival; NOS1 and NOS2 expression was a dependent variable, and their isolated or combined expression was related to lower overall survival rates (p = 0.046 and p = 0.004) (hazard ratio, 3.17 [95% confidence interval, 1.0 to 9.8] and 5.58 [95% confidence interval, 1.7 to 18.0], respectively). CONCLUSIONS Immunohistochemical markers may have an independent value in predicting the prognosis for patients with chondrosarcoma.
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Affiliation(s)
- Suely Akiko Nakagawa
- Departamentos de Cirurgia Pélvica-Ortopedia, Hospital A.C. Camargo, Rua Prof. Antonio Prudente, 211, São Paulo - S. P., CEP 01509-010, Brazil.
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24
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Choi IY, Kim SJ, Kim MC, Kim HL, Shin HJ, Kang TH, Jeong HJ, Shim JS, Kim JH, Yang DC, Hong SH, Kim HM, Um JY. Inhibitory effects of the transgenicPanax ginsengson phorbol ester plus A23187-induced IL-6 production and cyclooxygenase-2 via suppression of NF-κB and MAPKs in HMC-1. Immunopharmacol Immunotoxicol 2010; 33:205-10. [DOI: 10.3109/08923973.2010.496459] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Hermanova M, Karasek P, Tomasek J, Lenz J, Jarkovsky J, Dite P. Comparative analysis of clinicopathological correlations of cyclooxygenase-2 expression in resectable pancreatic cancer. World J Gastroenterol 2010; 16:1879-84. [PMID: 20397266 PMCID: PMC2856829 DOI: 10.3748/wjg.v16.i15.1879] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To perform a comparative analysis of clinicopathological correlations of cyclooxygenase-2 (COX-2) expression in pancreatic cancer, examined by monoclonal and polyclonal antibodies.
METHODS: The COX-2 expression in 85 resection specimens of pancreatic ductal adenocarcinoma was immunohistochemically examined using both monoclonal and polyclonal antibodies. The final immunoscores were obtained by multiplying the percentage of positive cells with the numeric score reflecting the staining intensity. COX-2 expression levels were classified into three categories (0, 1+, and 2+) and the clinicopathological correlations were statistically evaluated and analyzed.
RESULTS: The positive tumor expression rates of COX-2 were 80.5% using monoclonal antibody and 69.4% using polyclonal antibody. In the Kaplan-Meier analysis, no significant correlations were found between levels of COX-2 expression and overall survival (OS), but trends to longer OS were found in COX-2 negative cases using monoclonal antibody. Significantly longer disease free survival was revealed in COX-2 negative cases using monoclonal antibody (P = 0.019). No correlations between COX-2 expression levels and grade (G), tumor (T) status and nodal (N) status were demonstrated. Low histological grade showed a strong association with a longer OS (P < 0.001). Correlation of survival and T status revealed a shorter OS in T3 tumors, but the results reached only marginal statistical significance (P = 0.070). In the multivariate Cox proportional hazards regression model, histological grade, T and N status remained valuable predictors of a worse survival with borderline significance for T [hazards ratio (HR) = 4.18 for G (if G = 3, P < 0.001); HR = 1.64 for T (if T = 3, P = 0.065); HR = 2.53 for N (if N = 1, P = 0.006)]. Higher grade, T or N status was associated with a worse OS.
CONCLUSION: The immunohistochemically assessed level of COX-2 expression does not seem to represent a valuable independent prognostic factor and is not superior to the conventional prognostic factors.
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Zafirellis K, Zachaki A, Agrogiannis G, Gravani K. Inducible nitric oxide synthase expression and its prognostic significance in colorectal cancer. APMIS 2010; 118:115-24. [PMID: 20132175 DOI: 10.1111/j.1600-0463.2009.02569.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Nitric oxide synthases (NOS) are expressed in colorectal cancer. The aim of this study was to examine the inducible NOS (iNOS) expression in colorectal cancer and to investigate its prognostic relevance. Tissue sections of primary tumors from 132 patients undergoing curative resection for colorectal cancer were immunohistochemically examined for iNOS expression. The expression pattern of iNOS was correlated with various clinicopathological characteristics and survival. iNOS immunoreactivity was observed in the cytoplasm of tumor epithelial cells in 60 patients (45.5%) and positively correlated with lymph node involvement (p = 0.019). No significant correlation was found between iNOS expression and various clinicopathological characteristics, including age, gender, tumor location, tumor size, tumor grade, T stage, and Union International Contra la Cancrum (UICC) stage. Survival analysis showed a significant correlation between iNOS-positive tumors and poor disease-specific survival (p < 0.0001), with independent prognostic significance in multivariate analysis (HR = 4.42; p < 0.0001). Patients with stage II disease and iNOS-positive tumors had significantly worse disease-specific survival than those with iNOS-negative tumors (p < 0.0001). In addition, patients with stage III disease and iNOS-positive tumors had significantly worse disease-specific survival than those with iNOS-negative tumors (p = 0.001). The ability of iNOS to predict outcome in colorectal cancer patients may be independent of other known prognostic factors, providing a new molecular marker with significant potential for clinical utility.
