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Xu Y, Wang J, He Z, Rao Z, Zhang Z, Zhou J, Zhou T, Wang H. A review on the effect of COX-2-mediated mechanisms on development and progression of gastric cancer induced by nicotine. Biochem Pharmacol 2024; 220:115980. [PMID: 38081368 DOI: 10.1016/j.bcp.2023.115980] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/07/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023]
Abstract
Smoking is a documented risk factor for cancer, e.g., gastric cancer. Nicotine, the principal tobacco alkaloid, would exert its role of contribution to gastric cancer development and progression through nicotinic acetylcholine receptors (nAChRs) and β-adrenergic receptors (β-ARs), which then promote cancer cell proliferation, migration and invasion. As a key isoenzyme in conversion of arachidonic acid to prostaglandins, cyclooxygenase-2 (COX-2) has been demonstrated to have a wide range of effects in carcinogenesis and tumor development. At present, many studies have reported the effect of nicotine on gastric cancer by binding to nAChR, as well as indirectly stimulating β-AR to mediate COX-2-related pathways. This review summarizes these studies, and also proposes more potential COX-2-mediated mechanisms. These events might contribute to the growth and progression of gastric cancer exposed to nicotine through tobacco smoke or cigarette substitutes. Also, this review article has therefore the potential not only to make a significant contribution to the treatment and prognosis of gastric cancer for smokers but also to the clinical application of COX-2 antagonists. In addition, this work also discusses the considerable challenges of this field with special reference to the future perspective of COX-2-mediated mechanisms in development and progression of gastric cancer induced by nicotine.
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Affiliation(s)
- Yuqin Xu
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Juan Wang
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China
| | - Zihan He
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Zihan Rao
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Zhongwei Zhang
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Jianming Zhou
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Tong Zhou
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
| | - Huai Wang
- School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China.
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Mahboubi-Rabbani M, Abbasi M, Zarghi A. Natural-Derived COX-2 Inhibitors as Anticancer Drugs: A Review of their Structural Diversity and Mechanism of Action. Anticancer Agents Med Chem 2023; 23:15-36. [PMID: 35638275 DOI: 10.2174/1389450123666220516153915] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/07/2022] [Accepted: 03/01/2022] [Indexed: 02/08/2023]
Abstract
Cyclooxygenase-2 (COX-2) is a key-type enzyme playing a crucial role in cancer development, making it a target of high interest for drug designers. In the last two decades, numerous selective COX-2 inhibitors have been approved for various clinical conditions. However, data from clinical trials propose that the prolonged use of COX-2 inhibitors is associated with life-threatening cardiovascular side effects. The data indicate that a slight structural modification can help develop COX-2 selective inhibitors with comparative efficacy and limited side effects. In this regard, secondary metabolites from natural sources offer great hope for developing novel COX-2 inhibitors with potential anticancer activity. In recent years, various nature-derived organic scaffolds are being explored as leads for developing new COX-2 inhibitors. The current review attempts to highlight the COX-2 inhibition activity of some naturally occurring secondary metabolites, concerning their capacity to inhibit COX-1 and COX-2 enzymes and inhibit cancer development, aiming to establish a structure-activity relationship.
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Affiliation(s)
- Mohammad Mahboubi-Rabbani
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Abbasi
- Department of Medicinal Chemistry, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Afshin Zarghi
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Canine mammary carcinoma: current therapeutic targets and future perspectives – a review. ANNALS OF ANIMAL SCIENCE 2023. [DOI: 10.2478/aoas-2022-0085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Abstract
Canine mammary carcinoma (CMC) is the most common neoplasm in bitches, and it shares many biological similarities with breast cancer in humans. Drug resistance, high epigenetic mutations, and relapse rates are among the challenges which eventually urge the need for a veterinary oncologist to discover new therapeutic approaches that are more effective and safer. Therefore, in this review, we also cover the current therapeutic strategies from human medicine for the future perspectives of tumor immunotherapy in veterinary medicine. These strategies have great potential to be employed as therapeutic or prophylactic options due to their ability to modulate a specific and potent immune response against CMC. As we acquire a better understanding of canine tumor immunology, we can move towards a brighter prognosis. Additionally, we report on the recent successful studies in breast cancer that may benefit canines as well.
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Chemopreventive Properties of Black Raspberries and Strawberries in Esophageal Cancer Review. Antioxidants (Basel) 2022; 11:antiox11091815. [PMID: 36139889 PMCID: PMC9495642 DOI: 10.3390/antiox11091815] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/02/2022] [Accepted: 09/10/2022] [Indexed: 11/17/2022] Open
Abstract
Esophageal cancer is one of the most fetal malignancies in the world. Esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinoma (AC) are two main types of esophageal cancer and each with distinct epidemiological, etiological and histopathological characteristics. The continued global prevalence of tobacco use and alcohol consumption, coupled with limited intake of fresh fruits and vegetables, ensures that esophageal cancer will remain one of the major health threats. In addition to promoting quitting smoking and alcohol abuse, one of the strategies of cancer prevention is to identify foods, food components, or dietary patterns that can prevent or delay the onset of esophageal cancer. A food-based approach has the advantage of a complex of mixtures of bioactive components simultaneously targeting multiple processes in carcinogenesis. We have employed a preclinical rodent model of esophageal SCC to assess the effects of black raspberries (BRB) and strawberries. Our investigations demonstrate that BRB and strawberries are potent inhibitors of esophageal cancer. To prepare for this review, a literature search was performed to screen BRB and strawberries against esophageal cancer using electronic databases from PubMed, Science Direct and Google Scholar. Search was conducted covering the period from January 2000 to June 2022. Our present review has provided a systematic review about chemopreventive effects of BRB and strawberries in esophageal cancer by collecting and compiling diverse research findings from the above sources. In this review, we discussed the anti-tumor potentials of BRB and strawberries in esophageal SCC and esophageal AC separately. For each cancer type, we discuss animal models and research findings from both animal bioassays and human clinical studies. We also discuss the potential mechanisms of action of berries and their key bioactive components.
