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Zhang G, Xu Y, Zhou A, Yu Y, Ning X, Bao H. Bioengineered NanoAid synergistically targets inflammatory pro-tumor processes to advance glioblastoma chemotherapy. NANOSCALE 2025; 17:2753-2768. [PMID: 39831463 DOI: 10.1039/d4nr04557b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Through transcriptomic analysis of patient-derived glioblastoma tissues, we identify an overactivation of inflammatory pathways that contribute to the development of a tumor-promoting microenvironment and therapeutic resistance. To address this critical mechanism, we present NanoAid, a biomimetic nanoplatform designed to target inflammatory pro-tumor processes to advance glioblastoma chemotherapy. NanoAid employs macrophage-membrane-liposome hybrids to optimize the delivery of COX-2 inhibitor parecoxib and paclitaxel. By inheriting macrophage characteristics, NanoAid not only efficiently traverses the blood-brain barrier and precisely accumulates within tumors but also enhances cancer cell uptake, thereby improving overall anticancer efficacy. Notably, the combination of parecoxib and paclitaxel effectively disrupts inflammatory pro-tumor processes while inducing a synergistic effect that inhibits tumor growth, overcomes therapeutic resistance, and minimizes adverse effects. This results in substantial tumor growth inhibition and extends the median survival of tumor-bearing mice. Thus, our study bridges clinical insights with fundamental research, potentially revolutionizing tumor therapy paradigms.
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Affiliation(s)
- Gui Zhang
- The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yurui Xu
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, China.
| | - Anwei Zhou
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, China.
| | - Yongle Yu
- Medical College of Guangxi University, Nanning 530004, China
| | - Xinghai Ning
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, China.
| | - Hongguang Bao
- Department of Anaesthesiology, Perioperative and Pain Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 211101, China.
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Rodrigues P, Bangali H, Hammoud A, Mustafa YF, Al-Hetty HRAK, Alkhafaji AT, Deorari MM, Al-Taee MM, Zabibah RS, Alsalamy A. COX 2-inhibitors; a thorough and updated survey into combinational therapies in cancers. Med Oncol 2024; 41:41. [PMID: 38165473 DOI: 10.1007/s12032-023-02256-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 11/15/2023] [Indexed: 01/03/2024]
Abstract
Cyclooxygenase (COX) enzymes are pivotal in inflammation and cancer development. COX-2, in particular, has been implicated in tumor growth, angiogenesis, and immune evasion. Recently, COX-2 inhibitors have arisen as potential therapeutic agents in cancer treatment. In addition, combining COX inhibitors with other treatment modalities has demonstrated the potential to improve therapeutic efficacy. This review aims to investigate the effects of COX inhibition, both alone and in combination with other methods, on signaling pathways and carcinogenesis in various cancers. In this study, a literature search of all major academic databases was conducted (PubMed, Scholar google), including the leading research on the mechanisms of COX-2, COX-2 inhibitors, monotherapy with COX-2 inhibitors, and combining COX-2-inhibitors with chemotherapeutic agents in tumors. The study encompasses preclinical and clinical evidence, highlighting the positive findings and the potential implications for clinical practice. According to preclinical studies, multiple signaling pathways implicated in tumor cell proliferation, survival, invasion, and metastasis can be suppressed by inhibiting COX. In addition, combining COX inhibitors with chemotherapy drugs, targeted therapies, immunotherapies, and miRNA-based approaches has enhanced anti-tumor activity. These results suggest that combination therapy has the potential to overcome resistance mechanisms and improve treatment outcomes. However, caution must be exercised when selecting and administering combination regimens. Not all combinations of COX-2 inhibitors with other drugs result in synergistic effects; some may even have unfavorable interactions. Therefore, personalized approaches that consider the specific characteristics of the cancer and the medications involved are crucial for optimizing therapeutic strategies. In conclusion, as monotherapy or combined with other methods, COX inhibition bears promise in modulating signaling pathways and inhibiting carcinogenesis in various cancers. Additional studies and well-designed clinical trials are required to completely elucidate the efficacy of COX inhibition and combination therapy in enhancing cancer treatment outcomes. This narrative review study provides a detailed summary of COX-2 monotherapy and combination targeted therapy in cancer treatment.
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Affiliation(s)
- Paul Rodrigues
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Asir-Abha, Kingdom of Saudi Arabia
| | - Harun Bangali
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Asir-Abha, Kingdom of Saudi Arabia
| | - Ahmad Hammoud
- Department of Medical and Technical Information Technology, Bauman Moscow State Technical University, Moscow, Russia.
- Department of Mathematics and Natural Sciences, Gulf University for Science and Technology, Mishref Campus, Mubarak Al-Abdullah, Kuwait.