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Kim JJ, Kang TH, Seo JU, Na HJ, Kim SJ, Moon PD, Kim NH, Choi IY, Myung NY, Hong SH, Kim SH, Kim YA, Seo YW, Kim MH, Park JH, Kang IC, Um JY, Kim HM, Jeong HJ. Libanoridin inhibits the mast cell-mediated allergic inflammatory reaction. Immunopharmacol Immunotoxicol 2010; 32:258-64. [DOI: 10.3109/08923970903279991] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Jae-Joong Kim
- Cancer Preventive Material Development Research Center, Department of Pharmacology, Institute of Oriental Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
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Clinicopathological correlations of cyclooxygenase-2, MDM2, and p53 expressions in surgically resectable pancreatic invasive ductal adenocarcinoma. Pancreas 2009; 38:565-71. [PMID: 19346994 DOI: 10.1097/mpa.0b013e31819fef8b] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVES Cyclooxygenase-2 (COX-2) and p53 represent molecules linked to oncogenesis of pancreatic cancer, and there is also a known regulatory loop between mouse double minute 2 (MDM2) and p53. The complex cross talks between p53 and COX-2 and scenarios explaining patterns of p53 and COX-2 expressions in precursor and cancer lesions have been recently reported. METHODS The expressions of COX-2, p53, and MDM2 were examined using immunohistochemistry in 85 resection specimens of pancreatic ductal adenocarcinoma. RESULTS The positive tumor expression rates of COX-2, p53, and MDM2 were 69.4%, 60.0%, and 41.2%, respectively. Significant correlations between COX-2 and p53 expressions and between p53 and MDM2 expressions were revealed. In the Kaplan-Meier analysis, no statistically significant correlations were found among the levels of COX-2, p53, and MDM2 expressions and survival rates. In the multivariate Cox proportional hazards regression model, grade and nodal status showed to be a valuable predictor of a worse overall survival. CONCLUSIONS The reported findings confirmed the relationship of p53, MDM2, and COX-2 with the biological process of pancreatic cancer. The expression of none of the examined proteins showed to be a valuable independent prognostic factor. On the contrary, grade and nodal status showed to be a valuable predictor of a worse survival.
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Wang CH, Zheng WB, Qiang O, Tang CW. Effects of non-cytotoxic drugs on the growth of multidrug-resistance human gastric carcinoma cell line. J Dig Dis 2009; 10:91-8. [PMID: 19426390 DOI: 10.1111/j.1751-2980.2009.00370.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the effects of the non-cytotoxic drug (cyclooxygenase-2 (COX-2) inhibitor and octreotide) on growth of the multidrug-resistant human gastric carcinoma cell line SGC-7901/ADR. METHODS The effects of non-cytotoxic drug on the growth of SGC-7901 and SGC-7901/ADR cells were evaluated by (3)H-thymidine incorporation assay. The apoptosis of cells was measured by the TdT-mediated dUTP nick end-labeling assay (TUNEL) and flow cytometric assay. Western blotting was used to analysis the expression of cyclooxygenase (COX-2) protein in SGC-7901 cells and SGC-7901/ADR cells and P-glycoprotein (P-gp) from SGC-7901/ADR cells with variable treatments. Activator protein-1 binding activity was examined by electrophoretic mobility shift assay. RESULTS (3)H-thymidine incorporation into SGC-7901/ADR cells treated with celecoxib was significantly lower than that of control group (471.3 +/- 79.7 cpm vs 917.5 +/- 130.8 cpm, P < 0.05). When combined with octreotide, celecoxib presented lower (3)H-thymidine incorporations than its used alone and decreased to 53.3% of that amount original. Either celecoxib or the combination group markedly induced apoptosis in SGC-7901/ADR cells. COX-2 protein in the SGC-7901/ADR cells was higher than in that of the SGC-7901 cells (1.543 +/- 0.052 vs 0.564 +/- 0.021, P < 0.05). The inhibition of P-gp could be achieved with celecoxib alone and combination with octreotide (0.486 +/- 0.012, 0.252 +/- 0.014 vs 0.941 +/- 0.033, P < 0.05). Moreover, AP-1 binding activity could be suppressed by non-cytotoxic drug and showed a synergistic effect. CONCLUSION The combination of non-cytotoxic drug significantly improved the inhibitive effects on the growth of multidrug-resistant human gastric cancer cells.
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Affiliation(s)
- Chun Hui Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Sichuan Province, China
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Heller A. Apoptosis-inducing high (.)NO concentrations are not sustained either in nascent or in developed cancers. ChemMedChem 2009; 3:1493-9. [PMID: 18759245 DOI: 10.1002/cmdc.200800257] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Nitric oxide ((.)NO) induces apoptosis at high concentrations by S-nitrosating proteins such as glyceraldehyde-3-phosphate dehydrogenase. This literature analysis revealed that failure to sustain high (.)NO concentrations is common to all cancers. In cervical, gastric, colorectal, breast, and lung cancer, the cause of this failure is the inadequate expression of inducible nitric oxide synthase (iNOS), resulting from the inhibition of iNOS expression by TGF-beta1 at the mRNA level. In bladder, renal, and prostate cancer, the reason for the insufficient (.)NO levels is the depletion of arginine, resulting from arginase overexpression. Arginase competes with iNOS for arginine, catalyzing its hydrolysis to ornithine and urea. In gliomas and ovarian sarcomas, low (.)NO levels are caused by inhibition of iNOS by N-chlorotaurine, produced by infiltrating neutrophils. Stimulated neutrophils express myeloperoxidase, catalyzing H2O2 oxidation of Cl- to HOCl, which N-chlorinates taurine at its concentration of 19 mM in neutrophils. In squamous cell carcinomas of the skin, ovarian cancers, lymphomas, Hodgkin's disease, and breast cancers, low (.)NO concentrations arise from the inhibition of iNOS by N-bromotaurine, produced by eosinophil-peroxidase-expressing infiltrating eosinophils. Eosinophil peroxidase catalyzes the H2O2 oxidation of Br- to HOBr, which N-brominates taurine to N-bromotaurine at its concentration of 15 mM in eosinophils. In microvascularized tumors, the (.)NO concentration is further depleted; (.)NO is rapidly consumed by red blood cells (RBCs) through S-nitrosation of RBC glutathione and hemoglobin, and by oxidation to nitrate by RBC oxyhemoglobin. Angiogenesis-inhibiting antibodies are currently used to treat cancers; their mode of action is not, as previously thought, reduction of the tumor O2 or nutrient supply. They actually decrease the loss of (.)NO to RBCs.
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Affiliation(s)
- Adam Heller
- Department of Chemical Engineering, University of Texas, Austin, TX 78712, USA.