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Rojas A, Lindner C, Schneider I, Gonzàlez I, Araya H, Morales E, Gómez M, Urdaneta N, Araya P, Morales MA. Diabetes mellitus contribution to the remodeling of the tumor microenvironment in gastric cancer. World J Gastrointest Oncol 2021; 13:1997-2012. [PMID: 35070037 PMCID: PMC8713306 DOI: 10.4251/wjgo.v13.i12.1997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/10/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial contribution of diabetes mellitus (DM) as a risk factor associated with increased cancer incidence and mortality in many human neoplasms, including gastric cancer (GC). DM is considered a systemic inflammatory disease and therefore, this inflammatory status may have profound effects on the tumor microenvironment (TME), particularly by driving many molecular mechanisms to generate a more aggressive TME. DM is an active driver in the modification of the behavior of many cell components of the TME as well as altering the mechanical properties of the extracellular matrix (ECM), leading to an increased ECM stiffening. Additionally, DM can alter many cellular signaling mechanisms and thus favoring tumor growth, invasion, and metastatic potential, as well as key elements in regulating cellular functions and cross-talks, such as the microRNAs network, the production, and cargo of exosomes, the metabolism of cell stroma and resistance to hypoxia. In the present review, we intend to highlight the mechanistic contributions of DM to the remodeling of TME in GC.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Cristian Lindner
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Iván Schneider
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Ileana Gonzàlez
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Hernan Araya
- Department of Clinical Sciences, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Oncología, Hospital Regional de Talca, Talca 34600000, Chile
| | - Erik Morales
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Anatomía Patologica, Hospital Regional de Talca, Talca 34600000, Chile
| | - Milibeth Gómez
- Department of Clinical Sciences, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Oncología, Hospital Regional de Talca, Talca 34600000, Chile
| | - Nelson Urdaneta
- Department of Clinical Sciences, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Oncología, Hospital Regional de Talca, Talca 34600000, Chile
| | - Paulina Araya
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Miguel Angel Morales
- Department of Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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Rahimifard M, Haghi-Aminjan H, Hadjighassem M, Pourahmad Jaktaji R, Bagheri Z, Azami Movahed M, Zarghi A, Pourahmad J. Assessment of cytotoxic effects of new derivatives of pyrazino[1,2-a] benzimidazole on isolated human glioblastoma cells and mitochondria. Life Sci 2021; 286:120022. [PMID: 34626606 DOI: 10.1016/j.lfs.2021.120022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/22/2021] [Accepted: 09/29/2021] [Indexed: 01/01/2023]
Abstract
AIMS Glioblastoma multiforme (GBM) is a highly devastating malignant brain tumor with poor pharmacotherapy. Based on COX-2 inhibitory effects in preventing cancer progression, new pyrazino[1,2-a]benzimidazole derivatives were assessed on isolated human GBM cells. MAIN METHODS In this study, firstly, primary culture of astrocytes from human GBM samples was prepared and exposed to 2,6-dimethyl pyrazino[1,2-a]benzimidazole (L1) and 3,4,5-trimethoxy pyrazino[1,2-a]benzimidazole (L2) for finding their half-maximal inhibitory concentration (IC50). In the following, in two phases, cell apoptosis pathway and mitochondrial markers were investigated on GBM and also HEK293 cells (as non-cancerous normal cells). KEY FINDINGS The MTT results represented a remarkable selective cytotoxic effect of both L1 and L2 on GBM cells, and interestingly not on normal cells. After 48 h, IC50 of L1 and L2 were calculated as 13 μM and 85 μM, respectively. Annexin/PI staining showed that L1 and L2 induce apoptosis in GBM cells, and caspase measurement showed that apoptosis occurs through mitochondrial signaling. In the clonogenic assay, GBM cells formed more paraclones and fewer holoclones after treating with L1 and L2. L1 and L2 also selectively enhanced mitochondrial damaged markers, including reactive oxygen species (ROS) formation, and mitochondrial swelling, decreased mitochondrial membrane potential (MMP) and cytochrome c release in isolated cancerous GBM mitochondria. SIGNIFICANCE Our findings on human primary astrocyte cells illustrated that L1 and L2 compounds, with COX-2 inhibitory effect, through the intrinsic pathway of apoptosis concerning mitochondrial damage enhancement have therapeutic potentials on GBM.
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Affiliation(s)
- Mahban Rahimifard
- Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Haghi-Aminjan
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mahmoudreza Hadjighassem
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Zeinab Bagheri
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G.C., Tehran, Iran
| | - Mahsa Azami Movahed
- Department of Medicinal and Pharmaceutical Chemistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Zarghi
- Department of Medicinal and Pharmaceutical Chemistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Jalal Pourahmad
- Faculty of Pharmacy, Department of Pharmacology/Toxicology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Abdi E, Latifi-Navid S, Abedi Sarvestani F, Esmailnejad MH. Emerging therapeutic targets for gastric cancer from a host- Helicobacter pylori interaction perspective. Expert Opin Ther Targets 2021; 25:685-699. [PMID: 34410200 DOI: 10.1080/14728222.2021.1971195] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Gastric cancer (GC) has the higher genetic, cytologic, and architectural heterogeneity compared to other gastrointestinal cancers. By inducing gastric inflammation, Helicobacter pylori (HP) may lead to GC through combining bacterial factors with host factors. In this regard, identification of the major therapeutic targets against the host-HP interactions plays a critical role in GC prevention, diagnosis, and treatment. AREAS COVERED This study offers new insights into the promising therapeutic targets against the angiogenesis, invasion, or metastasis of GC from a host-HP interaction perspective. To this end, MEDLINE, EMBASE, LILACS, AIM, and IndMed databases were searched for relevant articles since 1992. EXPERT OPINION Wnt signaling and COX pathway have a well-documented history in the genesis of GC by HP and might be considered as the most promising targets for early GC treatment. Destroying HP may decrease the risk of GC, but it cannot fully hinder the GC development induced by HP infection. Therefore, targeting HP-activated pathways, especially COX-2/Wnt/beta-catenin/VEGF, TLR2/TLR9/COX-2, COX2-PGE2, and NF-κB/COX-2, as well as EPHA2, MMPs, and miR-543/SIRT1 axis, can be an effective measure in the early treatment of GC. However, different clinical trials and large, multi-center cohorts are required to validate these potentially effective targets for GC therapy.
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Affiliation(s)
- Esmat Abdi
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Saeid Latifi-Navid
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
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Khafaga AF, Shamma RN, Abdeen A, Barakat AM, Noreldin AE, Elzoghby AO, Sallam MA. Celecoxib repurposing in cancer therapy: molecular mechanisms and nanomedicine-based delivery technologies. Nanomedicine (Lond) 2021; 16:1691-1712. [PMID: 34264123 DOI: 10.2217/nnm-2021-0086] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
While cancer remains a significant global health problem, advances in cancer biology, deep understanding of its underlaying mechanism and identification of specific molecular targets allowed the development of new therapeutic options. Drug repurposing poses several advantages as reduced cost and better safety compared with new compounds development. COX-2 inhibitors are one of the most promising drug classes for repurposing in cancer therapy. In this review, we provide an overview of the detailed mechanism and rationale of COX-2 inhibitors as anticancer agents and we highlight the most promising research efforts on nanotechnological approaches to enhance COX-2 inhibitors delivery with special focus on celecoxib as the most widely studied agent for chemoprevention or combined with chemotherapeutic and herbal drugs for combating various cancers.
