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Kumari S, Sharma S, Advani D, Khosla A, Kumar P, Ambasta RK. Unboxing the molecular modalities of mutagens in cancer. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:62111-62159. [PMID: 34611806 PMCID: PMC8492102 DOI: 10.1007/s11356-021-16726-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 09/22/2021] [Indexed: 04/16/2023]
Abstract
The etiology of the majority of human cancers is associated with a myriad of environmental causes, including physical, chemical, and biological factors. DNA damage induced by such mutagens is the initial step in the process of carcinogenesis resulting in the accumulation of mutations. Mutational events are considered the major triggers for introducing genetic and epigenetic insults such as DNA crosslinks, single- and double-strand DNA breaks, formation of DNA adducts, mismatched bases, modification in histones, DNA methylation, and microRNA alterations. However, DNA repair mechanisms are devoted to protect the DNA to ensure genetic stability, any aberrations in these calibrated mechanisms provoke cancer occurrence. Comprehensive knowledge of the type of mutagens and carcinogens and the influence of these agents in DNA damage and cancer induction is crucial to develop rational anticancer strategies. This review delineated the molecular mechanism of DNA damage and the repair pathways to provide a deep understanding of the molecular basis of mutagenicity and carcinogenicity. A relationship between DNA adduct formation and cancer incidence has also been summarized. The mechanistic basis of inflammatory response and oxidative damage triggered by mutagens in tumorigenesis has also been highlighted. We elucidated the interesting interplay between DNA damage response and immune system mechanisms. We addressed the current understanding of DNA repair targeted therapies and DNA damaging chemotherapeutic agents for cancer treatment and discussed how antiviral agents, anti-inflammatory drugs, and immunotherapeutic agents combined with traditional approaches lay the foundations for future cancer therapies.
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Affiliation(s)
- Smita Kumari
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Sudhanshu Sharma
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Dia Advani
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Akanksha Khosla
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India.
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Mabrouk AA, Tadros MI, El-Refaie WM. Improving the efficacy of Cyclooxegenase-2 inhibitors in the management of oral cancer: Insights into the implementation of nanotechnology and mucoadhesion. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2020.102240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Aziz A, Hanif F, Majeed S, Iftikhar K, Simjee SU. N-(2-hydroxyphenyl) acetamide (NA-2) elicits potent antitumor effect against human breast cancer cell line (MCF-7). Toxicol In Vitro 2019; 60:296-304. [PMID: 31207345 DOI: 10.1016/j.tiv.2019.06.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/23/2019] [Accepted: 06/12/2019] [Indexed: 01/23/2023]
Abstract
Breast cancer is the most dominating malignancy in females worldwide. Treatment with conventional chemotherapeutics is associated with severe adverse effects. Thus need of new compounds, with better therapeutic potential and lesser side effects still exist. In this context the present study is planned to investigate therapeutic potential of anti-inflammatory compound N-(2- hydroxyphenyl) acetamide (NA-2) against breast cancer cells (MCF-7). The compound was selected on the basis of its reported anti-inflammatory, anti-arthritic and anti-glioblastoma activities in our previous studies. MTT, Annexin-V-FITC and wound healing assays were used to analyze the effect of compound on growth inhibition, apoptosis and metastasis. While flow cytometry, RT-PCR and immunocytochemistry techniques were used to assess the effect of NA-2 on cell cycle arrest, and expression of apoptotic markers (Bax and Bcl-2) at both mRNA and protein level respectively. Data analysis revealed that NA-2 significantly inhibits growth of MCF-7 cells after 48 h treatment (IC50 = 1.65 mM). NA-2 also delayed the wound healing process, arrested cell cycle at G0/G1 phase and induced apoptosis by enhancing Bax/Bcl-2 ratio. We concluded that NA-2 possesses strong anticancer activity against MCF-7 cells, which is mediated through different mechanisms, making it a useful molecule for the development of new antitumor drugs.
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Affiliation(s)
- Aisha Aziz
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Farina Hanif
- Institute of Biomedical Sciences, Dow University of Health Sciences, OJHA Campus, SUPARCO ROAD, Karachi 75330, Pakistan
| | - Saba Majeed
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Kanwal Iftikhar
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Shabana Usman Simjee
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
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Hanif F, Perveen K, Jawed H, Ahmed A, Malhi SM, Jamall S, Simjee SU. N-(2-hydroxyphenyl)acetamide (NA-2) and Temozolomide synergistically induce apoptosis in human glioblastoma cell line U87. Cancer Cell Int 2014; 14:133. [PMID: 25663820 PMCID: PMC4319240 DOI: 10.1186/s12935-014-0133-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Accepted: 11/19/2014] [Indexed: 01/24/2023] Open
Abstract
Background Despite the modern therapies available for treating glioblastoma multiforme (GBM), it is still a deadly disease. The development of new therapeutic strategies for the management of gliomas is therefore crucial. The present study is designed to analyze the therapeutic potentials of synthetic compound N-(2-hydroxyphenyl)acetamide (NA-2) in the treatment of GBM as a single agent or in combination with Temozolomide (TMZ) on glioblastoma cells. Methods MTT and TUNEL assays were used to detect the growth inhibitory effect and apoptotic activity of NA-2 alone and in combination with TMZ. Synergy was assessed using combination Index method. The expression of apoptosis related markers Bax, Bcl-2 and caspase-3 were assessed by RT-PCR, whereas, the active caspase-3 protein expression was determined using imunocytochemistry. Results Both NA-2 and TMZ inhibited the growth of U87 in a dose dependent manner. The combine administration of NA-2 (0.33 mM) and temozolomide (0.1 mM) significantly enhanced the cell growth inhibition and apoptosis. Furthermore RT-PCR and imunocytochemistry data revealed that cooperative apoptosis induction was associated with increased ratio of Bax to Bcl-2 and active Caspase-3 expression. Conclusion Our findings support that NA-2 possesses strong apoptotic activity and the combined administration of NA-2 and TMZ may be therapeutically exploited for the management of GBM. Electronic supplementary material The online version of this article (doi:10.1186/s12935-014-0133-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Farina Hanif
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan
| | - Kahkashan Perveen
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan
| | - Huma Jawed
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan
| | - Aqeel Ahmed
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan
| | - Saima M Malhi
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan
| | - Siddiqua Jamall
- Department of Biochemistry, University of Karachi, Karachi, 75270 Pakistan