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Jeong HJ, Na HJ, Kim SJ, Rim HK, Myung NY, Moon PD, Han NR, Seo JU, Kang TH, Kim JJ, Choi Y, Kang IC, Hong SH, Kim YA, Seo YW, Kim HM, Um JY. Anti-inflammatory Effect of Columbianetin on Activated Human Mast Cells. Biol Pharm Bull 2009; 32:1027-31. [DOI: 10.1248/bpb.32.1027] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
| | - Ho-Jeong Na
- Department of Pharmacology, College of Oriental Medicine, Institute of Oriental Medicine, Kyung Hee University
| | - Su-Jin Kim
- Department of Pharmacology, College of Oriental Medicine, Institute of Oriental Medicine, Kyung Hee University
- College of Pharmacy, VCRC of Wonkwang University
| | - Hong-Kun Rim
- Department of Pharmacology, College of Oriental Medicine, Institute of Oriental Medicine, Kyung Hee University
| | - Noh-Yil Myung
- Department of Pharmacology, College of Oriental Medicine, Institute of Oriental Medicine, Kyung Hee University
| | - Phil-Dong Moon
- Oriental Medical Science Center, College of Oriental Medicine, Kyung Hee University
| | - Na-Ra Han
- Oriental Medical Science Center, College of Oriental Medicine, Kyung Hee University
| | - Jae-Uk Seo
- Cancer Preventive Material Development Research Center, Department of Pharmacology, Institute of Oriental Medicine, College of Oriental Medicine, Kyung Hee University
| | - Tae-Hee Kang
- Cancer Preventive Material Development Research Center, Department of Pharmacology, Institute of Oriental Medicine, College of Oriental Medicine, Kyung Hee University
| | - Jae-Joong Kim
- Cancer Preventive Material Development Research Center, Department of Pharmacology, Institute of Oriental Medicine, College of Oriental Medicine, Kyung Hee University
| | | | | | | | - You-Ah Kim
- Division of Marine Environment & Bioscience, Korea Maritime University
| | - Young-Wan Seo
- Division of Marine Environment & Bioscience, Korea Maritime University
| | - Hyung-Min Kim
- Department of Pharmacology, College of Oriental Medicine, Institute of Oriental Medicine, Kyung Hee University
| | - Jae-Young Um
- Department of Pharmacology, College of Oriental Medicine, Institute of Oriental Medicine, Kyung Hee University
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Feo F, Frau M, Pascale RM. Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis. World J Gastroenterol 2008; 14:6601-15. [PMID: 19034960 PMCID: PMC2773299 DOI: 10.3748/wjg.14.6601] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma (HCC). Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway (BN) rats. Unrestrained extracellular signal-regulated kinase (ERK) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (DUSP1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-κB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-α transgenic mice. iNOS, IKK/NF-κB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.
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Expression of COX-2 is associated with accumulation of p53 in pancreatic cancer: analysis of COX-2 and p53 expression in premalignant and malignant ductal pancreatic lesions. Eur J Gastroenterol Hepatol 2008; 20:732-9. [PMID: 18617777 DOI: 10.1097/meg.0b013e3282f945fb] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Cyclooxygenase-2 (COX-2) and tumor suppressor p53 are molecules that are linked to the oncogenesis of pancreatic cancer. COX-2 represents a key modulatory molecule in inflammation and carcinogenesis, and is known to be implicated in the positive regulation of growth and tumorigenesis. Abnormal expression of p53 is common in many human neoplasms including pancreatic cancer. Recent studies demonstrated functional interactions between p53 and COX-2. The p53-dependent upregulation of COX-2 was proposed to be another mechanism by which p53 could abate its own growth-inhibitory and apoptotic effects. METHODS In this study, we immunohistochemically analyzed the expression of COX-2 and p53 in 95 pancreatic resection specimens [adenocarcinomas, 95 lesions; pancreatic intraepithelial neoplasias (PanINs), 155; normal ducts, 70]. RESULTS The expression of COX-2 increased progressively with the grade of ductal lesions (P<0.00001). A statistically significant difference of COX-2 expression between normal ducts and low-grade PanINs was revealed (P=0.0042). COX-2 overexpression was demonstrated in 82 PanINs (52.9%), and in 76 adenocarcinomas (80%). No significant correlation between the grade of adenocarcinoma and COX-2 expression was revealed (P=0.2). The expression of p53 again increased progressively with the grade of lesions (P<0.00001) with a significant increase in high-grade PanINs. A correlation between COX-2 and p53 expression levels in carcinomas was revealed (P=0.0002), and an accumulation of p53 was associated with COX-2 overexpression in premalignant and malignant ductal lesions. CONCLUSION These findings confirmed the generally accepted pancreatic cancer progression model, and supported the concept of the interactive role of COX-2 and p53 in pancreatic cancer carcinogenesis, which offers opportunities for targeted therapy and chemoprevention of pancreatic cancer using COX-2 inhibitors.