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Affiliation(s)
- Asmaa F Khafaga
- Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina, 22758, Egypt
| | - Rehab N Shamma
- Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Ahmed Abdeen
- Department of Forensic Medicine & Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh, 13736, Egypt
| | | | - Ahmed E Noreldin
- Department of Histology & Cytology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22516, Egypt
| | - Ahmed O Elzoghby
- Cancer Nanotechnology Research Laboratory (CNRL), Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.,Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
| | - Marwa A Sallam
- Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
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Maniewska J, Jeżewska D. Non-Steroidal Anti-Inflammatory Drugs in Colorectal Cancer Chemoprevention. Cancers (Basel) 2021; 13:cancers13040594. [PMID: 33546238 PMCID: PMC7913298 DOI: 10.3390/cancers13040594] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/29/2021] [Accepted: 01/30/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary There is growing evidence from epidemiologic, preclinical and clinical studies suggesting that non-steroidal anti-inflammatory drugs (NSAIDs) play a beneficial role in colorectal cancer chemoprevention. They reduce the risk of colorectal polyps, mostly by cyclooxygenase-2 inhibition. The aim of our work was to describe the current state of scientific knowledge on the potential added value of the use of NSAIDs (such as aspirin, sulindac, and celecoxib) as chemopreventive agents in patients at risk of colorectal cancer. The study confirmed that there is a link between the long-term use of the NSAIDs and a decrease in the risk of colorectal cancer. Abstract Since colorectal cancer is one of the world’s most common cancers, studies on its prevention and early diagnosis are an emerging area of clinical oncology these days. For this study, a review of randomized controlled, double-blind clinical trials of selected NSAIDs (aspirin, sulindac and celecoxib) in chemoprevention of colorectal cancer was conducted. The main molecular anticancer activity of NSAIDs is thought to be a suppression of prostaglandin E2 synthesis via cyclooxygenase-2 inhibition, which causes a decrease in tumor cell proliferation, angiogenesis, and increases apoptosis. The lower incidence of colorectal cancer in the NSAID patients suggests the long-lasting chemopreventive effect of drugs studied. This new approach to therapy of colorectal cancer may transform the disease from a terminal to a chronic one that can be taken under control.
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Celecoxib induces apoptosis through Akt inhibition in 5-fluorouracil-resistant gastric cancer cells. Toxicol Res 2021; 37:25-33. [PMID: 33489855 DOI: 10.1007/s43188-020-00044-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/10/2020] [Accepted: 03/04/2020] [Indexed: 10/24/2022] Open
Abstract
Gastric cancer is the fifth leading cause of cancer and a global public health problem. 5-Fluorouracil (5-FU) is the primary drug chosen for the treatment of advanced gastric cancer, but acquired cancer drug resistance limits its effectiveness and clinical use. Proliferation assays showed that a gastric carcinoma cell line, AGS and 5-FU-resistant AGS cells (AGS FR) treated with 3-100 μM 5-FU for 48 h or 72 h showed different sensitivities to 5-FU. Immunoblot assay demonstrated that AGS FR cells expressed more COX-2 and PGE2-cognated receptor EP2 than AGS cells. AGS FR cells considerably produced PGE2 than AGS upon stimulation with 5-FU. These results suggest that COX-2 expression is associated with 5-FU resistance. Unlike AGS FR cells, AGS cells showed increased levels of both cleaved caspase-3 and Bax following 5-FU treatment. Treatment of cells with the COX-2 selective inhibitor celecoxib induced cell death of AGS FR cells in a time- and concentration-dependent manner. FACS analysis showed that celecoxib at high doses caused apoptotic cell death, demonstrating a concentration-dependent increase in the cell populations undergoing early apoptosis and late apoptosis. This apoptotic induction was strongly supported by the expression profiles of apoptosis- and survival-associated proteins in response to celecoxib; pro-apoptotic cellular proteins increased while expressions of COX-2 and p-Akt were downregulated in a concentration-dependent manner. An increase in PTEN expression was accompanied with downregulation of p-Akt. Based on the data that downregulation of COX-2 was correlated with the concentrations of celecoxib, COX-2 may play a key role in celecoxib-induced cell death of AGS FR cells. Butaprost, the EP2 agonist, promoted proliferative activity of AGS FR cells in a concentration-dependent manner compared with AGS cells. In cells exposed to butaprost, expressions of COX-2 and p-Akt were increased in a concentration-dependent manner with concomitantly reduced PTEN levels. Taken together, 5-FU-resistance in gastric cancer is correlated with COX-2 expression, and therefore the selective inhibition of COX-2 leads to suppression of cell proliferation of AGS FR cells. Modulation of COX-2 expression and its catalytic activity may be a potential therapeutic strategy to overcome 5-FU-resistant gastric cancer.
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Omayone TP, Salami AT, Olopade JO, Olaleye SB. Attenuation of ischemia-reperfusion-induced gastric ulcer by low-dose vanadium in male Wistar rats. Life Sci 2020; 259:118272. [PMID: 32800836 DOI: 10.1016/j.lfs.2020.118272] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 08/02/2020] [Accepted: 08/10/2020] [Indexed: 12/15/2022]
Abstract
AIM Vanadium, a trace element found in food and water sources has been previous reported to attenuate ulcer formation without much insight into its mechanism of action. This study highlights the mechanism by which vanadium exhibits its gastro-protective activity. MAIN METHODS Eighty male Wistar rats (80-100 g) were randomized into 8 equal groups. Groups 1 (control) and 2 (Ulcerated control) received water only, groups 3-8 received vanadium at 5, 10, 25, 50, 100 and 200 ppm respectively in their drinking water for ten weeks. Gastric ulcer was thereafter induced in groups (2-8) via ischaemia-reperfusion (IR) technique. The stomachs were excised for macroscopic examination, evaluation of mucous content, oxidative stress markers, hydrogen/potassium (H+/K+) and calcium (Ca++) ATPases activities plus expression of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Vanadium at low doses inhibited IR induced gastric ulcer by 62.62% (10 ppm), 54.80% (25 ppm) and 43.50% (50 ppm). KEY FINDINGS Low dose vanadium increased mucous content, superoxide dismutase, catalase, glutathione activities and nitrite concentrations compared to ulcerated control group. The observed increase in malondialdehyde, Ca++ and H+/K+ ATPase activities, iNOS and COX-2 expression following IR were significantly reduced by pretreatment with vanadium. SIGNIFICANCE This study demonstrated that vanadium at low doses exhibit gastro-protective activities on IR induced gastric ulcer in rat model by inhibiting proton pump activities and decreasing expressions of iNOS and COX-2, thereby giving more insight into the protective action of vanadium.
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Affiliation(s)
- Tosan Peter Omayone
- Department of Physiology, University of Ibadan, Ibadan, Nigeria; Department of Physiology, Federal University of Technology Akure, Akure, Nigeria.