| | - Shabana U Simjee
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan ; H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan
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Gomes RN, Colquhoun A. E series prostaglandins alter the proliferative, apoptotic and migratory properties of T98G human glioma cells in vitro. Lipids Health Dis 2012; 11:171. [PMID: 23231886 PMCID: PMC3547780 DOI: 10.1186/1476-511x-11-171] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Accepted: 12/04/2012] [Indexed: 12/02/2022] Open
Abstract
Background In many types of cancer, prostaglandin E2 (PGE2) is associated with tumour related processes including proliferation, migration, angiogenesis and apoptosis. However in gliomas the role of this prostanoid is poorly understood. Here, we report on the proliferative, migratory, and apoptotic effects of PGE1, PGE2 and Ibuprofen (IBP) observed in the T98G human glioma cell line in vitro. Methods T98G human glioma cells were treated with IBP, PGE1 or PGE2 at varying concentrations for 24–72 hours. Cell proliferation, mitotic index and apoptotic index were determined for each treatment. Caspase-9 and caspase-3 activity was measured using fluorescent probes in live cells (FITC-LEHD-FMK and FITC-DEVD-FMK respectively). The migratory capacity of the cells was quantified using a scratch migration assay and a transwell migration assay. Results A significant decrease was seen in cell number (54%) in the presence of 50 μM IBP. Mitotic index and bromodeoxyuridine (BrdU) incorporation were also decreased 57% and 65%, respectively, by IBP. The apoptotic index was increased (167%) and the in situ activity of caspase-9 and caspase-3 was evident in IBP treated cells. The inhibition of COX activity by IBP also caused a significant inhibition of cell migration in the monolayer scratch assay (74%) and the transwell migration assay (36%). In contrast, the presence of exogenous PGE1 or PGE2 caused significant increases in cell number (37% PGE1 and 45% PGE2). When mitotic index was measured no change was found for either PG treatment. However, the BrdU incorporation rate was significantly increased by PGE1 (62%) and to a greater extent by PGE2 (100%). The apoptotic index was unchanged by exogenous PGs. The addition of exogenous PGs caused an increase in cell migration in the monolayer scratch assay (43% PGE1 and 44% PGE2) and the transwell migration assay (28% PGE1 and 68% PGE2). Conclusions The present study demonstrated that treatments which alter PGE1 and PGE2 metabolism influence the proliferative and apoptotic indices of T98G glioma cells. The migratory capacity of the cells was also significantly affected by the change in prostaglandin metabolism. Modifying PG metabolism remains an interesting target for future studies in gliomas.
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Affiliation(s)
- Renata N Gomes
- Department of Cell and Developmental Biology, University of São Paulo, São Paulo, SP, Brazil
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Kirane A, Toombs JE, Ostapoff K, Carbon JG, Zaknoen S, Braunfeld J, Schwarz RE, Burrows FJ, Brekken RA. Apricoxib, a novel inhibitor of COX-2, markedly improves standard therapy response in molecularly defined models of pancreatic cancer. Clin Cancer Res 2012; 18:5031-42. [PMID: 22829202 DOI: 10.1158/1078-0432.ccr-12-0453] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE COX-2 is expressed highly in pancreatic cancer and implicated in tumor progression. COX-2 inhibition can reduce tumor growth and augment therapy. The precise function of COX-2 in tumors remains poorly understood, but it is implicated in tumor angiogenesis, evasion of apoptosis, and induction of epithelial-to-mesenchymal transition (EMT). Current therapeutic regimens for pancreatic cancer are minimally effective, highlighting the need for novel treatment strategies. Here, we report that apricoxib, a novel COX-2 inhibitor in phase II clinical trials, significantly enhances the efficacy of gemcitabine/erlotinib in preclinical models of pancreatic cancer. EXPERIMENTAL DESIGN Human pancreatic cell lines were evaluated in vitro and in vivo for response to apricoxib ± standard-of-care therapy (gemcitabine + erlotinib). Tumor tissue underwent posttreatment analysis for cell proliferation, viability, and EMT phenotype. Vascular parameters were also determined. RESULTS COX-2 inhibition reduced the IC(50) of gemcitabine ± erlotinib in six pancreatic cancer cell lines tested in vitro. Furthermore, apricoxib increased the antitumor efficacy of standard combination therapy in several orthotopic xenograft models. In vivo apricoxib combination therapy was only effective at reducing tumor growth and metastasis in tumors with elevated COX-2 activity. In each model examined, treatment with apricoxib resulted in vascular normalization without a decrease in microvessel density and promotion of an epithelial phenotype by tumor cells regardless of basal COX-2 expression. CONCLUSIONS Apricoxib robustly reverses EMT and augments standard therapy without reducing microvessel density and warrants further clinical evaluation in patients with pancreatic cancer.
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Affiliation(s)
- Amanda Kirane
- Division of Surgical Oncology, Department of Surgery, The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Hillion J, Smail SS, Di Cello F, Belton A, Shah S, Huso T, Schuldenfrei A, Nelson DM, Cope L, Campbell N, Karikari C, Aderinto A, Maitra A, Huso DL, Resar LMS. The HMGA1-COX-2 axis: a key molecular pathway and potential target in pancreatic adenocarcinoma. Pancreatology 2012; 12:372-9. [PMID: 22898640 PMCID: PMC3466102 DOI: 10.1016/j.pan.2012.05.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
CONTEXT Although pancreatic cancer is a common, highly lethal malignancy, the molecular events that enable precursor lesions to become invasive carcinoma remain unclear. We previously reported that the high-mobility group A1 (HMGA1) protein is overexpressed in >90% of primary pancreatic cancers, with absent or low levels in early precursor lesions. METHODS Here, we investigate the role of HMGA1 in reprogramming pancreatic epithelium into invasive cancer cells. We assessed oncogenic properties induced by HMGA1 in non-transformed pancreatic epithelial cells expressing activated K-RAS. We also explored the HMGA1-cyclooxygenase (COX-2) pathway in human pancreatic cancer cells and the therapeutic effects of COX-2 inhibitors in xenograft tumorigenesis. RESULTS HMGA1 cooperates with activated K-RAS to induce migration, invasion, and anchorage-independent cell growth in a cell line derived from normal human pancreatic epithelium. Moreover, HMGA1 and COX-2 expression are positively correlated in pancreatic cancer cell lines (r(2) = 0.93; p < 0.001). HMGA1 binds directly to the COX-2 promoter at an AT-rich region in vivo in three pancreatic cancer cell lines. In addition, HMGA1 induces COX-2 expression in pancreatic epithelial cells, while knock-down of HMGA1 results in repression of COX-2 in pancreatic cancer cells. Strikingly, we also discovered that Sulindac (a COX-1/COX-2 inhibitor) or Celecoxib (a more specific COX-2 inhibitor) block xenograft tumorigenesis from pancreatic cancer cells expressing high levels of HMGA1. CONCLUSIONS Our studies identify for the first time an important role for the HMGA1-COX-2 pathway in pancreatic cancer and suggest that targeting this pathway could be effective to treat, or even prevent, pancreatic cancer.