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Calvisi DF, Pinna F, Ladu S, Pellegrino R, Muroni MR, Simile MM, Frau M, Tomasi ML, De Miglio MR, Seddaiu MA, Daino L, Sanna V, Feo F, Pascale RM. Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease. Carcinogenesis 2008; 29:1639-47. [DOI: 10.1093/carcin/bgn155] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Takahashi M, Kitahashi T, Ishigamori R, Mutoh M, Komiya M, Sato H, Kamanaka Y, Naka M, Maruyama T, Sugimura T, Wakabayashi K. Increased expression of inducible nitric oxide synthase (iNOS) in N-nitrosobis(2-oxopropyl)amine-induced hamster pancreatic carcinogenesis and prevention of cancer development by ONO-1714, an iNOS inhibitor. Carcinogenesis 2008; 29:1608-13. [PMID: 18567618 DOI: 10.1093/carcin/bgn152] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Elevated protein expression of inducible nitric oxide synthase (iNOS) has been observed in human pancreatic cancers and therefore, iNOS may play important roles in pancreatic carcinogenesis. This was examined in the present study, using an experimental model with N-nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters. Reverse transcription-polymerase chain reaction analysis demonstrated iNOS expression in a hamster pancreatic cancer cell line as well as in human pancreatic cancer cell lines. Immunohistochemical analysis revealed increased expression of iNOS protein in atypical hyperplasia and ductal adenocarcinomas of the pancreas in BOP-treated hamsters. In addition, iNOS expression was also observed in macrophages and islet cells in pancreatic tissue surrounding tumors. In order to assess the role of iNOS expression in carcinogenesis in the pancreas, the effects of ONO-1714 [(1S, 5S, 6R, 7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane], an iNOS inhibitor, on hamster pancreatic ductal carcinogenesis were investigated. Female Syrian golden hamsters were treated with BOP at 10 mg/kg body wt, four times for 1 week, and 1 week after the last carcinogen treatment, ONO-1714 was administered at doses of 100 and 200 p.p.m. in the diet for 15 weeks. The incidences and multiplicities of atypical hyperplasia and invasive adenocarcinoma and total adenocarcinomas (non-invasive and invasive adenocarcinomas) in the pancreas were significantly lowered by treatment with 200 p.p.m. ONO-1714. Treatment with 100 p.p.m. ONO-1714 also significantly decreased the multiplicities of invasive and total adenocarcinomas. Moreover, treatment with 200 p.p.m. ONO-1714 reduced the number of BOP-induced cholangiocellular tumors. These results suggest that iNOS plays roles in promoting pancreatic carcinogenesis in both early and late stages in hamsters.
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Affiliation(s)
- Mami Takahashi
- Cancer Prevention Basic Research Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
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Vissers YLJ, Debats IBJG, Luiking YC, Jalan R, van der Hulst RRWJ, Dejong CHC, Deutz NEP. Pros and cons of L-arginine supplementation in disease. Nutr Res Rev 2007; 17:193-210. [DOI: 10.1079/nrr200490] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The amino acid arginine and one of its metabolites NO have gathered broad attention in the last decade. Although arginine is regarded as a conditionally essential amino acid in disease, L-arginine supplementation in severe illness has not found its way into clinical practice. This might be due to the invalid interpretation of results from studies with immune-enhancing diets containing L-arginine amongst other pharmaconutrients. However, not much attention is given to research using L-arginine as a monotherapy and the possibility of the alternative hypothesis: that L-arginine supplementation is beneficial in disease. The present review will discuss data from studies in healthy and diseased animals and patients with monotherapy of L-arginine to come to an objective overview of positive and negative aspects of L-arginine supplementation in disease with special emphasis on sepsis, cancer, liver failure and wound healing.
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37
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Capurso G, Schünemann HJ, Terrenato I, Moretti A, Koch M, Muti P, Capurso L, Delle Fave G. Meta-analysis: the use of non-steroidal anti-inflammatory drugs and pancreatic cancer risk for different exposure categories. Aliment Pharmacol Ther 2007; 26:1089-99. [PMID: 17894651 DOI: 10.1111/j.1365-2036.2007.03495.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND A better understanding of predictors of risk for pancreatic ductal adenocarcinoma (PDAC) could inform preventive efforts against this lethal cancer. While aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDS) might protect against several gastrointestinal cancers, their role in the development of PDAC remains unclear. AIM To conduct a systematic review and meta-analysis on the relation between ASA/NSAIDs exposure and the risk of PDAC. Methods We searched Pubmed, Embase, Scopus, Cochrane database of systematic reviews and reference lists of identified papers and included observational (cohort or case-control) studies and randomized controlled trials examining exposure to ASA and/or NSAIDs and the incidence or mortality of PDAC. We defined three categories (low, intermediate, high), based on exposure duration and dose. RESULTS Eight studies fulfilled our inclusion criteria (four cohort, three case controls, and one randomized controlled trial studies) enrolling 6301 patients between 1971-2004; all but one study took place in the US. The pooled OR were 0.99 (0.83-1.19), 1.11 (0.84-1.47) and 1.09 (0.67-1.75) in the low, intermediate and high exposure groups respectively, with considerable heterogeneity (I(2) ranging 60-86%). Sensitivity analysis by ASA use only, study design or sex did not reveal additional important information. CONCLUSIONS This study did not show an association between ASA/NSAIDs and PDAC. The large baseline exposure in controls in North-America may have obscured an association. There is need for additional studies, especially in Europe, to clarify this issue.
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Affiliation(s)
- G Capurso
- Digestive and Liver Disease Unit, II Medical School, University La Sapienza, Rome, Italy
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Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 2007; 67:3853-61. [PMID: 17440100 DOI: 10.1158/0008-5472.can-06-4257] [Citation(s) in RCA: 436] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Gemcitabine is currently the best treatment available for pancreatic cancer, but the disease develops resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Curcumin, a component of turmeric (Curcuma longa), is one such agent that has been shown to suppress the transcription factor nuclear factor-kappaB (NF-kappaB), which is implicated in proliferation, survival, angiogenesis, and chemoresistance. In this study, we investigated whether curcumin can sensitize pancreatic cancer to gemcitabine in vitro and in vivo. In vitro, curcumin inhibited the proliferation of various pancreatic cancer cell lines, potentiated the apoptosis induced by gemcitabine, and inhibited constitutive NF-kappaB activation in the cells. In vivo, tumors from nude mice injected with pancreatic cancer cells and treated with a combination of curcumin and gemcitabine showed significant reductions in volume (P = 0.008 versus control; P = 0.036 versus gemcitabine alone), Ki-67 proliferation index (P = 0.030 versus control), NF-kappaB activation, and expression of NF-kappaB-regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase, and vascular endothelial growth factor) compared with tumors from control mice treated with olive oil only. The combination treatment was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31(+) microvessel density (P = 0.018 versus control). Overall, our results suggest that curcumin potentiates the antitumor effects of gemcitabine in pancreatic cancer by suppressing proliferation, angiogenesis, NF-kappaB, and NF-kappaB-regulated gene products.
