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Laila UE, Zhao ZL, Liu H, Xu ZX. Aspirin in Cancer Therapy: Pharmacology and Nanotechnology Advances. Int J Nanomedicine 2025; 20:2327-2365. [PMID: 40017626 PMCID: PMC11866938 DOI: 10.2147/ijn.s505636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 02/04/2025] [Indexed: 03/01/2025] Open
Abstract
Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has garnered significant attention for its anti-cancer potential. This review explores the pharmacological properties, chemical dynamics, and evolving therapeutic applications of aspirin, with an emphasis on its integration into advanced cancer therapies. Aspirin demonstrates broad-spectrum efficacy across diverse cancer types by modulating signaling pathways such as COX-dependent and COX-independent mechanisms, including Wnt, NF-κB, β-catenin/TCF, and IL-6/STAT3. Recent advancements highlight the role of nanotechnology in enhancing aspirin's targeted delivery, therapeutic effectiveness, and patient outcomes. Nanoparticle-based formulations, including liposomes, solid lipid nanoparticles, and mesoporous silica nanoparticles, offer improved solubility, stability, and bioavailability, enabling controlled drug release and tumor-specific targeting. These innovations reduce systemic toxicity and enhance therapeutic effects, paving the way for aspirin's integration into personalized cancer treatments. Ongoing clinical studies reinforce its safety profile, underscoring aspirin's role in cancer pharmacotherapy. This review calls for continued research into aspirin's repurposing in combination therapies and novel delivery systems to maximize its therapeutic potential.
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Affiliation(s)
- Umm E Laila
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Zi Lon Zhao
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Huai Liu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Zhi-Xiang Xu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
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Lin WY, Wen HP, Li JY, Wang JM, Feng HJ, Huang Z, Li R, Zeng L, Huang L. Compact Molecular Conformation of Prodrugs Enhances Photocleaving Performance for Tumor Vascular Growth Inhibition. Adv Healthc Mater 2025; 14:e2402690. [PMID: 39460488 DOI: 10.1002/adhm.202402690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/06/2024] [Indexed: 10/28/2024]
Abstract
Highly spatiotemporal-resolved photomodulation demonstrates promise for investigating key biological events in vivo and in vitro, such as cell signaling pathways, neuromodulation, and tumor treatment without side effects. However, enhancing the performance of photomodulation tools remains challenging due to the limitations of the physicochemical properties of the photoactive molecules. Here, a compact, stable intramolecular π-π stacking conformation forming between the target molecule (naproxen) and the perylene-based photoremovable protecting group is discovered to confine the motion of the photolabile bond and then enhance the photocleavage quantum yield. In conjunction with a red-absorbing photosensitizer, the photocleavage wavelength is extended to the red region via triplet-triplet annihilation. In particular, the triplet lifetime of the prodrug can be extended via the linked steric hindrance to improve the conversion yield via TTA. Using the new photomodulation tool, it is precisely photoreleased cyclooxygenase-2 inhibitors for tumor vascular growth suppression in vivo. In combination with cisplatin, over 90% efficient inhibition of malignant breast tumors is observed via the synergistic tumor treatment strategy. These findings provide a new concept for the rational design of efficient photocleavage and have implications for photomodulating cell signaling pathways in tumor therapy, as well as laying a solid foundation for the development of phototherapeutic approaches.
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Affiliation(s)
- Wen-Yue Lin
- Department Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, Haihe Laboratory of Sustainable Chemical Transformations, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Hui-Ping Wen
- Department Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, Haihe Laboratory of Sustainable Chemical Transformations, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Jia-Yao Li
- Department Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, Haihe Laboratory of Sustainable Chemical Transformations, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Juan-Mei Wang
- Department Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, Haihe Laboratory of Sustainable Chemical Transformations, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Hong-Juan Feng
- Department Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, Haihe Laboratory of Sustainable Chemical Transformations, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Zhi Huang
- Department Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, Haihe Laboratory of Sustainable Chemical Transformations, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Ran Li
- Department Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, Haihe Laboratory of Sustainable Chemical Transformations, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Le Zeng
- School of Materials Science and Engineering, Nankai University, Tianjin, 300350, P. R. China
| | - Ling Huang
- Department Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, Haihe Laboratory of Sustainable Chemical Transformations, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
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Majima M, Matsuda Y, Watanabe SI, Ohtaki Y, Hosono K, Ito Y, Amano H. Prostanoids Regulate Angiogenesis and Lymphangiogenesis in Pathological Conditions. Cold Spring Harb Perspect Med 2024; 14:a041182. [PMID: 38565267 PMCID: PMC11610754 DOI: 10.1101/cshperspect.a041182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Angiogenesis, the formation of new blood vessels from the preexistent microvasculature, is an essential component of wound repair and tumor growth. Nonsteroidal anti-inflammatory drugs that suppress prostanoid biosynthesis are known to suppress the incidence and progression of malignancies including colorectal cancers, and also to delay the wound healing. However, the precise mechanisms are not fully elucidated. Accumulated results obtained from prostanoid receptor knockout mice indicate that a prostaglandin E-type receptor signaling EP3 in the host microenvironment is critical in tumor angiogenesis inducing vascular endothelial growth factor A (VEGF-A). Further, lymphangiogenesis was also enhanced by EP signaling via VEGF-C/D inductions in pathological settings. These indicate the importance of EP receptor to facilitate angiogenesis and lymphangiogenesis in vivo. Prostanoids act beyond their commonly understood activities in smooth muscle contraction and vasoactivity, both of which are quick responses elicited within several seconds on stimulations. Prostanoid receptor signaling will be a potential therapeutic target for disease conditions related to angiogenesis and lymphangiogenesis.