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | | | | | - Maha Medha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | | | - Rahman S Zabibah
- College of Medical Technique, the Islamic University, Najaf, Iraq
| | - Ali Alsalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, 66002, Iraq
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Bouchet A, Le Clec'h C, Rogalev L, Le Duc G, Pelletier L. Meloxicam can Potentiate the Therapeutic Effects of Synchrotron Microbeam Radiation Therapy on High-Grade Glioma Bearing Rats. Radiat Res 2022; 197:655-661. [PMID: 35245385 DOI: 10.1667/rade-21-00107.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 01/24/2022] [Indexed: 11/03/2022]
Abstract
The microbeam radiation therapy (MRT), a spatially micro-fractionated synchrotron radiotherapy, leads to better control of incurable high-grade glioma than that obtained upon homogeneous radiotherapy. We evaluated the effect of meloxicam, a non-steroidal anti-inflammatory drug (NSAID), to increase the MRT response. Survival of rats bearing intracranial 9L gliosarcoma treated with meloxicam and/or MRT (400 Gy, 50 μm-wide microbeams, 200 μm spacing) was monitored. Tumor growth was assessed on histological tissue sections and COX-2 transcriptomic expression was studied 1 to 25 days after radiotherapy. Meloxicam significantly extended the median survival of microbeam-irradiated rats (from +10.5 to +20 days). Dual treatment led to last survivors until D90 (D39 for the MRT group) and to tumor 9.5 times smaller than MRT alone. No significant modification of COX-2 expression was induced by MRT in normal and tumor tissues. The meloxicam reinforced the anti-tumor effect of MRT for glioma treatment. Although the mechanisms of interaction between meloxicam and MRT remain to be elucidated, the addition of this NSAID, easily implemented as a supplement to water for example, is a very favorable therapeutic regimen since it doubled the survival benefit compared to MRT alone.
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Affiliation(s)
- Audrey Bouchet
- INSERM U1296 "Radiation: Defense, Health Environment", Centre Léon-Bérard, 28 Rue Laennec, 69008 Lyon, France.,Biomedical Beamline, European Synchrotron Radiation Facility, BP220, F38043 Grenoble cedex
| | - Céline Le Clec'h
- Biomedical Beamline, European Synchrotron Radiation Facility, BP220, F38043 Grenoble cedex
| | - Léonid Rogalev
- Biomedical Beamline, European Synchrotron Radiation Facility, BP220, F38043 Grenoble cedex
| | - Géraldine Le Duc
- Biomedical Beamline, European Synchrotron Radiation Facility, BP220, F38043 Grenoble cedex
| | - Laurent Pelletier
- Grenoble University Hospital, BP217, F-38043 Grenoble cedex.,INSERM U836, Team Nanomedicine and brain, 6 Rue Fortuné Ferrini, F38706 La Tronche
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Chen T, Huang Y, Hong J, Wei X, Zeng F, Li J, Ye G, Yuan J, Long Y. Preparation, COX-2 Inhibition and Anticancer Activity of Sclerotiorin Derivatives. Mar Drugs 2020; 19:md19010012. [PMID: 33383842 PMCID: PMC7823724 DOI: 10.3390/md19010012] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/21/2020] [Accepted: 12/23/2020] [Indexed: 12/24/2022] Open
Abstract
The latest research has indicated that anti-tumor agents with COX-2 inhibitory activity may benefit their anti-tumor efficiency. A series of sclerotiorin derivatives have been synthesized and screened for their cytotoxic activity against human lung cancer cells A549, breast cancer cells MDA-MB-435 using the MTT method. Among them, compounds 3, 7, 12, 13, 15, 17 showed good cytotoxic activity with IC50 values of 6.39, 9.20, 9.76, 7.75, 9.08, and 8.18 μM, respectively. In addition, all compounds were tested in vitro the COX-2 inhibitory activity. The results disclosed compounds 7, 13, 25 and sclerotiorin showed moderate to good COX-2 inhibition with the inhibitory ratios of 58.7%, 51.1%, 66.1% and 56.1%, respectively. Notably, compound 3 displayed a comparable inhibition ratio (70.6%) to the positive control indomethacin (78.9%). Furthermore, molecular docking was used to rationalize the potential of the sclerotiorin derivatives as COX2 inhibitory agents by predicting their binding energy, binding modes and optimal orientation at the active site of the COX-2. Additionally, the structure-activity relationships (SARS) have been addressed.
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Affiliation(s)
- Tao Chen
- School of Chemistry, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, South China Normal University, Guangzhou 510006, China; (T.C.); (J.H.); (X.W.); (F.Z.); (J.L.); (G.Y.)
| | - Yun Huang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China;
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Junxian Hong
- School of Chemistry, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, South China Normal University, Guangzhou 510006, China; (T.C.); (J.H.); (X.W.); (F.Z.); (J.L.); (G.Y.)
| | - Xikang Wei
- School of Chemistry, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, South China Normal University, Guangzhou 510006, China; (T.C.); (J.H.); (X.W.); (F.Z.); (J.L.); (G.Y.)
| | - Fang Zeng
- School of Chemistry, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, South China Normal University, Guangzhou 510006, China; (T.C.); (J.H.); (X.W.); (F.Z.); (J.L.); (G.Y.)
| | - Jialin Li
- School of Chemistry, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, South China Normal University, Guangzhou 510006, China; (T.C.); (J.H.); (X.W.); (F.Z.); (J.L.); (G.Y.)
| | - Geting Ye
- School of Chemistry, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, South China Normal University, Guangzhou 510006, China; (T.C.); (J.H.); (X.W.); (F.Z.); (J.L.); (G.Y.)
| | - Jie Yuan
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China;
- Correspondence: (J.Y.); (Y.L.)
| | - Yuhua Long
- School of Chemistry, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, South China Normal University, Guangzhou 510006, China; (T.C.); (J.H.); (X.W.); (F.Z.); (J.L.); (G.Y.)