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Affiliation(s)
- Ajaikumar B Kunnumakkara
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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Aho U, Zhao X, Löhr M, Andersson R. Molecular mechanisms of pancreatic cancer and potential targets of treatment. Scand J Gastroenterol 2007; 42:279-96. [PMID: 17354106 DOI: 10.1080/00365520601106384] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Ursula Aho
- Department of Surgery, Lund University Hospital, University of Lund, Lund, Sweden
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Crowell PL, Schmidt CM, Yip-Schneider MT, Savage JJ, Hertzler DA, Cummings WO. Cyclooxygenase-2 expression in hamster and human pancreatic neoplasia. Neoplasia 2006; 8:437-45. [PMID: 16820089 PMCID: PMC1601471 DOI: 10.1593/neo.04700] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cyclooxygenase-2 (COX-2) has been implicated in the development of gastrointestinal malignancies. The aim of the present study was to determine COX-2 expression/activity throughout stages of experimental and human pancreatic neoplasia. COX-2 immunohistochemistry was performed in pancreata of hamsters subjected to the carcinogen N-nitrosobis-(2-oxopropyl)amine (BOP) and in human pancreatic tumors. COX-2 activity was determined by prostaglandin E2 assay in tumor versus matched normal pancreatic tissues. The activity of the COX inhibitor sulindac was tested in the PC-1 hamster pancreatic cancer model. COX-2 expression was elevated in all pancreatic intraepithelial neoplasias (PanINs) and adenocarcinomas. In BOP-treated hamsters, there were significant progressive elevations in COX-2 expression throughout pancreatic tumorigenesis. In human samples, peak COX-2 expression occurred in PanIN2 lesions and remained moderately elevated in PanIN3 and adenocarcinoma tissues. COX-2 activity was significantly elevated in hamster and human pancreatic cancers compared to pair-matched normal pancreas. Furthermore, hamster pancreatic tumor engraftment/formation in the PC-1 hamster pancreatic cancer model was reduced 4.9-fold by oral administration of sulindac. Increased COX-2 expression is an early event in pancreatic carcinogeneses. The BOP-induced hamster carcinogenesis model is a representative model used to study the role of COX-2 in well-differentiated pancreatic tumorigenesis. COX inhibitors may have a role in preventing tumor engraftment/formation.
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Affiliation(s)
- Pamela L Crowell
- Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
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Juuti A, Louhimo J, Nordling S, Ristimäki A, Haglund C. Cyclooxygenase-2 expression correlates with poor prognosis in pancreatic cancer. J Clin Pathol 2006; 59:382-6. [PMID: 16467169 PMCID: PMC1860358 DOI: 10.1136/jcp.2005.026831] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cyclooxygenase-2 (COX-2) overexpression is related to poor outcome in several cancers. COX-2 is upregulated in 42-90% of pancreatic ductal adenocarcinomas and is a potential target for chemotherapy. Earlier studies have not shown the expression of COX-2 to be a prognostic factor in pancreatic cancer. OBJECTIVE To evaluate the prognostic value of COX-2 in a series of patients with pancreatic adenocarcinoma. METHODS 128 patients operated on for pancreatic adenocarcinoma at Helsinki University Central Hospital between 1974 and 1998 provided sections from primary tumours which were immunohistochemically stained with a COX-2-antihuman monoclonal antibody. RESULTS Cytoplasmic COX-2 reactivity (>5%) occurred in 46 specimens (36%), correlating neither with age, sex, stage, size, tumour stage, nodal metastases, nor grade. Lack of COX-2 expression correlated with distant metastases (p = 0.026). In univariate survival analysis, COX-2 expression (p = 0.0114), stage (p = 0.0002), grade (p = 0.0001), and age (p = 0.042) had prognostic significance. One, two, and five year survival rates were 51%, 32%, and 8% in the COX-2 negative groups compared with 34%, 5%, and 5% in the COX-2 positive groups (p = 0.011). Prognostic significance was especially high for patients operated on with curative intent (p = 0.004). In multivariate analysis, COX-2 was an independent prognostic factor (hazard ratio = 1.6 (95% confidence interval, 1.1 to 2.3)). CONCLUSIONS Expression of COX-2 was associated with poor outcome from pancreatic ductal adenocarcinoma and was independent of tumour stage, grade, or age in multivariate analysis.
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Affiliation(s)
- A Juuti
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
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Garcea G, Dennison AR, Steward WP, Berry DP. Role of inflammation in pancreatic carcinogenesis and the implications for future therapy. Pancreatology 2005; 5:514-29. [PMID: 16110250 DOI: 10.1159/000087493] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The link between inflammation and pancreatic cancer has been observed for a number of gastrointestinal neoplasms. This review examines the role of inflammation in pancreatic carcinogenesis and how it can be utilised to develop new therapies against pancreatic cancer. METHODS A literature review of Pubmed, Medline and Web of Science databases was undertaken using the key words, pancreatic cancer, inflammation, inducible nitric oxide, interleukins, pro-inflammatory cytokines, cyclooxygenase-2, NF-kappa B, reactive oxygen species, DNA adducts, lipoxygenases, chemoprevention. RESULTS Epidemiological evidence and molecular studies both in vitro and in vivo all support the hypothesis that inflammation plays an important in the initiation and progression of pancreatic tumours. CONCLUSION Sustained damage caused by chronic inflammation may precede the onset of frank malignancy by a significant interval. As such, suppression of inflammatory changes and oxidative damage, may help delay or even prevent the inception of pancreatic neoplasia.
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Affiliation(s)
- G Garcea
- Cancer Studies and Molecular Medicine, Robert Kilpatrick Clinical Sciences Building, The Leicester Royal Infirmary, UK.