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Affiliation(s)
- Joelle Hillion
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Shamayra S. Smail
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Francescopaolo Di Cello
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Amy Belton
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Sandeep Shah
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Tait Huso
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Andrew Schuldenfrei
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Dwella Moton Nelson
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Leslie Cope
- Oncology Center-Biostatistics/Bioinformatics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Nathaniel Campbell
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Collins Karikari
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Abimbola Aderinto
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Anirban Maitra
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - David L. Huso
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Linda M. S. Resar
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Palayoor ST, J-Aryankalayil M, Makinde AY, Cerna D, Falduto MT, Magnuson SR, Coleman CN. Gene expression profile of coronary artery cells treated with nonsteroidal anti-inflammatory drugs reveals off-target effects. J Cardiovasc Pharmacol 2012; 59:487-99. [PMID: 22668799 PMCID: PMC3370396 DOI: 10.1097/fjc.0b013e31824ba6b5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) have come under scrutiny because of the gastrointestinal, renal, and cardiovascular toxicity associated with prolonged use of these drugs. The purpose of this study was to identify molecular targets for NSAIDs related to cellular toxicity with a view to optimize drug efficacy in the clinic. Coronary artery smooth muscle cells and endothelial cells were treated with low (clinically achievable) and high (typically used in preclinical studies) concentrations of celecoxib, NS398, and ibuprofen for 24 hours. NSAIDs-induced gene expression changes were evaluated by microarray analysis and validated by real-time reverse-transcription polymerase chain reaction and western blotting. The functional significance of differentially expressed genes was evaluated by Ingenuity Pathway Analysis. At high concentrations, NSAIDs altered the expression of genes regulating cell proliferation and cell death. NSAIDs also altered genes associated with cardiovascular functions including inflammation, thrombosis, fibrinolysis, coronary artery disease, and hypertension. The gene expression was most impacted by ibuprofen, celecoxib, and NS398, in that order. This study revealed that NSAIDs altered expression of an array of genes associated with cardiovascular events and emphasizes the potential for fingerprinting drugs in preclinical studies to assess the potential drug toxicity and to optimize the drug efficacy in clinical settings.
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MESH Headings
- Anti-Inflammatory Agents, Non-Steroidal/administration & dosage
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Blotting, Western
- Celecoxib
- Cell Proliferation/drug effects
- Cells, Cultured
- Coronary Vessels/cytology
- Coronary Vessels/drug effects
- Coronary Vessels/metabolism
- Dose-Response Relationship, Drug
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Gene Expression Profiling
- Gene Expression Regulation/drug effects
- Humans
- Ibuprofen/pharmacology
- Microarray Analysis
- Molecular Targeted Therapy
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Nitrobenzenes/administration & dosage
- Nitrobenzenes/pharmacology
- Pyrazoles/administration & dosage
- Pyrazoles/pharmacology
- Reverse Transcriptase Polymerase Chain Reaction
- Sulfonamides/administration & dosage
- Sulfonamides/pharmacology
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Affiliation(s)
- Sanjeewani T Palayoor
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Building # 10, Room B3B406, Bethesda, MD 20892, USA.
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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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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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Khan MNA, Lee YS. Cyclooxygenase inhibitors: scope of their use and development in cancer chemotherapy. Med Res Rev 2011; 31:161-201. [PMID: 19967720 DOI: 10.1002/med.20182] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The traditional nonsteroidal anti-inflammatory drugs (NSAIDs) exert their effect by inhibition of cyclooxygenase-1 (COX-1) as well as COX-2 enzymes. As COX-1 is responsible for maintaining normal biological functions, the nonselective inhibition of these enzymes caused side effects including gastrointestinal (GI) problems. Recently developed selective COX-2 inhibitors could reduce these adverse effects, but the evidence of cardiovascular side effects including an increased risk of myocardial infarction began to emerge, and some of the COX-2 inhibitors were eventually withdrawn from the market and this led to the downfall of this research. So, the discovery of novel COX-2 inhibitors with their safety profile became the biggest challenge in pharmaceutical research. However, recent mechanistic and clinical studies revolutionized this area by indicating the fact that COX-2 is involved in apoptosis resistance, angiogenesis, and tumor progression. Epidemiological data suggest that selective COX-2 inhibitors might prevent the development of cancers. Moreover, COX-2 is found to be overexpressed in many cancers thus making it an attractive therapeutic target for the prevention and treatment of a number of malignancies. The purpose of this review is to focus on the medicinal chemistry aspects of COX-2 inhibitors in cancer chemotherapy and recent reports on these inhibitors as anticancer agents. We attempted to cover only the COX inhibitors that showed anticancer activity, although a number of potent COX-2 inhibitors have been reported without their anticancer effects. Furthermore, structure-activity relationships (SAR) of different classes of compounds for COX-2 inhibition as well as anticancer activity, and their future applications are discussed.
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Affiliation(s)
- Mohammed Naseer A Khan
- Department of Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemoon-ku, Seoul 130-701, Republic of Korea
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John-Aryankalayil M, Palayoor ST, Cerna D, Falduto MT, Magnuson SR, Coleman CN. NS-398, ibuprofen, and cyclooxygenase-2 RNA interference produce significantly different gene expression profiles in prostate cancer cells. Mol Cancer Ther 2009; 8:261-73. [PMID: 19139136 DOI: 10.1158/1535-7163.mct-08-0928] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cyclooxygenase-2 (COX-2) plays a significant role in tumor development and progression. Nonsteroidal anti-inflammatory drugs (NSAID) exhibit potent anticancer effects in vitro and in vivo by COX-2-dependent and COX-2-independent mechanisms. In this study, we used microarray analysis to identify the change of expression profile regulated by a COX-2-specific NSAID NS-398 (0.01 and 0.1 mmol/L), a nonspecific NSAID ibuprofen (0.1 and 1.5 mmol/L) and RNA interference (RNAi)-mediated COX-2 inhibition in PC3 prostate cancer cells. A total of 3,362 differentially expressed genes with 2-fold change and P<0.05 were identified. Low concentrations of NSAIDs and COX-2 RNAi altered very few genes (1-3%) compared with the higher concentration of NS-398 (17%) and ibuprofen (80%). Ingenuity Pathway Analysis was used for distributing the differentially expressed genes into biological networks and for evaluation of functional significance. The top 3 networks for both NSAIDs included functional categories of DNA replication, recombination and repair, and gastrointestinal disease. Immunoresponse function was specific to NS-398, and cell cycle and cellular movement were among the top functions for ibuprofen. Ingenuity Pathway Analysis also identified renal and urologic disease as a function specific for ibuprofen. This comprehensive study identified several COX-2-independent targets of NSAIDs, which may help explain the antitumor and radiosensitizing effects of NSAIDs. However, none of these categories were reflected in the identified networks in PC3 cells treated with clinically relevant low concentrations of NS-398 and ibuprofen or with COX-2 RNAi, suggesting the benefit to fingerprinting preclinical drug concentrations to improve their relevance to the clinical setting.