- Correspondence: (J.Y.); (Y.L.)
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Khodamoradi E, Hoseini-Ghahfarokhi M, Amini P, Motevaseli E, Shabeeb D, Musa AE, Najafi M, Farhood B. Targets for protection and mitigation of radiation injury. Cell Mol Life Sci 2020; 77:3129-3159. [PMID: 32072238 PMCID: PMC11104832 DOI: 10.1007/s00018-020-03479-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/04/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregulation of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.
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Affiliation(s)
- Ehsan Khodamoradi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mojtaba Hoseini-Ghahfarokhi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Peyman Amini
- Department of Radiology, Faculty of Paramedical, Tehran University of Medical Sciences, Tehran, Iran
| | - Elahe Motevaseli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Dheyauldeen Shabeeb
- Department of Physiology, College of Medicine, University of Misan, Misan, Iraq
- Misan Radiotherapy Center, Misan, Iraq
| | - Ahmed Eleojo Musa
- Department of Medical Physics, Tehran University of Medical Sciences (International Campus), Tehran, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Armando RG, Gómez DLM, Gomez DE. New drugs are not enough‑drug repositioning in oncology: An update. Int J Oncol 2020; 56:651-684. [PMID: 32124955 PMCID: PMC7010222 DOI: 10.3892/ijo.2020.4966] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 12/16/2019] [Indexed: 11/24/2022] Open
Abstract
Drug repositioning refers to the concept of discovering novel clinical benefits of drugs that are already known for use treating other diseases. The advantages of this are that several important drug characteristics are already established (including efficacy, pharmacokinetics, pharmacodynamics and toxicity), making the process of research for a putative drug quicker and less costly. Drug repositioning in oncology has received extensive focus. The present review summarizes the most prominent examples of drug repositioning for the treatment of cancer, taking into consideration their primary use, proposed anticancer mechanisms and current development status.
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Affiliation(s)
- Romina Gabriela Armando
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Bernal B1876, Argentina
| | - Diego Luis Mengual Gómez
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Bernal B1876, Argentina
| | - Daniel Eduardo Gomez
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Bernal B1876, Argentina
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McLaughlin MF, Donoviel DB, Jones JA. Novel Indications for Commonly Used Medications as Radiation Protectants in Spaceflight. Aerosp Med Hum Perform 2017. [PMID: 28641684 DOI: 10.3357/amhp.4735.2017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND In the space environment, the traditional radioprotective principles of time, distance, and shielding become difficult to implement. Additionally, the complex radiation environment inherent in space, the chronic exposure timeframe, and the presence of numerous confounding variables complicate the process of creating appropriate risk models for astronaut exposure. Pharmaceutical options hold tremendous promise to attenuate acute and late effects of radiation exposure in the astronaut population. Pharmaceuticals currently approved for other indications may also offer radiation protection, modulation, or mitigation properties along with a well-established safety profile. Currently there are only three agents which have been clinically approved to be employed for radiation exposure, and these only for very narrow indications. This review identifies a number of agents currently approved by the U.S. Food and Drug Administration (FDA) which could warrant further investigation for use in astronauts. Specifically, we examine preclinical and clinical evidence for statins, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), metformin, calcium channel blockers, β adrenergic receptor blockers, fingolimod, N-acetylcysteine, and pentoxifylline as potential radiation countermeasures.McLaughlin MF, Donoviel DB, Jones JA. Novel indications for commonly used medications as radiation protectants in spaceflight. Aerosp Med Hum Perform. 2017; 88(7):665-676.
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8
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Laube M, Kniess T, Pietzsch J. Development of Antioxidant COX-2 Inhibitors as Radioprotective Agents for Radiation Therapy-A Hypothesis-Driven Review. Antioxidants (Basel) 2016; 5:antiox5020014. [PMID: 27104573 PMCID: PMC4931535 DOI: 10.3390/antiox5020014] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 04/08/2016] [Accepted: 04/11/2016] [Indexed: 12/12/2022] Open
Abstract
Radiation therapy (RT) evolved to be a primary treatment modality for cancer patients. Unfortunately, the cure or relief of symptoms is still accompanied by radiation-induced side effects with severe acute and late pathophysiological consequences. Inhibitors of cyclooxygenase-2 (COX-2) are potentially useful in this regard because radioprotection of normal tissue and/or radiosensitizing effects on tumor tissue have been described for several compounds of this structurally diverse class. This review aims to substantiate the hypothesis that antioxidant COX-2 inhibitors are promising radioprotectants because of intercepting radiation-induced oxidative stress and inflammation in normal tissue, especially the vascular system. For this, literature reporting on COX inhibitors exerting radioprotective and/or radiosensitizing action as well as on antioxidant COX inhibitors will be reviewed comprehensively with the aim to find cross-points of both and, by that, stimulate further research in the field of radioprotective agents.
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Affiliation(s)
- Markus Laube
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, Dresden D-01328, Germany.
| | - Torsten Kniess
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, Dresden D-01328, Germany.
| | - Jens Pietzsch
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, Dresden D-01328, Germany.