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43
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Yuan A, Yu CJ, Shun CT, Luh KT, Kuo SH, Lee YC, Yang PC. Total cyclooxygenase-2 mRNA levels correlate with vascular endothelial growth factor mRNA levels, tumor angiogenesis and prognosis in non-small cell lung cancer patients. Int J Cancer 2005; 115:545-55. [PMID: 15704107 DOI: 10.1002/ijc.20898] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Interaction between cancer cells and adjacent stromal cells is important to promote tumor development. Our aim was to study total COX-2 mRNA expression in both cancer cells and surrounding stromal cells and its association with angiogenic factor VEGF mRNA expression, tumor angiogenesis and prognosis in patients with NSCLC. COX-2 mRNA expression in both cancer cells and stromal tissue was analyzed using real-time quantitative (RTQ) RT-PCR in 60 NSCLC surgical specimens. Immunohistochemistry (IHC) was used to localize COX-2 protein in tumor specimens. Correlations between tumoral total COX-2 mRNA expression and VEGF mRNA expression (measured by RTQ RT-PCR), intratumoral microvessel counts (evaluated by IHC), other clinicopathologic variables, survival and relapse were tested. COX-2 protein expression was found in cancer as well as the surrounding stromal cells (including infiltrating inflammatory cells and endothelial cells of tumor-associated microvessels). VEGF protein expression was mainly located in cancer cells. There was a significant association between high tumoral total COX-2 mRNA expression and high VEGF mRNA expression (p = 0.01) or high intratumoral MVC (p < 0.001) but not other clinicopathologic variables, including tumor status and lymph node metastasis. Patients with higher tumoral total COX-2 mRNA expression had a statistically shorter survival time (median 15.0 +/- 2.61 months) and relapse time (median 5.0 +/- 1.37 months) than those with lower tumoral total COX-2 mRNA expression (median 40.0 +/- 3.12 and 34.0 +/- 3.11 months; p < 0.0001 and p < 0.0001, respectively, log-rank test). A significant difference in survival and relapse time was also seen between patients with high and low tumoral VEGF mRNA expression and between those with high and low intratumoral MVC (p = 0.0046 and p = 0.0038, respectively). After stratification by disease stage or histologic subtype, the prognostic significance of high total COX-2 mRNA expression was still apparent in both stage I and stage II-IV and in both squamous cell carcinoma and adenocarcinoma (p < or = 0.01 for all). Multivariate analysis using the Cox regression model with backward elimination showed that tumoral total COX-2 mRNA expression and lymph node status were the 2 most important independent prognostic predictors for survival and disease relapse. We report that total COX-2 mRNA expression in cancer cells and surrounding stromal cells correlates strongly and positively with VEGF mRNA expression, intratumoral MVC and adverse prognosis in NSCLC patients. This implies that COX-2 expression in both cancer cells and stromal cells within the tumor microenvironment may play an important role in upregulating the expression of the angiogenic factor VEGF and tumor angiogenesis in NSCLC and explains, in part, the adverse prognostic effect of COX-2 overexpression in patients with NSCLC.
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Affiliation(s)
- Ang Yuan
- Division of Chest Medicine, Departments of Internal Medicine and Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Kim SJ, Jeong HJ, Choi IY, Lee KM, Park RK, Hong SH, Kim HM. Cyclooxygenase-2 inhibitor SC-236 [4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1-pyrazol-1-l] benzenesulfonamide] suppresses nuclear factor-kappaB activation and phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and c-Jun N-terminal kinase in human mast cell line cells. J Pharmacol Exp Ther 2005; 314:27-34. [PMID: 15784648 DOI: 10.1124/jpet.104.082792] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
SC-236 [4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1-pyrazol-1-l] benzenesulfonamide; C16H11ClF3N3O2S] is a highly selective cyclooxygenase (COX)-2 inhibitor. However, the exact mechanism that accounts for the anti-inflammatory effect of SC-236 is not completely understood. The aim of the present study was to elucidate whether and how SC-236 modulates the inflammatory reaction in a stimulated human mast cell (HMC) line, HMC-1. SC-236 inhibited the expression of tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, vascular endothelial growth factor, COX-2, inducible nitric-oxide synthase, and hypoxia-inducible factor-1alpha in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated HMC-1. SC-236 suppressed nuclear factor (NF)-kappaB activation induced by PMACI, leading to suppression of IkappaB-alpha phosphorylation and degradation. SC-236 also suppressed strong induction of NF-kappaB promoter-mediated luciferase activity. In addition, SC-236 suppressed PMACI-induced phosphorylation of the mitogen-activated protein kinase p38, the extracellular-regulated kinase p44, and the c-Jun N-terminal kinase and induced expression of mitogen-activated protein kinase phosphatase-1. These results provide new insight into the pharmacological actions of SC-236 as a potential molecule for therapy of mast cell-mediated inflammatory diseases.
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Affiliation(s)
- Su-Jin Kim
- College of Oriental Medicine, Kyung Hee University, Dongdaemun-Gu, Seoul, Republic of Korea
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Bulut AS, Erden E, Sak SD, Doruk H, Kursun N, Dincol D. Significance of inducible nitric oxide synthase expression in benign and malignant breast epithelium: an immunohistochemical study of 151 cases. Virchows Arch 2005; 447:24-30. [PMID: 15947943 DOI: 10.1007/s00428-005-1250-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2004] [Accepted: 03/04/2005] [Indexed: 01/16/2023]
Abstract
The role of calcium independent inducible nitric oxide synthase (iNOS) in breast carcinoma is controversial, and the implications of iNOS expression on prognosis are not known. In this study, we aimed to investigate the significance of immunohistochemical iNOS expression in 100 invasive ductal carcinomas. In addition, 11 normal breast tissues, 20 cases of usual ductal hyperplasias (UDHs) and 20 fibroadenomas were included. We found that 78% of malignant and 75% of benign cases showed iNOS immunoreactivity. However, the intensity and the quantity of iNOS expression were significantly higher in the cancer group when compared with benign breasts (P<0.001), suggesting a role of iNOS in breast carcinogenesis. We were unable to show a correlation between iNOS expression and tumor grade, axillary lymph node status, and estrogen receptor expression. In 50 axilla negative cases having 5--12 years follow-up, disease free survival (DFS) rate was significantly lower in cases showing strong iNOS expression (P=0.05). As strong iNOS expression was correlated with short DFS, we concluded that further studies would be necessary to elucidate if iNOS expression might be a useful prognostic marker in breast carcinoma, especially in the axilla negative group.