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Affiliation(s)
- Molykutty John-Aryankalayil
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Room B3 B 406, Building 10, Bethesda, MD 20892, USA.
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13
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Sun WH, Chen GS, Ou XL, Yang Y, Luo C, Zhang Y, Shao Y, Xu HC, Xiao B, Xue YP, Zhou SM, Zhao QS, Ding GX. Inhibition of COX-2 and activation of peroxisome proliferator-activated receptor gamma synergistically inhibits proliferation and induces apoptosis of human pancreatic carcinoma cells. Cancer Lett 2008; 275:247-55. [PMID: 19056168 DOI: 10.1016/j.canlet.2008.10.023] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2008] [Revised: 10/05/2008] [Accepted: 10/17/2008] [Indexed: 01/03/2023]
Abstract
Although inhibition of cyclooxygenase-2 (COX-2) or activation of peroxisome proliferators-activated receptor gamma (PPAR-gamma) leads to growth inhibition in malignancies, the synergistic anti-tumor effects of combination of COX-2 inhibitor (NS-398) and PPAR-gamma agonist (rosiglitazone) on the human pancreatic cancer cells remains unknown. Here, we evaluated the effects of NS-398 and/or rosiglitazone on the cell proliferation and apoptosis in a pancreatic cancer cell line, SW1990. NS-398 and rosiglitazone decreased cell proliferation in a dose- and time-dependent manner. Proliferating cell nuclear antigen (PCNA) labeling index significantly decreased in the cells treated with either NS-398 or rosiglitazone. Both NS-398 and rosiglitazone alone induced apoptotic cell death of SW1990. The combination of NS-398 and rosiglitazone exerted synergistic effects on proliferation inhibition, and apoptosis induction in SW1990 cells, with down-regulation of Bcl-2 and up-regulation of Bax expression. Our results indicate that simultaneous targeting of COX-2 and PPAR-gamma inhibits pancreatic cancer development more effectively than targeting each molecule alone.
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Affiliation(s)
- Wei-Hao Sun
- Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, PR China.
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Hasan S, Satake M, Dawson DW, Funahashi H, Angst E, Go VLW, Reber HA, Hines OJ, Eibl G. Expression analysis of the prostaglandin E2 production pathway in human pancreatic cancers. Pancreas 2008; 37:121-7. [PMID: 18665070 DOI: 10.1097/mpa.0b013e31816618ba] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVES There is strong evidence for an important role of cyclooxygenase (COX) 2 and COX-2-generated PGE2 during pancreatic tumorigenesis. Cyclooxygenase 2 has therefore become a potential chemotherapeutic target for pancreatic cancer. However, recent studies raised concerns regarding the safety of selective COX-2 inhibitors. Although the benefits of COX-2 inhibition may eventually outweigh the associated cardiovascular risks, there are a number of alternative targets for inhibiting the formation of PGE2 in human tumors that may prove less harmful to the patient. This study aimed at analyzing the expression of various proteins involved in the generation of PGE2 in human pancreatic cancers. METHODS AND RESULTS Real-time polymerase chain reaction and Western blot analyses demonstrated overexpression of cytoplasmic phospholipase A2, COX-2, cytoplasmic prostaglandin E synthase, and microsomal prostaglandin E synthases 1 and 2 in most human pancreatic cancers when compared with matched normal pancreas. Immunohistochemistry revealed expression of these proteins predominantly by pancreatic cancer cells. Variable expression of these proteins was also confirmed in several human pancreatic cancer cell lines. CONCLUSIONS Our studies demonstrated for the first time that various proteins involved in the generation of PGE2 are overexpressed in human pancreatic cancers. These proteins may represent potentially novel targets for the therapy of pancreatic cancers.
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Affiliation(s)
- Sascha Hasan
- Department of Surgery, Hirshberg Laboratories for Pancreatic Cancer Research, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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Qi ZD, Zhou B, Qi X, Chuan S, Liu Y, Dai J. Interaction of rofecoxib with human serum albumin: Determination of binding constants and the binding site by spectroscopic methods. J Photochem Photobiol A Chem 2008. [DOI: 10.1016/j.jphotochem.2007.06.011] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Abstract
INTRODUCTION Pancreatic cancer is a devastating malignancy and a leading cause of cancer mortality. Furthermore, early diagnosis represents a serious hurdle for clinicians, as symptoms are non-specific and usually manifest in advanced, treatment-resistant stages of the disease. SOURCES OF DATA Here, we review the rationale and progress of targeted therapies currently under investigation. AREAS OF AGREEMENT At present, chemoradiation regimes are administered palliatively, and produce only marginal survival benefits, underscoring a desperate need for more effective treatment modalities. AREAS OF CONTROVERSY Questions have been raised as to whether erlotinib, the only targeted therapy to attain a statistically significant increase in median survival, is cost-effective. GROWING POINTS The last decade of research has provided us with a wealth of information regarding the molecular nature of pancreatic cancer, leading to the identification of signalling pathways and their respective components which are critical for the maintenance of the malignant phenotype. AREAS TIMELY FOR DEVELOPING RESEARCH These proteins thus represent ideal targets for novel molecular therapies which embody an urgently needed novel treatment strategy.