- Department of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden D-01062, Germany.
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Laube M, Kniess T, Pietzsch J. Radiolabeled COX-2 inhibitors for non-invasive visualization of COX-2 expression and activity--a critical update. Molecules 2013; 18:6311-55. [PMID: 23760031 PMCID: PMC6269837 DOI: 10.3390/molecules18066311] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Revised: 05/16/2013] [Accepted: 05/24/2013] [Indexed: 01/21/2023] Open
Abstract
Cyclooxygenase-2 (COX-2) is a key player in inflammation. Its overexpression is directly associated with various inflammatory diseases and, additionally, with several processes of carcinogenesis. The development of new selective COX-2 inhibitors (COXIBs) for use in cancer treatment is in the focus of the medicinal chemistry research field. For this purpose, a set of methods is available to determine COX-2 expression and activity in vitro and ex vivo but it is still a problem to functionally characterize COX-2 in vivo. This review focusses on imaging agents targeting COX-2 which have been developed for positron emission tomography (PET) and single photon emission computed tomography (SPECT) since 2005. The literature reveals that different radiochemical methods are available to synthesize COXIBs radiolabeled with fluorine-18, carbon-11, and isotopes of radioiodine. Unfortunately, most of the compounds tested did not show sufficient stability in vivo due to de[18F]fluorination or de[11C]methylation or they failed to bind specifically in the target region. So, suitable stability in vivo, matching lipophilicity for the target compartment and both high affinity and selectivity for COX-2 were identified as prominent criteria for radiotracer development. Up to now, it is not clear what approach and which model is the most suited to evaluate COX-2 targeting imaging agents in vivo. However, for proof of principle it has been shown that some radiolabeled compounds can bind specifically in COX-2 overexpressing tissue which gives hope for future work in this field.
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Affiliation(s)
- Markus Laube
- Department Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany; E-Mails: (T.K.); (J.P.)
- Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +49-351-260-2810; Fax: +49-351-260-2915
| | - Torsten Kniess
- Department Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany; E-Mails: (T.K.); (J.P.)
| | - Jens Pietzsch
- Department Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany; E-Mails: (T.K.); (J.P.)
- Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany
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Edden Y, Wexner SD, Berho M. The use of molecular markers as a method to predict the response to neoadjuvant therapy for advanced stage rectal adenocarcinoma. Colorectal Dis 2012; 14:555-61. [PMID: 21689364 DOI: 10.1111/j.1463-1318.2011.02697.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM The response to combined neoadjuvant therapy for advanced stage rectal adenocarcinoma is predictive of outcome. In addition to both clinical and pathological features, the expression of a variety of molecules may provide another method of identifying tumour responsiveness to pre-operative therapy. The aim of this study was to evaluate several markers in the apoptotic pathway as well as expression of Cox-2 and vascular endothelial growth factor (VEGF) to determine their ability to predict response to neoadjuvant therapy. METHOD In total, 152 patients with advanced rectal adenocarcinoma were treated with neoadjuvant therapy followed by resection. Paraffin-embedded sections obtained before and after therapy were assessed by immunohistochemical staining for Cox-2, VEGF, p53, p21, p27, Bax, BCL-2 and apoptosis protease-activating factor 1 (APAF-1). These stains were correlated with tumour regression grade, complete pathological response and T-downstaging of the surgical specimen. Clinical and pathological data were also collected. Data were analysed using the χ2 and Spearman's correlation tests. RESULTS Pathological complete response was seen in 24.5% of patients. Amongst the apoptosis-associated markers, only APAF-1 expression was found to be significantly associated with tumour regression grade (P<0.001), complete pathological response (P<0.031) and T-downstaging (P<0.004). On multivariate analysis, APAF-1 expression was found to be independently associated with good tumour regression grade. In contrast, overexpression of Cox-2 and VEGF in pretreatment biopsies was related to less tumour regression (P<0.003) and less likelihood of T-downstaging (P<0.03). CONCLUSION Immunohistochemical evaluation of initial biopsy specimens of rectal cancer with APAF-1, Cox-2 and VEGF may predict tumour response to neoadjuvant therapy in patients with advanced rectal adenocarcinoma. Those with an expected limited response may be considered for other investigational neoadjuvant protocols.
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Affiliation(s)
- Y Edden
- Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, Florida 33331, USA
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Halamka M, Cvek J, Kubes J, Zavadova E, Kominek P, Horacek J, Dusek L, Feltl D. Plasma levels of vascular endothelial growth factor during and after radiotherapy in combination with celecoxib in patients with advanced head and neck cancer. Oral Oncol 2011; 47:763-7. [PMID: 21696999 DOI: 10.1016/j.oraloncology.2011.05.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Revised: 05/17/2011] [Accepted: 05/18/2011] [Indexed: 10/18/2022]
Abstract
Celebrex and radiotherapy in advanced head and neck cancer. This phase I dose-escalation study seeks to determine the phase II recommended dose of cyclooxygenase type 2 (COX-2) inhibitor in patients with locally advanced squamous cell head and neck (H&N) cancer, treated with accelerated radiotherapy. Anti-vasculogenic effect of this treatment on serum vascular endothelial growth factor (VEGF) is examined. Patients were irradiated with curative intent (72Gy in 6weeks). Celecoxib was administered throughout the radiotherapy course. Serum VEGF level were tested during radiotherapy and in follow-up. Tumor specimens were stained to quantify the COX-2 expression. Thirty-two patients completed the treatment. The dose of celecoxib was escalated (200, 400 and 800mg bid, then de-escalated to 600mg bid). The acute toxicity related to the treatment in the first and second cohort did not reach grade III; in the third cohort three patients had grade III radiation toxicity and one had celecoxib-related toxicity. In the last fourth cohort the toxicity was acceptable. Significant VEGF level drop (p=0.011) was found between radiation day 1 and post-treatment visit. Significant decrease (p=0.022) of the VEGF level was shown in patients with high COX-2 expression in the tumor. Phase II recommended dose of celecoxib combined with accelerated radiotherapy in advanced H&N cancer was 600mg bid. A significant decrease of the post-treatment serum VEGF level compared to the initial level was noticed only in patients with high COX-2 expression in tumors.