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Affiliation(s)
- Asiye Safak Bulut
- Department of Pathology, Medical School of Ankara University, Ankara, Turkey.
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Ali-Fehmi R, Morris RT, Bandyopadhyay S, Che M, Schimp V, Malone JM, Munkarah AR. Expression of cyclooxygenase-2 in advanced stage ovarian serous carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, and survival. Am J Obstet Gynecol 2005; 192:819-25. [PMID: 15746677 DOI: 10.1016/j.ajog.2004.10.587] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
OBJECTIVE Cyclo-oxygenase-2 seems to be involved at various steps in the processes of tumor progression. The objective of this study was to examine the relationship between cyclo-oxygenase-2 expression and tumor proliferation, apoptosis and angiogenesis in patients with advanced stage high-grade ovarian carcinoma. STUDY DESIGN Specimens from 118 patients with high-grade and advanced stage (III, IV) serous ovarian carcinoma were evaluated by immunohistochemistry for cyclo-oxygenase-2, Ki-67, vascular endothelial growth factor, and bcl-2 expression. Tumor microvessel density was assessed with CD34 immunostaining. We investigated the relationships between cyclo-oxygenase-2 expression and clinicopathologic characteristics, tumor angiogenesis (tumor microvessel density and vascular endothelial growth factor expression), and tumor proliferation and apoptosis. The effect of cyclooxygenase-2 expression on patient survival was determined. RESULTS There was a significant positive correlation between cyclo-oxygenase-2 expression in tumor cells and markers of tumor proliferation and angiogenesis. In univariate survival analysis, high cyclo-oxygenase-2 and high Ki-67 expression showed a significant impact of on patient survival (P < .001). In multivariate regression analysis, only Ki-67 expression retained its significance as an independent poor prognostic factor (death hazard ratio, 2.0; 95% CI, 1.2-3.3; P < .001). CONCLUSION Expression of cyclo-oxygenase-2 correlates with tumor proliferation and tumor angiogenesis but not with apoptotic markers (bcl-2 expression) in high-grade, advanced-stage serous ovarian carcinoma.
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Affiliation(s)
- Rouba Ali-Fehmi
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA
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Chen J, Yan Y, Li J, Ma Q, Stoner GD, Ye J, Huang C. Differential requirement of signal pathways for benzo[ a ]pyrene (B[ a ]P)-induced nitric oxide synthase (iNOS) in rat esophageal epithelial cells. Carcinogenesis 2005; 26:1035-43. [PMID: 15718251 DOI: 10.1093/carcin/bgi052] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Overexpression of inducible nitric oxide synthase (iNOS) has been reported in several human cancers, including esophageal squamous cell carcinoma (SCC). Benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon carcinogen found in tobacco smoke and in the environment, induces cancer in multiple organ sites in animals and may be a causative agent for certain human cancers, such as esophageal cancer. In the present study, the effects of B[a]P on the induction of iNOS and the signaling pathways that lead to the induction were investigated in cultured rat esophageal epithelial (RE-149) cells. Treatment of RE-149 cells with B[a]P led to a marked increase in the expression of iNOS. The induction of iNOS by B[a]P was found to occur through an extracellular signal-regulated protein kinases (ERKs)-dependent pathway, since inhibition of ERKs by either pretreatment of RE-149 cells with PD98059, an inhibitor of ERKs upstream kinase MEK1/2, or overexpression of DN-ERK2, blocked the induction of iNOS by B[a]P. Furthermore, impairing nuclear factor-kappaB (NFkappaB) activation by either NEMO-BDBP, an NFkappaB specific inhibitor, or overexpression of DN-IkappaBalpha or IKK-KM markedly inhibited the expression of B[a]P-induced iNOS, suggesting that the NFkappaB pathway is also required for the induction of iNOS by B[a]P. In addition, treatment of RE-149 cells with either SB202190, a p38 kinase inhibitor, or c-JunN-terminal kinase inhibitor II, resulted in an increased induction of iNOS. Pretreatment of RE-149 cells with wortmannin, a PI-3K inhibitor, or with rapamycin, an mTOR/p70S6K pathway inhibitor, had no effect on the expression of iNOS. These results suggest that B[a]P initiates the signaling pathways leading to the induction of iNOS in cultured rat esophageal epithelial cells. In view of the potential role of iNOS in the development of esophageal SCC in humans, we speculate that the induction of iNOS by B[a]P may be one mechanism by which B[a]P could produce carcinogenic effects in the human esophagus.