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Hu Z, Hu Y, Jiang H. Overexpression of COX-2 and clinicopathological features of gastric cancer: a meta-analysis. Transl Cancer Res 2020; 9:2200-2209. [PMID: 35117580 PMCID: PMC8798741 DOI: 10.21037/tcr.2020.03.52] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 02/14/2020] [Indexed: 01/11/2023]
Abstract
Background To evaluate the correlation between COX-2 overexpression and clinicopathological features of gastric cancer, thus providing theoretical basis for anti-COX-2 targeted therapy. Methods The literature about COX-2 expression and gastric cancer was searched in PubMed, Wangfang, VIP, CNKI from the inception to September 2019, with “gastric cancer”, “COX-2”, “cyclooxygenase” as keywords. Stata 15.0 was used to analyze. Age, gender, differentiation, infiltration depth, lymph node metastasis, tumor size, TNM staging were analyzed by OR (95% CI). Results Nine studies involving 1,289 patients with gastric cancer were identified, among which 878 cases existed COX-2 overexpression. COX-2 overexpression was related to the infiltration depth (OR=1.76; 95% CI: 1.01–1.306; P<0.01) and lymph node metastasis (OR=3.08; 95% CI: 1.64–5.79; P<0.01). While, it was not related to age, gender, differentiation and tumor size. Conclusions COX-2 overexpression is valuable in predicting infiltration depth and lymph node metastasis, and could be a predictor of poor prognosis in gastric cancer. COX-2-targeted therapy can be considered as one of the comprehensive treatments for gastric cancer.
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Affiliation(s)
- Zhili Hu
- Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.,Department of General Surgery, The Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
| | - Yangzhi Hu
- Department of General Surgery, The Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
| | - Haiping Jiang
- Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China
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Lin XM, Luo W, Wang H, Li RZ, Huang YS, Chen LK, Wu XP. The Role of Prostaglandin-Endoperoxide Synthase-2 in Chemoresistance of Non-Small Cell Lung Cancer. Front Pharmacol 2019; 10:836. [PMID: 31440159 PMCID: PMC6694719 DOI: 10.3389/fphar.2019.00836] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 07/01/2019] [Indexed: 12/22/2022] Open
Abstract
The prostaglandin-endoperoxide synthase-2 (PTGS2) plays essential roles in diverse pathological process. Although recent studies implied that PTGS2 was closely related with chemoresistance, the precise roles and the underlying mechanisms of PTGS2 in the developing process of chemoresistance in non-small cell lung cancer (NSCLC) remained elusive. In the present study, we revealed a novel molecular mechanism of PTGS2 implicated in the chemoresistance of NSCLC and proposed a model for the positive feedback regulation of PTGS2 in the process of developing resistance phenotype in NSCLC cells. Our results demonstrated that cisplatin induced PTGS2 expression through the ROS-ERK1/2-NF-κB signaling axis. The prostaglandin E2 (PGE2) derived from PTGS2 catalyzation further strengthened PTGS2 expression via the PGE2-EPs-ERK1/2 positive feedback loop, which induced multidrug resistance of NSCLC cells through up-regulation of BCL2 expression and the subsequent attenuation of cell apoptosis. Consistently, high levels of both PTGS2 and BCL2 were closely associated with poor survival in NSCLC patients. Inhibition of PTGS2 significantly reversed the chemoresistance in the resistant NSCLC in vitro and in vivo. Our results suggested that PTGS2 might be employed as an adjunctive therapeutic target for improving the response to the therapeutic agents in a subset of resistant NSCLC.
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Affiliation(s)
- Xiao-Mian Lin
- Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Wu Luo
- Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Heng Wang
- Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Rong-Zhen Li
- Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Yi-Shan Huang
- Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Lian-Kuai Chen
- Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Xiao-Ping Wu
- Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
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Şenkardeş S, Han Mİ, Kulabaş N, Abbak M, Çevik Ö, Küçükgüzel İ, Küçükgüzel ŞG. Synthesis, molecular docking and evaluation of novel sulfonyl hydrazones as anticancer agents and COX-2 inhibitors. Mol Divers 2019; 24:673-689. [PMID: 31302853 DOI: 10.1007/s11030-019-09974-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 07/04/2019] [Indexed: 10/26/2022]
Abstract
In trying to develop new anticancer agents, a series of sulfonylhydrazones were synthesized. All synthesized compounds were checked for identity and purity using elemental analysis, TLC and HPLC and were characterized by their melting points, FT-IR and NMR spectral data. All synthesized compounds were evaluated for their cytotoxic activity against prostate cancer (PC3), breast cancer (MCF-7) and L929 mouse fibroblast cell lines. Among them, N'-[(2-chloro-3-methoxyphenyl)methylidene]-4-methylbenzenesulfonohydrazide (3k) showed the most potent anticancer activity against both cancer cells with good selectivity (IC50 = 1.38 μM on PC3 with SI = 432.30 and IC50 = 46.09 μM on MCF-7 with SI = 12.94). Further investigation confirmed that 3k displayed morphological alterations in PC3 and MCF-7 cells and promoted apoptosis through down-regulation of the Bcl-2 and upregulation of Bax expression. Additionally, compound 3k was identified as the most potent COX-2 inhibitor (91% inhibition) beside lower COX-1 inhibition. Molecular docking of the tested compounds represented important binding modes which may be responsible for their anticancer activity via inhibition of the COX-2 enzyme. Overall, the lead compound 3k deserves further development as a potential anticancer agent. Sulfonylhydrazones was synthesized and N'-[(2-chloro-3-methoxyphenyl)methylidene]-4- methylbenzenesulfonohydrazide (3k) was identified as the most potent anticancer agent and COX-2 inhibitor. In addition, this compound docked inside the active site of COX-2 succesfully.
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Affiliation(s)
- Sevil Şenkardeş
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa, 34668, İstanbul, Turkey.