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Affiliation(s)
- Magdalena Halamka
- Department of Oncology, University Hospital Ostrava, 17 Listopadu 1790, Ostrava-Poruba 708 52, Czech Republic
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Che SM, Zhang XZ, Liu XL, Chen X, Hou L. The radiosensitization effect of NS398 on esophageal cancer stem cell-like radioresistant cells. Dis Esophagus 2011; 24:265-73. [PMID: 21087344 DOI: 10.1111/j.1442-2050.2010.01138.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This study aimed to investigate the cancer stem cell (CSC) properties of radioresistant esophageal cancer cells and the radiosensitization effect of NS398, a cyclooxygenase (COX)-2 inhibitor, on them. Fractionated irradiation was applied to acquire radioresistant esophageal cancer cells. Clone formation assay was employed to detect cell radiosensitivity and cloning formation ability. Cell viability was determined by methyl tetrazolium colorimetry assay. Cell cycle distribution and apoptosis were detected by flow cytometry. Tumorigenicity was investigated by xenograft tumorigenicity assay. Expression levels of β-catenin were detected by reverse transcription polymerase chain reaction or Western blot. As results, radioresistant Eca109R50Gy cells were obtained through fractional irradiation from Eca109 cells; Eca109R50Gy cells displayed higher ability of proliferation, colony-formation, and 40 times tumorigenic ability as high as that of the Eca109 cells in vivo. Meantime stem cell marker β-catenin was elevated in Eca109R50Gy cells. All of the above implied that Eca109R50Gy cells have some properties of CSCs. NS398 enhanced the radiosensitivity of Eca109R50Gy cells accompanied by down-regulating the expression of β-catenin. In conclusion, radioresistant Eca109R50Gy cells carried some CSC-like properties; NS398 enhanced the radiosensitivity of CSC-like Eca109R50Gy cells and this function may partly through down-regulating the expression of β-catenin. These findings both stress the important role of CSCs in esophageal cancer radioresistance and provide new insight on possible application of COX-2 inhibitors on CSCs.
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Affiliation(s)
- S-M Che
- Department of Radiation Oncology, First Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, China
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13
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Loo WTY, Jin L, Cheung MNB, Wang M, Chow LWC. Epigenetic change in E-cadherin and COX-2 to predict chronic periodontitis. J Transl Med 2010; 8:110. [PMID: 21047437 PMCID: PMC2998472 DOI: 10.1186/1479-5876-8-110] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2010] [Accepted: 11/04/2010] [Indexed: 12/27/2022] Open
Abstract
Background DNA methylation of certain genes frequently occurs in neoplastic cells. Although the cause remains unknown, many genes have been identified with such atypical methylation in neoplastic cells. The hypermethylation of E-Cadherin and Cyclooxygenase 2 (COX-2) in chronic inflammation such as chronic periodontitis may demonstrate mild lesion/mutation epigenetic level. This study compares the hypermethylation status of E-Cadherin and COX-2 genes which are often found in breast cancer patients with that in chronic periodontitis. Methods Total DNA was extracted from the blood samples of 108 systemically healthy non-periodontitis subjects, and the gingival tissues and blood samples of 110 chronic periodontitis patient as well as neoplastic tissues of 106 breast cancer patients. Methylation-specific PCR for E-Cadherin and COX-2 was performed on these samples and the PCR products were analyzed on 2% agarose gel. Results Hypermethylation of E-Cadherin and COX-2 was observed in 38% and 35% of the breast cancer samples, respectively. In chronic periodontitis patients the detection rate was 25% and 19% respectively, and none was found in the systemically healthy non-periodontitis control subjects. The hypermethylation status was shown to be correlated among the three groups with statistical significance (p < 0.0001). The methylation of CpG islands in E-Cadherin and COX-2 genes in periodontitis patients occurs more frequently in periodontitis patients than in the control subjects, but occurs less frequently than in the breast cancer patients. Conclusions This set of data shows that the epigenetic change in E-Cadherin and Cyclooxygenase-2 is associated with chronic periodontitis. The epigenetic changes presented in chronic inflammation patients might demonstrate an irreversible destruction in the tissues or organs similar to the effects of cancer. Chronic periodontitis to some extent might be associated with DNA hypermethylation which is related to cancer risk factors.