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Affiliation(s)
- Jingyuan Chen
- Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
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Perfetto B, Buommino E, Canozo N, Paoletti I, Corrado F, Greco R, Donnarumma G. Interferon-gamma cooperates with Helicobacter pylori to induce iNOS-related apoptosis in AGS gastric adenocarcinoma cells. Res Microbiol 2004; 155:259-66. [PMID: 15142623 DOI: 10.1016/j.resmic.2004.01.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2003] [Accepted: 01/16/2004] [Indexed: 12/29/2022]
Abstract
Helicobacter pylori colonizes the human stomach and causes gastric disease. The resulting gastric damage is a multi-step process involving several molecular factors and different target cells. Th1 cytokines released by neutrophils and lymphoid cells that infiltrate gastric mucosa, nitric oxide production and inducible nitric oxide synthase (iNOS) are associated with immune activation and tissue injury. Many other molecular processes such as apoptosis, as well as angiogenic factors and integrins, are involved in H. pylori pathogenesis. We used cancer gastric cells AGS and MKN as experimental models to evaluate apoptotic rates, iNOS gene expression with and without the presence of interferon-gamma (IFN-gamma), placenta growth factor gene expression and alphav modulation. Our results show that AGS cells stimulated with H. pylori underwent apoptosis. Moreover, the addition of IFN-gamma caused a further increase in iNOS gene expression and in the apoptotic rates. We also found early modulation in PlGF and alphav expression, and noted that p53 and bax gene expression was involved in the apoptotic process. Taken together, these findings demonstrate that H. pylori employs a series of mechanisms to avoid the host defense and cause gastric mucosa damage. One H. pylori pathogenic mechanism for causing gastric damage is the induction of iNOS-dependent apoptosis that is strongly enhanced by IFN-gamma. Thus, data obtained indicate that Th1 cytokines such as IFN-gamma, via modulation of iNOS gene expression, may contribute to an increase in the pathogenicity of H. pylori infections.
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Affiliation(s)
- Brunella Perfetto
- Department of Experimental Medicine, Microbiology and Clinical Microbiology Section, Faculty of Medicine and Surgery, Second University of Naples, Via Costantinopoli 16, 80138 Napoli, Italy
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Kasper HU, Wolf H, Drebber U, Wolf HK, Kern MA. Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma: Correlation with microvessel density. World J Gastroenterol 2004; 10:1918-22. [PMID: 15222037 PMCID: PMC4572231 DOI: 10.3748/wjg.v10.i13.1918] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: Cyclooxygenases (COX) are key enzymes for conversion of arachidonic acid to prostaglandins. Nitric oxide synthase (NOS) is the enzyme responsible for formation of nitric oxide. Both have constitutive and inducible isoforms. The inducible isoforms (iNOS and COX-2) are of great interest as regulators of tumor angiogenesis, tumorigenesis and inflammatory processes. This study was to clarify their role in pancreatic adenocarcinomas.
METHODS: We investigated the immunohistochemical iNOS and COX-2 expression in 40 pancreatic ductal adenocarcinomas of different grade and stage. The results were compared with microvessel density and clinicopathological data.
RESULTS: Twenty-one (52.5%) of the cases showed iNOS expression, 15 (37.5%) of the cases were positive for COX-2. The immunoreaction was heterogeneously distributed within the tumors. Staining intensity was different between the tumors. No correlation between iNOS and COX-2 expression was seen. There was no relationship with microvessel density. However, iNOS positive tumors developed more often distant metastases and the more malignant tumors showed a higher COX-2 expression. There was no correlation with other clinicopathological data.
CONCLUSION: Approximately half of the cases expressed iNOS and COX-2. These two enzymes do not seem to be the key step in angiogenesis or carcinogenesis of pancreatic adenocarcinomas. Due to a low prevalence of COX-2 expression, chemoprevention of pancreatic carcinomas by COX-2 inhibitors can only achieve a limited success.
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Affiliation(s)
- Hans-U Kasper
- Department of Pathology, University of Cologne, Joseph-Stelzmann-Strasse 9, D-50931 Koeln, Germany.
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Li HL, Sun BZ, Ma FC. Expression of COX-2, iNOS, p53 and Ki-67 in gastric mucosa-associated lymphoid tissue lymphoma. World J Gastroenterol 2004; 10:1862-6. [PMID: 15222024 PMCID: PMC4572218 DOI: 10.3748/wjg.v10.i13.1862] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To assess the expression of cyclooxygenase-2 (COX-2), nitric oxide synthase (iNOS), p53 and Ki-67 in gastric mucosa-associated lymphoid tissue (MALT) lymphoma and clarify the relationship between COX-2 expression and iNOS or p53 expression in these patients.
METHODS: The expressions of COX-2, iNOS, p53 and Ki-67 were detected in 32 gastric MALT lymphoma specimens and 10 adjacent mucosal specimens by immunohistochemical Envision method.
RESULTS: COX-2 and iNOS expressions were significantly higher in gastric MALT lymphoma tissues than those in adjacent normal tissues. The expression of COX-2 was observed in 22 of 32 cases of MALT lymphoma tissues (68.8%). A positive cytoplasmic immunoreactivity for iNOS was detected in 17 of 31 cases (53.1%). COX-2 expression in gastric MALT lymphoma tissues was positively correlated with iNOS expression (r = 0.448, P = 0.010) and cell proliferative activity analyzed by Ki-67 labeling index (r = 0.410, P = 0.020). The expression of COX-2 protein did not correlate with age, sex, stage of disease, lymph node metastasis or differentiation. The accumulation of p53 nuclear phosphoprotein was detected in 19 (59.4%) of tumors. p53 protein was expressed in 11 of 23 assessed LG tumors and in 8 of 9 assessed HG tumors. The difference of p53 positivity was found statistically significant between LG and HG cases (P = 0.0302). The p53 accumulation correlated with advanced clinical stage (stage III + IV vs stage I + II, P = 0.017). There was a significant positive correlation between COX-2 expression and p53 accumulation status (r = 0.403, P = 0.022). The mean PI of Ki-67 in each grade group were 36.0% ± 7.73% in HG and 27.4% ± 9.21% in LG. High-proliferation rate correlated with HG tumors (r = 0.419, P = 0.017). The correlation coefficient showed a significant positive correlation between PI and COX-2 expression in MALT lymphoma patients (r = 0.410, P = 0.020).
CONCLUSION: COX-2 expresses in the majority of gastric MALT lymphoma tissues and correlates with cellular proliferation and iNOS expression. COX-2 overexpression is closely associated with p53 accumulation status. iNOS and COX-2 may play a synergistic role in the pathogenesis of gastric MALT lymphoma.
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Affiliation(s)
- Hong-Ling Li
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, Shaanxi Province, China.
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