| | - M İhsan Han
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey
| | - Necla Kulabaş
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa, 34668, İstanbul, Turkey
| | - Mürüvvet Abbak
- Scientific Technology Research and Application Centre, Adnan Menderes University, Aydın, Turkey
| | - Özge Çevik
- Department of Biochemistry, School of Medicine, Adnan Menderes University, Aydın, Turkey
| | - İlkay Küçükgüzel
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa, 34668, İstanbul, Turkey
| | - Ş Güniz Küçükgüzel
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa, 34668, İstanbul, Turkey
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Korga A, Ostrowska M, Iwan M, Skierucha M, Józefczyk A, Pawłowski P, Dudka J, Maciejewski R, Sitarz R. Ethanol extracts of Allium sp. regulate cyclooxygenase-2 and E-cadherin expression in gastric cancer MKN74 cell line and enhance doxorubicin toxicity. Food Nutr Res 2019; 63:3449. [PMID: 31297043 PMCID: PMC6604903 DOI: 10.29219/fnr.v63.3449] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/30/2019] [Accepted: 05/08/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) remains one of the leading causes of cancer-related death. Its aetiology is multifactorial, but the major risk factor is a high in salt diet. During gastric carcinogenesis, cadherin-1 (CDH1) down-expression and cyclooxygenase 2 (COX2) overexpression may be observed. The intensity of these alterations contributes to the GC invasion, its metastases and poor prognosis. As the diet plays a significant role in the aetiology of GC, it is reasonable to include the nutritional chemoprevention agents. One of the plant genus demonstrating chemoprotective properties is Allium genus, which includes garlic. The relationship between CDH1 and COX2 in GC cells treated with Allium species extract has never been evaluated. METHODS In this study, the MKN28 and MKN74 GC cell lines were treated with ethanol extracts of Allium angulosum L., Allium lusitanicum Lam., Allium sativum L. (from Malaysia and Poland), Allium tibeticum Rendle and Allium ursinum L. The cytotoxicity of the extracts and their influence on COX2 and CDH1 mRNA and protein expression were evaluated as well as their influence on doxorubicin's (DOX) efficacy - a drug that has been used in GC treatment. RESULTS Among the tested species, ethanol extracts of A. sativum L. (Poland and Malaysia), A. tibeticum Rendle and A. ursinum L. influenced the levels of CDH1 and COX2, but only in the MKN74 cell line. Thus, it is possible that tumours with increased COX2 expression will be more susceptible to garlic treatment. Observed phenomenon was independent of Allium extract's toxicity. In comparison to DOX, tested extracts were more toxic. Moreover, A. sativum revealed synergistic effect with the drug. CONCLUSION In conclusion, the results indicate the potential application of Allium genus to GC chemoprevention and treatment support through CDH restoration and COX2 downregulation. This issue needs further investigations as it might be used in clinics.
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Affiliation(s)
- Agnieszka Korga
- Department of Medical Biology, Medical University of Lublin, Lublin, Poland
| | - Marta Ostrowska
- Department of Toxicology, Medical University of Lublin, Lublin, Poland
| | - Magdalena Iwan
- Department of Medical Biology, Medical University of Lublin, Lublin, Poland
| | - Małgorzata Skierucha
- Department of Anatomy, Medical University of Lublin, Lublin, Poland
- Surgical Oncology Department, Medical University of Lublin, Lublin, Poland
| | - Aleksandra Józefczyk
- Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, Lublin, Poland
| | - Piotr Pawłowski
- Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, Lublin, Poland
| | - Jarosław Dudka
- Department of Toxicology, Medical University of Lublin, Lublin, Poland
| | | | - Robert Sitarz
- Department of Anatomy, Medical University of Lublin, Lublin, Poland
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Zhang J, He J, Zhang L. The down-regulation of microRNA-137 contributes to the up-regulation of retinoblastoma cell proliferation and invasion by regulating COX-2/PGE2 signaling. Biomed Pharmacother 2018; 106:35-42. [PMID: 29945115 DOI: 10.1016/j.biopha.2018.06.099] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 06/13/2018] [Accepted: 06/13/2018] [Indexed: 02/07/2023] Open
Abstract
MicroRNA-137 (miR-137) plays an important role in the development and progression of many types of human cancers; however, the role of miR-137 in retinoblastoma (RB) remains unclear. In this study, we aimed to investigate the functional significance and molecular mechanisms of miR-137 in RB. We reported that miR-137 was frequently down-regulated in RB tissues and cell lines. The overexpression of miR-137 inhibited RB cell proliferation and invasion, while the suppression of miR-137 promoted RB cell proliferation and invasion. Bioinformatic analysis predicted that cyclooxygenase-2 (COX-2) was a potential target gene of miR-137, which was validated by a dual-luciferase reporter assay. Moreover, our results showed that miR-137 negatively regulated the expression of COX-2 and the production of prostaglandin E2 (PGE2) in RB cells. The knockdown of COX-2 suppressed the proliferation and invasion of RB cells as well as the production of PGE2. The overexpression of COX-2 significantly reversed the inhibitory effect of miR-137 overexpression on RB cell proliferation and invasion. Taken together, these results suggest that miR-137 suppresses the proliferation and invasion of RB cells by targeting COX-2/PGE2. Our study reveals a tumor suppressive role of miR-137 in the progression of RB and suggests miR-137 as a potentially effective therapeutic target for the treatment of RB.
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Affiliation(s)
- Jian Zhang
- Department of Ophthalmology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - Jing He
- Department of Obstetrics, The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, China.
| | - Le Zhang
- Department of Ophthalmology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
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17
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Yoo JH, Lee JS, Lee YS, Ku S, Lee HJ. Protective effect of bovine milk against HCl and ethanol–induced gastric ulcer in mice. J Dairy Sci 2018; 101:3758-3770. [DOI: 10.3168/jds.2017-13872] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 01/06/2018] [Indexed: 12/23/2022]
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Ma X, Wang B, Wang X, Luo Y, Fan W. NANOGP8 is the key regulator of stemness, EMT, Wnt pathway, chemoresistance, and other malignant phenotypes in gastric cancer cells. PLoS One 2018; 13:e0192436. [PMID: 29689047 PMCID: PMC5915267 DOI: 10.1371/journal.pone.0192436] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 01/22/2018] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Accumulating evidence demonstrated that NANOG1, the key transcription factor for embryonic stem cells, is associated with human cancers. NANOGP8, one of the pseudogenes in NANOG gene family, contains an intact open reading frame and also said to be expressed in cancer tissues. Therefore, a systematic study is greatly needed to address the following questions: among NANOG1 and NANOGP8, which gene is the main contributor for NANOG expression in cancer cells and which one is the key regulator responsible for stemness, epithelial-mesenchymal transition (EMT), metastasis, chemoresistance and other malignant phenotypes. Here we try to explore these issues with gastric adenocarcinoma cell lines in vitro using variety of molecular and cellular techniques. METHODS Special primers were designed to distinguish PCR products from NANOG1 and NANOGP8. Sphere-forming cells were cultured with serum-free and selective medium. A stable cell line was established with infection of lentivirus containing NANOGP8. qPCR was performed to measure NANOGP8 expression and its association with stemness, EMT and CSC markers in adherent cells and sphere-forming cells. Western blot analysis was deployed to confirm results of the transcript analysis. Experiments of cell proliferation, migration, invasion, clonogenic assay, sphere cell growth assays, cell cycle analysis, β-catenin accumulation and translocation in nucleus, and drug resistance were conducted to measure the impact of NANOGP8 on malignant statuses of gastric cancer cells. Immunofluorescence staining was used to analyze cell subpopulations with different markers. RESULTS NANOGP8 is mainly responsible for NANOG expression in sphere-forming (stem cell-like) cells derived from gastric cancer cell lines regardless their differentiation status. Ectopic expression of NANOGP8 significantly up-regulates stemness transcription factors, EMT inducers, and cancer stem cell markers (CSC) including Lgr5. NANOGP8 also promotes expression of the signature genes vimentin and N-caderin for mesenchymal cells and down-regulates the signature gene E-caderin for epithelial cells whereby confer the cells with mesenchymal cell phenotype. In NANOGP8 over-expressed adherent and sphere-forming cells, Lgr5+ cells are significantly increased. Ectopic expression of NANOGP8 endows gastric cells with enhanced proliferation, migration, invasion, sphere-forming and clonogenic capacity, and chemoresistance. NANOGP8 expression also enhances β-catenin accumulation in nucleus and strengthens Wnt signal transduction. CONCLUSION NANOGP8 is the main regulator of gastric cancer stem cells. It is closely associated with EMT, stemness, and CSC marker as well as Wnt signal pathway. NANOGP8 is correlated with cell proliferation, migration, invasion, clonogenic capacity, β-catenin accumulation in nucleus, and chemoresistance in gastric cancer. NANOGP8 is a promising molecular target for clinical intervention of gastric cancer.