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Affiliation(s)
- Wings T Y Loo
- Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.
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14
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Liao X, Che X, Zhao W, Zhang D, Long H, Chaudhary P, Li H. Effects of propranolol in combination with radiation on apoptosis and survival of gastric cancer cells in vitro. Radiat Oncol 2010; 5:98. [PMID: 20977754 PMCID: PMC2974742 DOI: 10.1186/1748-717x-5-98] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2010] [Accepted: 10/26/2010] [Indexed: 01/09/2023] Open
Abstract
Background The National Comprehensive Cancer Network (NCCN) guidelines recommend radiotherapy as a standard treatment for patients with a high risk of recurrence in gastric cancer. Because gastric cancer demonstrates limited sensitivity to radiotherapy, a radiosensitizer might therefore be useful to enhance the radiosensitivity of patients with advanced gastric carcinoma. In this study, we evaluated if propranolol, a β-adrenoceptor (β-AR) antagonist, could enhance radiosensitivity and explored its precise molecular mechanism in gastric cancer cells. Methods Human gastric adenocarcinoma cell lines (SGC-7901 and BGC-823) were treated with or without propranolol and exposed to radiation. Cell viability and clonogenic survival assays were performed, and cell apoptosis was evaluated with flow cytometry. In addition, the expression of nuclear factor κB (NF-κB), vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2), and epidermal growth factor receptor (EGFR) were detected by western blot and real-time reverse transcription polymerase chain reaction (PCR). Results Propranolol combined with radiation decreased cell viability and clonogenic survivability. Furthermore, it also induced apoptosis in both cell lines tested, as determined by Annexin V staining. In addition, treatment with propranolol decreased the level of NF-κB and, subsequently, down-regulated VEGF, COX-2, and EGFR expression. Conclusions Taken together, these results suggested that propranolol enhanced the sensitivity of gastric cancer cells to radiation through the inhibition of β-ARs and the downstream NF-κB-VEGF/EGFR/COX-2 pathway.
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Affiliation(s)
- Xinhua Liao
- Department of General Surgery, First Affiliated Hospital of Medical College of Xi'an Jiao-Tong University, Yanta West Road 277, Xi'an 710061, PR China
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15
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Che SM, Zhang XZ, Hou L, Song TB. Cyclooxygenase-2 Inhibitor NS398 Enhances Radiosensitivity of Radioresistant Esophageal Cancer Cells by Inhibiting AKT Activation and Inducing Apoptosis. Cancer Invest 2010; 28:679-88. [DOI: 10.3109/07357907.2010.483504] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Citrin D, Cotrim AP, Hyodo F, Baum BJ, Krishna MC, Mitchell JB. Radioprotectors and mitigators of radiation-induced normal tissue injury. Oncologist 2010; 15:360-71. [PMID: 20413641 PMCID: PMC3076305 DOI: 10.1634/theoncologist.2009-s104] [Citation(s) in RCA: 330] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2008] [Accepted: 04/05/2009] [Indexed: 11/17/2022] Open
Abstract
Radiation is used in the treatment of a broad range of malignancies. Exposure of normal tissue to radiation may result in both acute and chronic toxicities that can result in an inability to deliver the intended therapy, a range of symptoms, and a decrease in quality of life. Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. Herein, we review agents in clinical use or in development as radioprotectors and mitigators of radiation-induced normal tissue injury. Few agents are approved for clinical use, but many new compounds show promising results in preclinical testing.
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Affiliation(s)
- Deborah Citrin
- Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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17
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Kim YM, Lee EJ, Park SY, Cho KH, Kim JY, Pyo H. Cyclooxygenase-2 up-regulates ataxia telangiectasia and Rad3 related through extracellular signal-regulated kinase activation. Mol Cancer Res 2009; 7:1158-68. [PMID: 19584262 DOI: 10.1158/1541-7786.mcr-08-0493] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cyclooxygenase-2 (COX-2) overexpression caused prolonged G2 arrest after exposure to ionizing radiation (IR) in our previous study. We were therefore interested in investigating the function of COX-2 in the G2 checkpoint pathway. Interestingly, we found that cells in which COX-2 is overexpressed showed up-regulated ataxia telangiectasia and Rad3 related (ATR) expression compared with control cells. In this study, we investigated the mechanism of ATR up-regulation by COX-2 and tested our hypothesis that COX-2-induced extracellular signal-regulated kinase (ERK) activation mediates up-regulation of ATR by COX-2. To investigate the relationship between COX-2 and ATR, we used two stable COX-2-overexpressing cancer cell lines (HCT116-COX-2 and H460-COX-2), a COX-2 knockdown A549 lung cancer cell line (AS), and an ATR knockdown HCT116 cell line. Cells were treated with various drugs [celecoxib, prostaglandin E2 (PGE2), PD98059, U0126, and hydroxyurea] and were then analyzed using reverse transcription-PCR, confocal microscopy, Western blotting, and clonogenic assay. COX-2-overexpressing cells were shown to have increased ERK phosphorylation and ATR expression compared with control cells, whereas AS cells were shown to have decreased levels of phospho-ERK and ATR. In addition, exogenously administered PGE2 increased ERK phosphorylation. Inhibition of ERK phosphorylation decreased ATR expression in both HCT116-COX-2 and A549 cells. HCT116-COX-2 cells were resistant to IR or hydroxyurea compared with HCT116-Mock cells, whereas administration of ATR shRNA showed the opposite effect. COX-2 stimulates ERK phosphorylation via PGE2. This COX-2-induced ERK activation seems to increase ATR expression and activity in endogenous COX-2-overexpressing cancer cells as well as in COX-2-overexpressing stable cell lines.