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Affiliation(s)
- S A Danovi
- Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK
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COX-2 and NF-KB overexpression is common in pancreatic cancer but does not predict for COX-2 inhibitors activity in combination with gemcitabine and oxaliplatin. Am J Clin Oncol 2007; 30:526-30. [PMID: 17921715 DOI: 10.1097/coc.0b013e318054675c] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The attempt to improve therapeutic results in pancreatic carcinoma has recently focused on the emerging role of molecular biology. We investigated the role of COX-2 and NF-KB expression in relation to the use of a COX-2 inhibitor (celecoxib) associated to gemcitabine and oxaliplatin in pancreatic cancer. METHODS Forty-four patients with histologically or cytologically verified, locally advanced unresectable and/or metastatic pancreatic carcinoma were eligible for the study. RESULTS Thirty-three patients (75%) assumed celecoxib for all their treatment period. Treatment was repeated every 2 weeks, until there was evidence of disease progression, patient refusal, or unacceptable toxicity. Efficacy was assessed according to tumor response, clinical benefit, and time-related parameters. Five patients had a partial response, 24 had a stable disease, and 15 had a disease progression, for an overall response rate of 11%. Biochemical response rate based on CA 19.9 levels showed 2 complete and 10 partial responses, whereas 31 patients presented no changes of CA 19.9 levels. COX-2 protein expression was found in 30 tumors, while a moderate or weak/absent expression was present in 10 patients. Sixteen tumors showed a strong expression for NF-KB, 4 a moderate expression, and 5 a weak/absent expression. CONCLUSION The use of a COX-2 inhibitor does not add any valuable activity to a gemcitabine/oxaliplatin combination, even in patients with COX-2 and NF-KB overexpressing tumors.
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Alam M, Wang JH, Coffey JC, Qadri SS, O'Donnell A, Aherne T, Redmond HP. Characterization of the Effects of Cyclooxygenase-2 Inhibition in the Regulation of Apoptosis in Human Small and Non–Small Cell Lung Cancer Cell Lines. Ann Surg Oncol 2007; 14:2678-84. [PMID: 17602268 DOI: 10.1245/s10434-007-9359-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2006] [Accepted: 12/07/2006] [Indexed: 11/18/2022]
Abstract
BACKGROUND Cyclooxygenase-2 enzyme (COX-2) is overexpressed in human non-small cell lung cancer (NSCLC) but is not expressed in small cell lung cancer. Selective COX-2 inhibitors have been shown to induce apoptosis in NSCLC cells, an effect which is associated with the regulation of intracellular MAP kinase (MAPK) signal pathways. Our aims were to characterize the effects of COX-2 inhibition by rofecoxib on apoptosis in human NSCLC and small cell lung cancer cell lines. METHODS The human NSCLC cell line NCI-H2126 and small cell lung cancer cell line DMS-79 were used. Constitutive COX-2 protein levels were first determined by Western blot test. Levels of apoptosis were evaluated by using propidium iodide staining on FACScan analysis after incubation of NCI-H2126 and DMS-79 with p38 MAPK inhibitor SB202190 (25 ?microM), NF-kappaB inhibitor SN50 (75 microg/mL), and rofecoxib at 100 and 250 microM. All statistical analysis was performed by analysis of variance. RESULTS Western blot test confirmed the presence of COX-2 enzyme in NCI-H2126 and absence in DMS-79. Interestingly, rofecoxib treatment demonstrated a dose-dependent increase in apoptosis in both cell lines. Given this finding, the effect of rofecoxib on NF-kappaB and p38 MAPK pathways was also examined. Apoptosis in both cell lines was unaltered by SN50, either alone or in combination with rofecoxib. A similar phenomenon was observed in NCI-H2126 cells treated with SB202190, either alone or in combination with rofecoxib. In contrast, p38 MAPK inhibition greatly upregulated DMS-79 apoptosis in a manner that was unaltered by the addition of rofecoxib. CONCLUSIONS Rofecoxib led to a dose-dependent increase in apoptosis in both tumor cell lines. This effect occurred independently of COX-2, NF-kappaB, and p38 MAPK pathways in DMS-79 cells. As such, rofecoxib must act on alternative pathways to regulate apoptosis in human small cell lung cancer cells.
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Affiliation(s)
- Mahmood Alam
- Department of Cardiothoracic Surgery, Cork University Hospital, Cork, Republic of Ireland
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Matsumoto G, Muta M, Tsuruta K, Horiguchi S, Karasawa K, Okamoto A. Tumor size significantly correlates with postoperative liver metastases and COX-2 expression in patients with resectable pancreatic cancer. Pancreatology 2007; 7:167-73. [PMID: 17592230 DOI: 10.1159/000104241] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2006] [Accepted: 12/20/2006] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIM Local treatment often fails in patients with resectable pancreatic cancer due to the postoperative development of distant metastases, especially liver metastases. We determined the prognostic factors for postoperative liver metastases in pancreatic cancer patients following surgical resection with combined radiotherapy. METHODS Sixty-four patients with nonmetastatic, resectable pancreatic cancer were entered into this study. All of these patients had pancreatic resection surgery combined with radiotherapy. The development of postoperative liver metastases was carefully followed, and the survival ratio was evaluated using the Kaplan-Meier method. The prognostic importance of clinicopathological factors and molecular characteristics was analyzed by the Cox proportional hazards model. The correlation study was performed using Fisher's exact test. RESULTS Tumor size, curability, and histological type of differentiation were statistically significant independent prognostic factors. On multivariate analysis, curability and histological type of differentiation were statistically significant. Only tumor size (> or = 3 cm) was significantly correlated with postoperative liver metastases, as well as cyclooxygenase-2 expression. CONCLUSIONS There were three significant prognostic factors in patients with resectable pancreatic cancer who had local therapy. Patients who have a large tumor require particularly careful follow-up for postoperative liver metastases.
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Affiliation(s)
- Gaku Matsumoto
- Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
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Sooriakumaran P, Langley SEM, Laing RW, Coley HM. COX-2 inhibition: a possible role in the management of prostate cancer? J Chemother 2007; 19:21-32. [PMID: 17309847 DOI: 10.1179/joc.2007.19.1.21] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
There is mounting evidence to support a role for cyclooxygenase-2 (COX-2) inhibitors (coxibs) in the management of prostate cancer. This review considers the current evidence base for the use of coxibs in prostate cancer as well as their adverse event profile. A systematic literature review using the search terms 'cyclooxygenase', 'COX-2', 'coxibs', 'cardiovascular risk', and 'prostate cancer' was performed using Medline. Celecoxib appears safer in terms of cardiovascular toxicity than other coxibs, and this may relate to its lower selectivity for the COX-2 enzyme. This lower selectivity also provides rationale for its putative broader anti-cancer effects, via non-COX-2-dependent pathways that affect cell cycle regulation, angiogenesis, and hypoxic modulation. There are also interacting relationships between COX-2, chronic inflammation, and prostate cancer. There is much promise for the coxibs as anti-cancer agents. The future might be to pharmacologically adapt these agents to exert their COX-2 independent mechanisms of action while minimizing their COX-2-dependent adverse cardiovascular effects.