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Affiliation(s)
- Xia Ma
- Molecular Biology Lab of Gastric Cancer, School of Life Sciences, Hebei University, Baoding, Hebei Province, China
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding, Hebei Province, China
| | - Bei Wang
- Molecular Biology Lab of Gastric Cancer, School of Life Sciences, Hebei University, Baoding, Hebei Province, China
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding, Hebei Province, China
| | - Xiaofang Wang
- Molecular Biology Lab of Gastric Cancer, School of Life Sciences, Hebei University, Baoding, Hebei Province, China
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding, Hebei Province, China
| | - Yujiao Luo
- Molecular Biology Lab of Gastric Cancer, School of Life Sciences, Hebei University, Baoding, Hebei Province, China
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding, Hebei Province, China
| | - Wufang Fan
- Molecular Biology Lab of Gastric Cancer, School of Life Sciences, Hebei University, Baoding, Hebei Province, China
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding, Hebei Province, China
- * E-mail:
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19
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Dietary n-3 and n-6 polyunsaturated fatty acids, the FADS gene, and the risk of gastric cancer in a Korean population. Sci Rep 2018; 8:3823. [PMID: 29491470 PMCID: PMC5830640 DOI: 10.1038/s41598-018-21960-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 02/02/2018] [Indexed: 02/07/2023] Open
Abstract
n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs are reported to have immunomodulatory effects, but few studies have examined these functions. Thus, we examined whether dietary n-3 and n-6 PUFAs are associated with the risk of gastric cancer and further investigated whether fatty acid desaturases 1 and 2 (FADS1 and FADS2) modify this association. In a case-control study, 1,464 participants (402 cases and 1,062 controls) were enrolled. A semi-quantitative food frequency questionnaire was utilized to measure dietary PUFA intake. Genotyping was performed using the Axiom® Exome 319 Array. Multivariable logistic models were established after adjusting for confounding variables. The risk of gastric cancer was significantly decreased among participants who had the highest tertile intake of docosahexaenoic acid (DHA), an n-3 PUFA, even after adjusting for covariates [odds ratios (OR) = 0.72, 95% confidence intervals (95% CIs) = 0.53-0.99]. However, no significant interaction according to FADS1 rs174546 or FADS2 rs174583 was observed. In conclusion, we observed a significant inverse association between dietary DHA and the risk of gastric cancer but found that FADS1 rs174546 and FADS2 rs174583 did not modify the association between dietary n-3 or n-6 PUFAs and gastric cancer risk.
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20
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Huang XZ, Chen Y, Wu J, Zhang X, Wu CC, Zhang CY, Sun SS, Chen WJ. Aspirin and non-steroidal anti-inflammatory drugs use reduce gastric cancer risk: A dose-response meta-analysis. Oncotarget 2018; 8:4781-4795. [PMID: 27902474 PMCID: PMC5354871 DOI: 10.18632/oncotarget.13591] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 11/14/2016] [Indexed: 12/21/2022] Open
Abstract
Background The association between non-steroidal anti-inflammatory drugs (NSAIDs) and gastric cancer (GC) risk is controversial. The aim of this study is to evaluate the chemopreventive effect of NSAIDs for GC. Methods A literature search was performed for relevant studies using the PubMed and Embase database (up to March 2016). Risk ratios (RRs) and 95% confidence intervals (CIs) were used as the effect measures. The dose–response analysis and subgroup analysis were also performed. Results Twenty-four studies were included. Our results indicated that NSAIDs could reduce GC risk (any NSAIDs: RR=0.78, 96%CI=0.72-0.85; aspirin: RR=0.70, 95%CI=0.62-0.80; non-aspirin NSAIDs: RR=0.86, 95%CI=0.80-0.94), especially for non-cardia GC risk. Moreover, the dose-response analysis indicated the risk of GC decreased by 11% and 5% for 2 years increment of any NSAIDs and aspirin use, respectively. There were nonlinear relationships between the frequency of any NSAIDs use and aspirin use and GC risk (P for non-linearity<0.01), with a threshold effect of 5 times/week. A monotonically decreasing trend was observed only for the frequency of less than 5 times/week. Conclusions Our results indicate that NSAIDs is inversely associated with GC risk, especially for non-cardia GC risk. NSAIDs use may become a feasible approach to prevent GC.
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Affiliation(s)
- Xuan-Zhang Huang
- Department of Chemotherapy and Radiotherapy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou City 325027, P.R. China
| | - You Chen
- The Wenzhou Dental Hospital, Wenzhou City 325027, P.R. China
| | - Jian Wu
- Department of Chemotherapy and Radiotherapy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou City 325027, P.R. China
| | - Xi Zhang
- Department of Chemotherapy and Radiotherapy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou City 325027, P.R. China
| | - Cong-Cong Wu
- Department of Chemotherapy and Radiotherapy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou City 325027, P.R. China
| | - Chao-Ying Zhang
- Department of Chemotherapy and Radiotherapy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou City 325027, P.R. China
| | - Shuang-Shuang Sun
- Department of Chemotherapy and Radiotherapy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou City 325027, P.R. China
| | - Wen-Jun Chen
- Department of Chemotherapy and Radiotherapy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou City 325027, P.R. China
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Yao Q, Gu A, Wang Z, Xue Y. MicroRNA-144 functions as a tumor suppressor in gastric cancer by targeting cyclooxygenase-2. Exp Ther Med 2018; 15:3088-3095. [PMID: 29456712 DOI: 10.3892/etm.2018.5763] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 11/29/2017] [Indexed: 12/23/2022] Open
Abstract
Gastric cancer (GC) poses a serious public health threat and the 5-year survival rate of patients with GC is low. MicroRNAs (miRNAs/miRs) may serve oncogenic or tumor suppressor functions during tumorigenesis by regulating cell proliferation, apoptosis, migration and invasion and it has been demonstrated that they may be dysregulated in various types of cancer. The present study demonstrated that miR-144 and GATA4 were downregulated in GC tissues and cell lines and suggested that this may be due to hypermethylation. Additionally, miR-144 and GATA4 had synergistic effects on GC cells by repressing cell proliferation and inducing cell cycle arrest and apoptosis. The results of bioinformatics and a luciferase reporter assay indicated that cyclooxygenase-2 (COX-2) is a direct target of miR-144 and that miR-144 negatively regulated the expression of COX-2, which inhibits the viability of GC cells. GATA4 also induced a similar effect on COX-2. Taken together, the results of the present study may improve understanding of the underlying mechanism of miR-144 and GATA4 in GC.