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Affiliation(s)
- Masataka Majima
- Department of Medical Therapeutics, Kanagawa Institute of Technology, 1030 Shimo-Ogino, Atsugi, Kanagawa 243-0292, Japan
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan
- Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan
| | - Yasuhiro Matsuda
- Department of Life Support Engineering, Kanagawa Institute of Technology, 1030 Shimo-Ogino, Atsugi, Kanagawa 243-0292, Japan
| | - Shin-Ichi Watanabe
- Department of Exercise Physiology and Health Sciences, Kanagawa Institute of Technology, 1030 Shimo-Ogino, Atsugi, Kanagawa 243-0292, Japan
| | - Yasuaki Ohtaki
- Department of Human Sensing, Kanagawa Institute of Technology, 1030 Shimo-Ogino, Atsugi, Kanagawa 243-0292, Japan
| | - Kanako Hosono
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan
- Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan
| | - Yoshiya Ito
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan
- Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan
| | - Hideki Amano
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan
- Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan
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Amin N, Abbasi IN, Wu F, Shi Z, Sundus J, Badry A, Yuan X, Zhao BX, Pan J, Mi XD, Luo Y, Geng Y, Fang M. The Janus face of HIF-1α in ischemic stroke and the possible associated pathways. Neurochem Int 2024; 177:105747. [PMID: 38657682 DOI: 10.1016/j.neuint.2024.105747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 03/01/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024]
Abstract
Stroke is the most devastating disease, causing paralysis and eventually death. Many clinical and experimental trials have been done in search of a new safe and efficient medicine; nevertheless, scientists have yet to discover successful remedies that are also free of adverse effects. This is owing to the variability in intensity, localization, medication routes, and each patient's immune system reaction. HIF-1α represents the modern tool employed to treat stroke diseases due to its functions: downstream genes such as glucose metabolism, angiogenesis, erythropoiesis, and cell survival. Its role can be achieved via two downstream EPO and VEGF strongly related to apoptosis and antioxidant processes. Recently, scientists paid more attention to drugs dealing with the HIF-1 pathway. This review focuses on medicines used for ischemia treatment and their potential HIF-1α pathways. Furthermore, we discussed the interaction between HIF-1α and other biological pathways such as oxidative stress; however, a spotlight has been focused on certain potential signalling contributed to the HIF-1α pathway. HIF-1α is an essential regulator of oxygen balance within cells which affects and controls the expression of thousands of genes related to sustaining homeostasis as oxygen levels fluctuate. HIF-1α's role in ischemic stroke strongly depends on the duration and severity of brain damage after onset. HIF-1α remains difficult to investigate, particularly in ischemic stroke, due to alterations in the acute and chronic phases of the disease, as well as discrepancies between the penumbra and ischemic core. This review emphasizes these contrasts and analyzes the future of this intriguing and demanding field.
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Affiliation(s)
- Nashwa Amin
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Department of Zoology, Faculty of Science, Aswan University, Egypt; Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Irum Naz Abbasi
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Fei Wu
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Zongjie Shi
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Javaria Sundus
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Azhar Badry
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xia Yuan
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Bing-Xin Zhao
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Jie Pan
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Xiao-Dan Mi
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yuhuan Luo
- Department of Pediatrics, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Geng
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Marong Fang
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China; Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
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Dinikina YV, Zheludkova OG, Belogurova MB, Spelnikov DM, Osipov NN, Nikitina IL. Personalized treatment options of refractory and relapsed medulloblastoma in children: literature review. JOURNAL OF MODERN ONCOLOGY 2024; 25:454-465. [DOI: 10.26442/18151434.2023.4.202521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Medulloblastoma (MB) is the most common malignant tumor of the central nervous system in pediatric patients. Despite the complex anticancer therapy approach, refractory and relapsing forms of the disease remain fatal in most cases and account for approximately 30%. To date, repeated surgery, radiation, and chemotherapy can be used as life-prolonging treatment options; nevertheless, it should be emphasized that there are no standardized approaches based on existing data of molecular variants of MB. It is obvious that only a deep understanding of the biological mechanisms in association with clinical aspects in refractory and relapsing forms of MB would make it possible to personalize second- and subsequent-line therapy in order to achieve maximum efficiency and minimize early and long-term toxicity. The article presents the current understanding of prognostic factors in relapsed/refractory forms of MB, methods of modern diagnostics, as well as existing and perspective treatment options based on the biological and clinical aspects of the disease.