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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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23
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Zeng G, Germinaro M, Micsenyi A, Monga NK, Bell A, Sood A, Malhotra V, Sood N, Midda V, Monga DK, Kokkinakis DM, Monga SPS. Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 2006; 8:279-89. [PMID: 16756720 PMCID: PMC1600679 DOI: 10.1593/neo.05607] [Citation(s) in RCA: 173] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Wnt/beta-catenin signaling plays an important role in normal development. However, its aberrant activation is associated with several cancers. The aim of this study is to examine the Wnt/beta-catenin pathway in patients with advanced pancreatic adenocarcinoma (n = 31). Paraffin sections from tumors (n = 16) and normal pancreata (n = 3) were used to determine the localization of beta-catenin. An additional 15 frozen tumors, adjacent normal pancreata (n = 5), or normal pancreata (n = 4) were utilized for protein isolation. Tumors were also examined for mutations in exon 3 of the CTNNB1 gene. More than 65% of the tumors showed an increase in total beta-catenin, consistent with its enhanced membranous, cytoplasmic, and nuclear localization, but only two showed mutations in CTNNB1. The majority of the remaining tumors demonstrated concurrent increases in Wnt-1 and frizzled-2 (positive regulators) and a decrease in Ser45/Thr41-phospho-beta-catenin. Electrophoretic mobility shift assay demonstrated beta-catenin-T-cell factor binding in tumors only. Adenomatous polyposis coli and axin, which are both negative regulators, remained unchanged. Unexpectedly, total glycogen synthase kinase-3beta protein was elevated in these tumors. Elevated levels of E-cadherin were also observed, although E-cadherin-beta-catenin association in tumors remained unaffected. Thus, Wnt/beta-catenin activation was observed in 65% of pancreatic adenocarcinomas, independently of beta-catenin gene mutations in most tumors.
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Affiliation(s)
- Gang Zeng
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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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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Doucas H, Garcea G, Neal CP, Manson MM, Berry DP. Chemoprevention of pancreatic cancer: a review of the molecular pathways involved, and evidence for the potential for chemoprevention. Pancreatology 2006; 6:429-39. [PMID: 16847380 DOI: 10.1159/000094560] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer has a poor prognosis. The use of drugs or natural agents which inhibit or slow down tumour growth therefore has important potential in the development of future therapies. METHODS A literature search of the PubMed and ISI Web of Science databases was undertaken to review the current data available on the alterations in signalling pathways found in pancreatic carcinogenesis, in order to identify sites that could be targeted by chemopreventive agents. Several agents of particular relevance to pancreatic cancer were identified, and their possible mechanisms of action reviewed. RESULTS Chemopreventive agents such as non-steroidal anti-inflammatory drugs, green tea constituents, and antioxidants have been shown to target various steps in intracellular signalling pathways, particularly those controlling cell proliferation and survival. Work on cell lines and animal models has shown that some of these agents may be able to modulate the growth of pancreatic tumours. Initial clinical trials of some chemopreventives in pancreatic cancer have been undertaken, and have yielded mixed results, prompting the need for further studies. CONCLUSION As the molecular pathology of pancreatic cancer becomes better understood, sites of action of chemopreventive substances have been uncovered. Several agents have shown promising results by their ability to inhibit pancreatic carcinogenesis in laboratory studies. If these effects can be successfully translated into human studies then these agents may prove to be valuable adjuvant therapies in the future.
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Affiliation(s)
- H Doucas
- Department of Cancer Studies and Molecular Medicine, Biocentre, Leicester, UK.
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Grösch S, Maier TJ, Schiffmann S, Geisslinger G. Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst 2006; 98:736-47. [PMID: 16757698 DOI: 10.1093/jnci/djj206] [Citation(s) in RCA: 353] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Nonsteroidal antiinflammatory drugs (NSAIDs) appear to reduce the risk of developing cancer. One mechanism through which NSAIDs act to reduce carcinogenesis is to inhibit the activity of cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in various cancer tissues. Overexpression of COX-2 increases cell proliferation and inhibits apoptosis. However, selective COX-2 inhibitors can also act through COX-independent mechanisms. In this review, we describe the COX-2-independent molecular targets of these COX-2 inhibitors and discuss how these targets may be involved in the anticarcinogenic activities of these selective COX-2 inhibitors. We also compare the concentrations of these inhibitors used in in vitro and in vivo experiments and discuss the implications of the in vitro studies for clinical management of cancer with these drugs.
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Affiliation(s)
- Sabine Grösch
- Pharmazentrum Frankfurt, ZAFES, Institut für klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe, Universität Frankfurt, Theodor Stern Kai 7, Frankfurt/Main, Germany.
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Ouyang N, Williams JL, Tsioulias GJ, Gao J, Iatropoulos MJ, Kopelovich L, Kashfi K, Rigas B. Nitric Oxide–Donating Aspirin Prevents Pancreatic Cancer in a Hamster Tumor Model. Cancer Res 2006; 66:4503-11. [PMID: 16618778 DOI: 10.1158/0008-5472.can-05-3118] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
To evaluate the chemopreventive effect of nitric oxide-donating aspirin (NO-ASA), an ASA bearing a NO-releasing moiety, against pancreatic cancer, we studied six groups of female Syrian golden hamsters: groups 1 to 3 (n = 12 each) were given saline and groups 4 to 6 (n = 17) the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) s.c. in five weekly injections (the first, 70 mg/kg, and the remaining, 20 mg/kg each). Control and BOP-treated hamsters were fed a NO-ASA 3,000 ppm or conventional ASA 3,000 ppm or control diet for 19 weeks. Groups 1 to 3 had no tumors. Compared with the BOP/vehicle group, NO-ASA reduced the incidence (88.9%, P < 0.003) and multiplicity (94%, P < 0.05) of pancreatic cancer; ASA had no statistically significant effect. NO-ASA arrested the transition from PanIN2 to PanIN3 and carcinoma. The proliferation (proliferating cell nuclear antigen) / apoptosis (terminal deoxyribonucleotide transferase-mediated nick-end labeling) ratio of ductal cells increased with the histologic severity of the ductal lesion; NO-ASA suppressed it significantly during all stages except PanIN1A. p21(WAF1/CIP1), undetectable in normal cells, was progressively induced in neoplastic cells and suppressed by NO-ASA up to PanIN3. Nuclear factor-kappaB activation, absent in normal tissue, increased progressively (17-fold in cancer); NO-ASA suppressed it throughout and significantly in PanIN1B and PanIN2. Cyclooxygenase-2 expression, absent during early stages, was induced 6-fold in carcinoma and suppressed by NO-ASA in PanIN3 and carcinoma. Conventional ASA had no effect on these molecular markers. Thus, NO-ASA profoundly prevented pancreatic cancer and modulated multiple molecular targets in this model system; conventional ASA had no such effects. NO-ASA merits further evaluation as a chemopreventive agent against pancreatic cancer.