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Affiliation(s)
- Young Mee Kim
- Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Republic of Korea
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18
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Pfister C, Ritz R, Pfrommer H, Bornemann A, Tatagiba MS, Roser F. Are there attacking points in the eicosanoid cascade for chemotherapeutic options in benign meningiomas? Neurosurg Focus 2007; 23:E8. [DOI: 10.3171/foc-07/10/e8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Object
The current treatment for recurrent or malignant meningiomas with adjuvant therapies has not been satisfactory, and there is an intense interest in evaluating new molecular markers to act as therapeutic targets. Enzymes of the arachidonic acid (AA) cascade such as cyclooxygenase (COX)–2 or 5-lipoxygenase (5-LO) are upregulated in a number of epithelial tumors, but to date there are hardly any data about the expression of these markers in meningiomas. To find possible targets for chemotherapeutic intervention, the authors evaluated the expression of AA derivatives at different molecular levels in meningiomas.
Methods
One hundred and twenty-four meningioma surgical specimens and normal human cortical tissue samples were immunohistochemically and cytochemically stained for COX-2, COX-1, 5-LO, and prostaglandin E receptor 4 (PTGER4). In addition, Western blot and polymerase chain reaction (PCR) analyses were performed to detect the presence of eicosanoids in vivo and in vitro.
Results
Sixty (63%) of 95 benign meningiomas, 21 (88%) of 24 atypical meningiomas, all five malignant meningiomas, and all normal human cortex samples displayed high COX-2 immunoreactivity. All cultured specimens and IOMM-Lee cells stained positive for COX-2, COX-1, 5-LO, and PTGER4. The PCR analysis demonstrated no changes in eicosanoid expression among meningiomas of different World Health Organization grades and in normal human cortical and dura mater tissue.
Conclusions
Eicosanoid derivatives COX-1, COX-2, 5-LO, and PTGER4 enzymes show a high universal expression in meningiomas but are not upregulated in normal human cortex and dura tissue. This finding of the ubiquitous presence of these enzymes in meningiomas offers an excellent baseline for testing upcoming chemotherapeutic treatments.
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Affiliation(s)
| | | | | | - Antje Bornemann
- 2the Institute of Brain Research, University of Tübingen, Germany
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Ning S, Chen Z, Dirks A, Husbeck B, Hsu M, Bedogni B, O'Neill M, Powell MB, Knox SJ. Targeting integrins and PI3K/Akt-mediated signal transduction pathways enhances radiation-induced anti-angiogenesis. Radiat Res 2007; 168:125-133. [PMID: 17722999 DOI: 10.1667/rr0829.1] [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] [Received: 09/19/2006] [Accepted: 02/14/2007] [Indexed: 11/03/2022]
Abstract
The integrins and PI3K/Akt are important mediators of the signal transduction pathways involved in tumor angiogenesis and cell survival after exposure to ionizing radiation. Selective targeting of either integrins or PI3K/Akt can radiosensitize tumors. In this study, we tested the hypothesis that the combined inhibition of integrin alphanubeta3 by cRGD and PI3K/Akt by LY294002 would significantly enhance radiation-induced inhibition of angiogenesis by vascular endothelial cells. Treatment with cRGD inhibited the adhesion and tube formation of human umbilical vein endothelial cells (HUVECs). The inhibitory effect was further increased when cRGD and LY294002 were applied simultaneously. Both radiation and cRGD induced Akt phosphorylation, up-regulated COX2 expression, and increased PGE2 production in HUVECs. Treatment with LY294002 effectively inhibited radiation- and cRGD-induced Akt phosphorylation and up-regulation of COX2 and increased apoptosis of HUVECs. The combined use of cRGD and LY294002 enhanced radiation-induced cell killing. The clonogenic survival of HUVECs was decreased from 34% with 2 Gy radiation to 4% with these agents combined. These results demonstrate that combined use of ionizing radiation, cRGD and LY294002 inhibited multiple signaling transduction pathways involved in tumor angiogenesis and enhanced radiation-induced effects on vascular endothelial cells.