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Affiliation(s)
- Qiang Yao
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Anxin Gu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Zhuozhong Wang
- Department of Statistics, Harbin Medical University, Harbin, Heilongjiang 150000, P.R. China
| | - Yingwei Xue
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
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Tian P, Liang C. Transcriptome profiling of cancer tissues in Chinese patients with gastric cancer by high-throughput sequencing. Oncol Lett 2017; 15:2057-2064. [PMID: 29434905 PMCID: PMC5777123 DOI: 10.3892/ol.2017.7548] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 01/19/2017] [Indexed: 12/15/2022] Open
Abstract
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-associated mortality worldwide. Therefore, there is a requirement to identify sufficiently sensitive biomarkers for GC. Genome-wide screening of transcriptome dysregulation among cancerous and normal tissues may provide insights into the underlying molecular mechanisms of GC initiation and progression. At present, high-throughput sequencing techniques have begun to innovate biomedical studies. The RNA-seq method has become an advanced approach in medical studies; it is capable of the accurate detection of gene expression levels. The present study used RNA-seq to evaluate the transcriptional changes between tumor and matched normal samples, and these changes were confirmed by differentially expressed genes in larger samples using the results of sequencing. In total, the upregulation of 28 mRNAs and downregulation of 22 mRNAs between cancerous and normal tissue samples were identified. Subsequently, five differentially expressed genes were selected to verify in large samples and cadherin-1 (CDH1) was selected to detect protein expression levels. The results revealed that CDH1, cyclooxygenase-2 and matrix metalloproteinase genes had significantly higher expression levels, whereas the expression levels of dermatopontin and transforming growth factor β receptor 2 were decreased in GC samples. In particular, CDH1 demonstrated a 36-fold higher expression level in cancer tissues. The western blotting results also revealed high CDH1 expression levels in the validation cohorts. Furthermore, these genes are highly enriched in certain gene ontology categories, including the digestive system process, secretion and digestion. The present study provided a preliminary survey of the transcriptome of Chinese patients with GC, which may improve the detection of aberrant gene expression in GC and the understanding of the mechanisms of tumorigenesis.
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Affiliation(s)
- Peiying Tian
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, Shanghai 201399, P.R. China
| | - Chunli Liang
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, P.R. China
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23
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Liu D, Yuan N, Yu G, Song G, Chen Y. Can rheumatoid arthritis ever cease to exist: a review of various therapeutic modalities to maintain drug-free remission? Am J Transl Res 2017; 9:3758-3775. [PMID: 28861167 PMCID: PMC5575190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 05/20/2017] [Indexed: 06/07/2023]
Abstract
Therapies for rheumatoid arthritis (RA) were mostly aimed at reducing the pain, stiffness and further progression of joint destruction. However, with the advent of biologic agents that act against specific inflammatory cytokines contributing to RA pathogenesis (treat-to-target strategy), the degree of remission achieved has been remarkably impressive. In particular, inhibition of tumor necrosis factor α (TNFα), interleukins-1 and -6 and receptor-activator of nuclear kappa B ligand by neutralizing antibodies in early diagnosed RA patients has resulted in lowering of disease activity to levels that enable them to function as in the pre-disease stage. There are other biologic approaches such as depletion of B cells and blocking T-cell co-stimulators that have been included successfully in RA therapy under the class of disease-modifying anti-rheumatic drugs (DMARD). Given the excellent clinical outcomes of biologic DMARDs when initiated early in RA, discontinuation or dose tapering is practised. Because biologic DMARDs are expensive and also known to make users vulnerable to viral infections, dose reduction and drug holiday are reasonable steps when sustained good clinical response has been achieved. Majority clinical studies have been done with TNF inhibitors and data suggest that sustained remission of RA is achieved in several multi-centric studies carried out worldwide. However, high flare rate and reappearance of disease has been reported in several cases. This review critically discusses response predictors of biologic DMARDs, the case for treatment relaxation, strategizing drug tapering considering patient eligibility and timing in light of available clinical practice guidelines of RA.
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Affiliation(s)
- Di Liu
- Department of Rheumatology, The Affiliated Hospital to Changchun University of Chinese MedicineChangchun, China
| | - Na Yuan
- Department of Rheumatology, The Affiliated Hospital to Changchun University of Chinese MedicineChangchun, China
| | - Guimei Yu
- Department of Rheumatology, The Affiliated Hospital to Changchun University of Chinese MedicineChangchun, China
| | - Ge Song
- Department of Neurology, The First Hospital of Jilin UniversityJilin, China
| | - Yan Chen
- Department of Hematology, The First Clinical Hospital of Jilin Province Academy of Traditional Chinese MedicineJilin, China
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lncRNA HULC promotes the growth of hepatocellular carcinoma cells via stabilizing COX-2 protein. Biochem Biophys Res Commun 2017. [PMID: 28634076 DOI: 10.1016/j.bbrc.2017.06.103] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Highly upregulated in liver cancer (HULC), a lncRNA overexpressed in hepatocellular carcinoma (HCC), has been demonstrated to be involved in the carcinogenesis and progression of HCC. However, the mechanisms of HULC promoting the abnormal growth of HCC cells are still not well elucidated. In the present study, we for the first time demonstrated that HULC promoted the growth of HCC cells through elevating COX-2 protein. Moreover, the study of the corresponding mechanism by which HULC upregulated COX-2 showed that HULC enhanced the level of ubiquitin-specific peptidase 22 (USP22), which decreased ubiquitin-mediated degradation of COX-2 protein by removing the conjugated polyubiquitin chains from COX-2 and finally stabilized COX2 protein. In addition, knockdown of USP22 or COX-2 attenuated HULC-mediated abnormal growth of HCC cells. In conclusion, our results demonstrated that "USP22/COX-2" axis played an important role in HULC promoting growth of HCC cells. The identification of this novel pathway may pave a road for developing new potential anti-HCC strategies.