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Affiliation(s)
- Nengtai Ouyang
- Division of Cancer Prevention, State University of New York at Stony Brook, Stony Brook, New York 11794-5200, USA
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Naruse T, Nishida Y, Hosono K, Ishiguro N. Meloxicam inhibits osteosarcoma growth, invasiveness and metastasis by COX-2-dependent and independent routes. Carcinogenesis 2005; 27:584-92. [PMID: 16219634 DOI: 10.1093/carcin/bgi240] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cyclooxygenase-2 (COX-2) inhibitors exert antitumor activity via COX-2-dependent and independent pathways. We wished to evaluate the antitumor activity of meloxicam, a preferential COX-2 inhibitor, in osteosarcoma, the most common primary malignant bone tumor, and determine whether its antitumor effect is COX-2-dependent. COX-2 expression in the osteosarcoma cell lines MG-63, HOS and U2-OS was determined by real-time RT-PCR and western blotting. Subsequently, the inhibitory effects of meloxicam on osteosarcoma cell growth and invasiveness were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and matrigel invasion assays, respectively. Apoptotic activity was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining and semi-quantification of Bax and Bcl-2 expression by real time RT-PCR and western blotting. Prostaglandin-E(2) (PGE(2)) production in the presence and absence of meloxicam was analyzed by enzyme immunoassay, and to determine whether the effects of meloxicam are COX-2-dependent or independent, PGE(2) was added to see if it reversed the effects of meloxicam. In addition, the effects of meloxicam on tumor growth and metastasis were evaluated in an in vivo mouse model using grafted LM-8 mouse osteosarcoma cells, together with immunohistochemical analysis for vascular endothelial growth factor in lung metastatic lesion. Meloxicam inhibited PGE(2) production, proliferation and invasiveness especially in MG-63 cells, which express relatively high levels of COX-2. Only high concentrations of meloxicam caused apoptosis and upregulated Bax mRNA and protein in MG-63 cell culture. In contrast, meloxicam did not induce apoptosis in HOS and U2-OS cells, expressing relatively low levels of COX-2. Exogenous PGE(2) reduced the effects of meloxicam on cell viability and invasiveness, but not its effect on Bax mRNA. In vivo, high doses of meloxicam suppressed LM-8 tumor growth and lung metastasis. Meloxicam, may have both COX-2-dependent and independent inhibitory actions on osteosarcoma. Its effects are more prominent in osteosarcoma cells that have relatively high levels of COX-2.
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Affiliation(s)
- Takahiro Naruse
- Department of Orthopedic Surgery, Nagoya University School and Graduate School of Medicine, 65 Tsurumai-cho, Showa, Nagoya 466-8550, Japan
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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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Dauer M, Herten J, Bauer C, Renner F, Schad K, Schnurr M, Endres S, Eigler A. Chemosensitization of Pancreatic Carcinoma Cells to Enhance T Cell-Mediated Cytotoxicity Induced by Tumor Lysate-Pulsed Dendritic Cells. J Immunother 2005; 28:332-42. [PMID: 16000951 DOI: 10.1097/01.cji.0000164038.41104.f5] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Dendritic cells (DCs) can induce cytotoxic T-cell (CTL) responses against tumor antigens in vitro and in vivo, yet few cancer patients experience tumor regression after DC-based vaccination. Combination with other treatment modalities, such as radiation or pharmacologic anticancer agents, may reduce tumor cell resistance against immune responses. The authors tested whether treatment with gemcitabine or cyclooxygenase-2 (COX-2) inhibitors increases the sensitivity of pancreatic carcinoma cells to CTL-mediated killing. Monocyte-derived DCs of HLA-A2+ donors were loaded with lysate from the HLA-A2+ pancreatic carcinoma cell line Panc-1 and co-cultured with autologous CD3+ T cells. ELISPOT and cytotoxicity assays performed after two rounds of in vitro stimulation confirmed induction of a tumor-specific CTL response. Changes in the magnitude and the effector mechanism of the CTL response were analyzed after treatment of Panc-1 cells with gemcitabine and COX-2 inhibitors. Compared with gemcitabine, COX-2 inhibitors more effectively sensitized Panc-1 cells to CTL-mediated killing and showed less inhibition of T-cell activation by DCs in vitro. Using anti-CD95 blocking antibody, the authors showed that the increase in CTL-mediated tumor cell killing observed after treatment with COX-2 inhibitors is dependent on CD95/CD95 ligand interaction. Increased apoptosis of Panc-1 cells treated with COX-2 inhibitor was also observed after incubation with agonistic anti-CD95 antibody. Sensitization of cancer cells to CD95-dependent killing by CTLs represents a novel mechanism of action for COX-2 inhibitors and provides a rationale for their concomitant use with immunotherapeutic strategies such as DC-based vaccination.
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Affiliation(s)
- Marc Dauer
- Section of Gastroenterology, Medizinische Klinik Innenstadt, University of Munich, 80336 Munich, Germany
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31
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des Guetz G, Benamouzig R, Chaussade S, Breau JL. [NSAID, type 2 cyclo-oxygenase inhibitors and pancreatic carcinogenesis]. ACTA ACUST UNITED AC 2005; 29:411-4. [PMID: 15864204 DOI: 10.1016/s0399-8320(05)80794-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Gaëtan des Guetz
- Service d'Oncologie Médicale, Hôpital Avicenne, Bobigny, France.
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Yu GZ, Zhu MH, Zhu Z, Ni CR, Zheng JM, Li FM. Genetic alterations and reduced expression of tumor suppressor p33 ING1b in human exocrine pancreatic carcinoma. World J Gastroenterol 2004; 10:3597-601. [PMID: 15534913 PMCID: PMC4611999 DOI: 10.3748/wjg.v10.i24.3597] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [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 detect the expression of p33ING1b protein and the change of p33ING1b gene in pancreatic carcinoma and to evaluate the significance of p33ING1b in pancreatic cell carcinogenesis.
METHODS: Pathological specimens from pancreatic carcinoma and matched non-tumor pancreatic tissues were examined for p33ING1b expression and mutation by immunohistochemistry, polymerase chain reaction single-strand conformation polymorphisms (PCR-SSCP) and loss of heterozygosity (LOH).