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Affiliation(s)
- Shoucheng Ning
- Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA 94305-5152, USA
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Bijnsdorp IV, van den Berg J, Kuipers GK, Wedekind LE, Slotman BJ, van Rijn J, Lafleur MVM, Sminia P. Radiosensitizing potential of the selective cyclooygenase-2 (COX-2) inhibitor meloxicam on human glioma cells. J Neurooncol 2007; 85:25-31. [PMID: 17447009 DOI: 10.1007/s11060-007-9385-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2006] [Accepted: 03/28/2007] [Indexed: 12/27/2022]
Abstract
The COX-2 protein is frequently overexpressed in human malignant gliomas. This expression has been associated with their aggressive growth characteristics and poor prognosis for patients. Targeting the COX-2 pathway might improve glioma therapy. In this study, the effects of the selective COX-2 inhibitor meloxicam alone and in combination with irradiation were investigated on human glioma cells in vitro. A panel of three glioma cell lines (D384, U87 and U251) was used in the experiments from which U87 cells expressed constitutive COX-2. The response to meloxicam and irradiation (dose-range of 0-6 Gy) was determined by the clonogenic assay, cell proliferation was evaluated by growth analysis and cell cycle distribution by FACS. 24-72 h exposure to 250-750 microM meloxicam resulted in a time and dose dependent growth inhibition with an almost complete inhibition after 24 h for all cell lines. Exposure to 750 microM meloxicam for 24 h increased the fraction of cells in the radiosensitive G(2)/M cell cycle phase in D384 (18-27%) and U251 (17-41%) cells. 750 microM meloxicam resulted in radiosensitization of D384 (DMF:2.19) and U87 (DMF:1.25) cells, but not U251 cells (DMF:1.08). The selective COX-2 inhibitor meloxicam exerted COX-2 independent growth inhibition and radiosensitization of human glioma cells.
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Affiliation(s)
- Irene V Bijnsdorp
- Department of Radiation Oncology, Division Radiobiology, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands
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Ning QJ, Qin SW, Xu CS. Expression patterns and action analysis of genes associated with drug-induced liver diseases during rat liver regeneration. World J Gastroenterol 2006; 12:6966-72. [PMID: 17109518 PMCID: PMC4087340 DOI: 10.3748/wjg.v12.i43.6966] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To study the action of the genes associated with drug-induced liver diseases at the gene transcriptional level during liver regeneration (LR) in rats.
METHODS: The genes associated with drug-induced liver diseases were obtained by collecting the data from databases and literature, and the gene expression changes in the regenerating liver were checked by the Rat Genome 230 2.0 array.
RESULTS: The initial and total expression numbers of genes occurring in phases of 0.5-4 h after partial hepatectomy (PH), 4-6 h after PH (G0/G1 transition), 6-66 h after PH (cell proliferation), 66-168 h after PH (cell differentiation and structure-function reconstruction) were 21, 3, 9, 2 and 21, 9, 19, 18, respectively. It is illustrated that the associated genes were mainly triggered at the initial stage of LR and worked at different phases. According to their expression similarity, these genes were classified into 5 types: only up-regulated (12 genes), predominantly up-regulated (4 genes), only down-regulated (11 genes), predominantly down-regulated (3 genes), and approximately up-/down-regulated (2 genes). The total times of their up- and down-expression were 130 and 79, respectively, demonstrating that expression of most of the genes was increased during LR, while a few decreased. The cell physiological and biochemical activities during LR were staggered according to the time relevance and were diverse and complicated in gene expression patterns.
CONCLUSION: Drug metabolic capacity in regenerating liver was enhanced. Thirty-two genes play important roles during liver regeneration in rats.
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Affiliation(s)
- Qian-Ji Ning
- College of Life Science, Henan Normal University, Xinxiang 453007, Henan Province, China
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22
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Sminia P, Stoter TR, van der Valk P, Elkhuizen PHM, Tadema TM, Kuipers GK, Vandertop WP, Lafleur MVM, Slotman BJ. Expression of cyclooxygenase-2 and epidermal growth factor receptor in primary and recurrent glioblastoma multiforme. J Cancer Res Clin Oncol 2005; 131:653-61. [PMID: 16133570 DOI: 10.1007/s00432-005-0020-5] [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] [Received: 01/04/2005] [Accepted: 05/15/2005] [Indexed: 10/25/2022]
Abstract
PURPOSE To investigate the pattern and level of cyclooxygenase-2 (COX-2) expression in a series of high grade primary and recurrent glioblastoma multiforme (GBM) and correlation with time to recurrence and patients' survival following therapy. The relationship between COX-2 and epidermal growth factor receptor (EGFR) immunoreactivities was evaluated. MATERIALS AND METHODS Specimens of 14 primary and 14 recurrent GBMs (eight pairs) following surgery and full course radiation therapy were processed for immunostaining on COX-2 and EGFR. Tumor cell positivity was semi-quantitatively scored. COX-2 scores of the primary tumor and recurrence were correlated with the time to radiological tumor progression and patients' survival. RESULTS COX-2 positive tumor cells were disseminated throughout the tumor parenchyma. The intensity and pattern of COX-2 expression were heterogeneous, with predominant expression in areas surrounding tumor necrosis. Scoring of COX-2 positivity revealed values between 1 and 80% of the cells. Primary GBMs with COX-2 expression levels between 25% and 70% of the tumor cells showed a shorter time to radiological recurrence than GBMs with <10% COX-2 positive tumor cells (respectively, 219 +/- 50 and 382 +/- 77 days). No correlation was found between the COX-2 expression in the primary tumor and patients' survival (r (s) = -0.073) following therapy. No correlation was found either between COX-2 and EGFR immunoreactivity. CONCLUSIONS Immunohistochemical expression of COX-2 in GBM showed large variation. Hence, determination of COX-2 expression in tumor specimen for each individual might be relevant for selection of those patients, who could benefit from adjuvant therapy with selective COX-2 inhibitors.
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Affiliation(s)
- Peter Sminia
- Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
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