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Hou H, Xing W, Li W. Brahma-related gene 1 induces apoptosis in a p53-dependent manner in human rheumatoid fibroblast-like synoviocyte MH7A. Medicine (Baltimore) 2016; 95:e5241. [PMID: 28002318 PMCID: PMC5181802 DOI: 10.1097/md.0000000000005241] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Blocked apoptosis and aggressive inflammatory responses occur in fibroblast-like synoviocyte (FLS) of rheumatoid arthritis (RA) patients. Although Brahma-related gene 1 (BRG1) is considered as a tumor suppressor, few research covers its role in RA. This study aims to reveal effects and potential mechanisms of BRG1 in human FLS cell line MH7A.BRG1 expression in MH7A cells was altered by transfection of overexpression vectors or short hairpin RNAs (shRNAs). Cell viability and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry after transfection. Factors involved in inflammation and apoptosis were quantified by qPCR and Western blot. The interaction between BRG1 and p53 was assessed by immunoprecipitation (IP).Results showed that BRG1 overexpression significantly suppressed MH7A cell viability and induced apoptosis (P < 0.01), and its knockdown had opposite effects. BRG1 reduced mRNA levels of matrix metallopeptidase 3, TIMP metallopeptidase inhibitor 2, cyclooxygenase 2, and interleukin 6, implying its suppressive effects on inflammation. BRG1 interacted with and promoted p53 (P < 0.05). B-cell chronic lymphocytic leukemia/lymphoma 2 was suppressed (P < 0.05), while cytochrome c, caspase 3 (CASP3) and CASP9 were activated (P < 0.01) by BRG1. However, the regulation on these factors was abrogated by p53 knockdown (P < 0.01).These findings suggest that BRG1 may induce apoptosis and suppress inflammation in MH7A cells. Potential functional mechanisms involve the regulation of apoptotic factors by BRG1, which may depend on the recruitment and promotion of p53. This study provides the essential proof for applying BRG1 to the molecular therapy of RA.
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Expression of cyclooxygenase 2 and vascular endothelial growth factor in gastric carcinoma: Relationship with clinicopathological parameters. J Egypt Natl Canc Inst 2016; 28:149-56. [PMID: 27342370 DOI: 10.1016/j.jnci.2016.05.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 05/18/2016] [Accepted: 05/30/2016] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Gastric cancer is one of the most common cancers and the second most common cause of cancer-related death worldwide. Identification of specific prognostic indicators might allow a better prognostic stratification and more effective therapy. AIM To assess the expression and relationship between COX-2 and VEGF protein in gastric adenocarcinoma and whether these markers are useful in predicting clinicopathological prognostic parameters. MATERIALS AND METHODS The study included 83 formalin-fixed paraffin embedded tissue samples of excised gastric adenocarcinoma and 20 non tumorous tissue controls. The slides were subjected to COX-2 and VEGF immunohistochemical staining using a streptavidin-biotinperoxidase according to the manufacturer's protocol. The results were assessed independently by two pathologists. The relationships among COX-2 and VEGF expression and clinicopathological parameters were statistically analyzed. RESULTS COX-2 and VEGF expressions were obviously higher in carcinoma tissues compared to normal mucosae (p<0.001). The expression rate of COX-2 was 54.2% and of VEGF was 68.7%. COX-2 positive tumors were significantly correlated with Lauren classification, tumor depth and Helicobacter pylori infection (p<0.001, p=0.008, p=0.035). VEGF was significantly associated with lymph node metastasis and tumor depth (p<0.001). There was a positive association between VEGF and COX-2 expression in gastric adenocarcinoma (Kappa value=0.55). CONCLUSION In gastric adenocarcinoma, COX-2 expression might serve as a powerful indicator for intestinal type carcinoma, locally advanced disease and H. pylori infection, while VEGF was related to loco-regional progression. COX-2 might be involved in the development of angiogenesis in gastric carcinoma through VEGF upregulation.
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Zhou T, Ding JW, Wang XA, Zheng XX. Long noncoding RNAs and atherosclerosis. Atherosclerosis 2016; 248:51-61. [PMID: 26987066 DOI: 10.1016/j.atherosclerosis.2016.02.025] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 02/18/2016] [Accepted: 02/18/2016] [Indexed: 01/13/2023]
Abstract
Atherosclerosis is universally recognized as a chronic lipid-induced inflammation of the vessel wall in response to dyslipidemia and haemodynamic stress involving dysfunction and activation of resident vascular cells as well as infiltration of leukocytes. As members of nonprotein-coding RNAs, the long noncoding RNAs (lncRNAs) are implicated in various biological processes. Accumulating evidences suggest that lncRNAs regulate the function of vascular wall, activation of macrophages, lipid metabolism and immune response. Here, we review the effects of lncRNAs on the progress of atherosclerosis.
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Affiliation(s)
- Tian Zhou
- Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang 443000, Hubei Province, China; Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Jia-wang Ding
- Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang 443000, Hubei Province, China; Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China.
| | - Xin-an Wang
- Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang 443000, Hubei Province, China; Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Xia-xia Zheng
- Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang 443000, Hubei Province, China; Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
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Martin OA, Yin X, Forrester HB, Sprung CN, Martin RF. Potential strategies to ameliorate risk of radiotherapy-induced second malignant neoplasms. Semin Cancer Biol 2015; 37-38:65-76. [PMID: 26721424 DOI: 10.1016/j.semcancer.2015.12.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 12/15/2015] [Accepted: 12/15/2015] [Indexed: 12/18/2022]
Abstract
This review is aimed at the issue of radiation-induced second malignant neoplasms (SMN), which has become an important problem with the increasing success of modern cancer radiotherapy (RT). It is imperative to avoid compromising the therapeutic ratio while addressing the challenge of SMN. The dilemma is illustrated by the role of reactive oxygen species in both the mechanisms of tumor cell kill and of radiation-induced carcinogenesis. We explore the literature focusing on three potential routes of amelioration to address this challenge. An obvious approach to avoiding compromise of the tumor response is the use of radioprotectors or mitigators that are selective for normal tissues. We also explore the opportunities to avoid protection of the tumor by topical/regional radioprotection of normal tissues, although this strategy limits the scope of protection. Finally, we explore the role of the bystander/abscopal phenomenon in radiation carcinogenesis, in association with the inflammatory response. Targeted and non-targeted effects of radiation are both linked to SMN through induction of DNA damage, genome instability and mutagenesis, but differences in the mechanisms and kinetics between targeted and non-targeted effects may provide opportunities to lessen SMN. The agents that could be employed to pursue each of these strategies are briefly reviewed. In many cases, the same agent has potential utility for more than one strategy. Although the parallel problem of chemotherapy-induced SMN shares common features, this review focuses on RT associated SMN. Also, we avoid the burgeoning literature on the endeavor to suppress cancer incidence by use of antioxidants and vitamins either as dietary strategies or supplementation.
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Affiliation(s)
- Olga A Martin
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC 3002, Australia; Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC 3002, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
| | - Xiaoyu Yin
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC 3002, Australia; Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC 3002, Australia.
| | - Helen B Forrester
- Centre for Innate Immunity and Infectious Disease, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia.
| | - Carl N Sprung
- Centre for Innate Immunity and Infectious Disease, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia.
| | - Roger F Martin
- Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC 3002, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
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