RESULTS: The rate of p33ING1b protein expression was 85% (34/40). A single germline missense mutation was detected in 1 of 40 tumors located at codon 215: TGC-TCC (Cys-Ser). Fourteen (60.9%) of 23 tumor samples showed LOH in all of the informative markers tested, but no mutation was detected in these tumors and only two of the informative tumors lacked expressions of p33ING1b protein.
CONCLUSION: Mutation and loss of expression are not the main reasons for the disfunction of p33ING1b in pancreatic carcinoma, an abnormality at the level of chromosome and/or transcription may inhibit their normal functions, potentially contributing to pancreatic cell carcinogenesis.
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Affiliation(s)
- Guan-Zhen Yu
- Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
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33
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Affiliation(s)
- Guido Eibl
- Section of Gastrointestinal Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
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34
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Yamanaka S, Sunamura M, Furukawa T, Sun L, Lefter LP, Abe T, Yatsuoka T, Fujimura H, Shibuya E, Kotobuki N, Oshimura M, Sakurada A, Sato M, Kondo T, Matsuno S, Horii A. Chromosome 12, frequently deleted in human pancreatic cancer, may encode a tumor-suppressor gene that suppresses angiogenesis. J Transl Med 2004; 84:1339-51. [PMID: 15300227 DOI: 10.1038/labinvest.3700160] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Several lines of evidence have suggested that the long arm of chromosome 12 may carry a tumor-suppressor gene(s) that plays a role in pancreatic ductal carcinogenesis. We have previously found a significant association between loss of heterozygosity of the 12q arm and a poor prognosis in pancreatic cancer patients. In this study, we introduced a normal copy of chromosome 12 into some pancreatic ductal carcinoma cells. Both anchorage-dependent and -independent proliferations as well as invasiveness were similar throughout the hybrid clones when compared with their corresponding parental cells. In sharp contrast, significant suppression of tumorigenesis was observed after inoculation of the hybrid clones into nude mice. Measurements made up to 1 month later showed that there was a significant delay in the growth of tumors into which the introduced normal copy of chromosome 12 had been restored. More significantly, using our dorsal skin chamber and an intravital microscopy system experiment in SCID mice, we demonstrated and visualized directly that implantation of the hybrids failed to promote the angiogenic phenotype encountered in the parental cells. Gene expression profiling using the complementary DNA microarray system identified a set of 24 genes differentially expressed between the hybrids and parental cells. An additional set of 18 genes was also identified that were differentially expressed between the hybrid clone that lost its growth-suppression activity and one that retained such activity. Another set of 25 genes mapped on 12q was detected that showed high expression levels in the hybrid clones retaining growth-suppressive activity. In summary, this study provides the first functional evidence of the existence of an additional tumor-suppressor gene(s) on chromosome 12, whose absence is responsible for the pathogenesis in pancreatic ductal carcinogenesis.
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MESH Headings
- Animals
- Carcinoma, Pancreatic Ductal/blood supply
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Chromosome Deletion
- Chromosomes, Human, Pair 12
- Clone Cells
- Female
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Humans
- Hybrid Cells
- In Situ Hybridization, Fluorescence
- Mice
- Mice, Nude
- Mice, SCID
- Neoplasm Transplantation
- Neovascularization, Pathologic/prevention & control
- Oligonucleotide Array Sequence Analysis
- Pancreatic Neoplasms/blood supply
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
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Affiliation(s)
- Sumitaka Yamanaka
- Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan
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Müller R. Crosstalk of oncogenic and prostanoid signaling pathways. J Cancer Res Clin Oncol 2004; 130:429-44. [PMID: 15205946 DOI: 10.1007/s00432-004-0570-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2004] [Accepted: 03/16/2004] [Indexed: 12/21/2022]
Affiliation(s)
- Rolf Müller
- Institute of Molecular Biology and Tumor Research (IMT), Philipps-University, Emil-Mannkopff-Strasse 2, 35033 Marburg, Germany.
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Fernandez-Zapico ME, Callahan G, Delgado S, Urrutia R. Expression profiling in pancreatic cancer research: the initial steps and the road ahead. Curr Opin Gastroenterol 2003; 19:467-72. [PMID: 15703590 DOI: 10.1097/00001574-200309000-00005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
A part of living in a new and exciting era for the biologic sciences and medicine, novel high throughput tools allow exploration of the human genome in an unprecedented manner. This "information revolution" is fueled by the study of genome-wide expression profiles for complex biologic and pathophysiologic conditions using DNA arrays, as well as the development and use of robust bioinformatic algorithms. Meticulous translational experiments are becoming possible because of the development of efficient DNA printing technology for producing high-density microarrays. Therefore, there is no doubt that microarray experiments, combined with bioinformatics, will advance the understanding of the pathobiology of pancreatic cancer, assist in the diagnoses and prognoses of this disease, and develop novel therapies. In this article, the most recent advances in the application of microarray technology to pancreatic cancer research are reviewed, and areas for further development are identified.
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37
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Eibl G, Bruemmer D, Okada Y, Duffy JP, Law RE, Reber HA, Hines OJ. PGE(2) is generated by specific COX-2 activity and increases VEGF production in COX-2-expressing human pancreatic cancer cells. Biochem Biophys Res Commun 2003; 306:887-97. [PMID: 12821125 DOI: 10.1016/s0006-291x(03)01079-9] [Citation(s) in RCA: 96] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
In some cancers cyclooxygenase (COX) inhibition appears to be anti-mitogenic and anti-angiogenic, but the actions of COX-derived prostaglandins in pancreatic cancer (PaCa) are unknown. In this study COX-2 was detected in three of six PaCa cell lines while COX-1 was identified in all cell lines. COX-2 expression correlated with basal and arachidonic acid (AA) stimulated PGE(2) production. PGE(2) production was inhibited by the COX-2 inhibitor nimesulide. In COX-2 expressing cells, exogenous AA and PGE(2) increased VEGF synthesis via the EP(2) receptor. Whereas PGE(2) stimulated intracellular cAMP formation in COX-2 positive and negative cells, 8-bromo cAMP stimulated VEGF production only in COX-2 expressing cells. Stimulating COX-2 expressing PaCa cell lines with AA enhanced migration of endothelial cells, an effect which was inhibited by a COX-2 inhibitor and EP(2) receptor antagonist. These data identify a subset of human PaCa cell lines that express functional COX-2 enzyme. PGE(2) generated by specific COX-2 activity increases VEGF secretion in human PaCa cells through an autocrine mechanism.
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Affiliation(s)
- Guido Eibl
- Section of Gastrointestinal Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 72-231 CHS, Los Angeles, CA 90095-6904, USA
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