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Lygina E, Morgacheva D, Khadela A, Postwala H, Shah Y, Dinikina Y. Effectiveness of metronomic chemotherapy in a child with medulloblastoma: A case report. Oncol Lett 2023; 25:194. [PMID: 37113402 PMCID: PMC10126878 DOI: 10.3892/ol.2023.13780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 02/28/2023] [Indexed: 04/29/2023] Open
Abstract
Medulloblastoma (MB) is one of the most common pediatric malignant tumors arising from the central nervous system with an unknown etiology and variable prognosis. Relapsed or refractory MB in pediatric patients after intensive anticancer therapy (chemo-, radiotherapy) is associated with treatment resistance and poor survival prognosis. Metronomic chemotherapy in combination with mTOR inhibitors may have advantages due to an alternate mechanism of cytotoxicity and a favourable adverse effects profile. Furthermore, it is considered to be a prospective anticancer regimen regardless of the presence/absence of molecular targets. The present study reported a successful result of this treatment option with optimal tolerability in relapsed MB in a pediatric male patient and highlighted the advantages for a selected group of patients.
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Affiliation(s)
- Elena Lygina
- Department of Chemotherapy for Hematologic Diseases and Bone Marrow Transplantation for Children, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Daria Morgacheva
- Department of Chemotherapy for Hematologic Diseases and Bone Marrow Transplantation for Children, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Avinash Khadela
- Department of Pharmacology, L.M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat 380009, India
| | - Humzah Postwala
- Pharm D Section, L.M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat 380009, India
| | - Yesha Shah
- Pharm D Section, L.M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat 380009, India
| | - Yulia Dinikina
- Department of Chemotherapy for Hematologic Diseases and Bone Marrow Transplantation for Children, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
- Correspondence to: Dr Yulia Dinikina, Department of Chemotherapy for Hematologic Diseases and Bone Marrow Transplantation for Children, Almazov National Medical Research Centre, 2 Akkuratova Street, St. Petersburg 197341, Russia, E-mail:
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7
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Galley JC, Singh S, Awata WMC, Alves JV, Bruder-Nascimento T. Adipokines: Deciphering the cardiovascular signature of adipose tissue. Biochem Pharmacol 2022; 206:115324. [PMID: 36309078 PMCID: PMC10509780 DOI: 10.1016/j.bcp.2022.115324] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/19/2022] [Accepted: 10/20/2022] [Indexed: 11/02/2022]
Abstract
Obesity and hypertension are intimately linked due to the various ways that the important cell types such as vascular smooth muscle cells (VSMC), endothelial cells (EC), immune cells, and adipocytes, communicate with one another to contribute to these two pathologies. Adipose tissue is a very dynamic organ comprised primarily of adipocytes, which are well known for their role in energy storage. More recently adipose tissue has been recognized as the largest endocrine organ because of its ability to produce a vast number of signaling molecules called adipokines. These signaling molecules stimulate specific types of cells or tissues with many adipokines acting as indicators of adipocyte healthy function, such as adiponectin, omentin, and FGF21, which show anti-inflammatory or cardioprotective effects, acting as regulators of healthy physiological function. Others, like visfatin, chemerin, resistin, and leptin are often altered during pathophysiological circumstances like obesity and lipodystrophy, demonstrating negative cardiovascular outcomes when produced in excess. This review aims to explore the role of adipocytes and their derived products as well as the impacts of these adipokines on blood pressure regulation and cardiovascular homeostasis.
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Affiliation(s)
- Joseph C. Galley
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Pediatrics Research in Obesity and Metabolism (CPROM), University of Pittsburgh, Pittsburgh, PA, USA
| | - Shubhnita Singh
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Pediatrics Research in Obesity and Metabolism (CPROM), University of Pittsburgh, Pittsburgh, PA, USA
| | - Wanessa M. C. Awata
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Pediatrics Research in Obesity and Metabolism (CPROM), University of Pittsburgh, Pittsburgh, PA, USA
| | - Juliano V. Alves
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Pediatrics Research in Obesity and Metabolism (CPROM), University of Pittsburgh, Pittsburgh, PA, USA
| | - Thiago Bruder-Nascimento
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Pediatrics Research in Obesity and Metabolism (CPROM), University of Pittsburgh, Pittsburgh, PA, USA
- Endocrinology Division at UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
- Vascular Medicine Institute (VMI), University of Pittsburgh, Pittsburgh, PA, USA
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The Interaction of Human Papillomavirus Infection and Prostaglandin E2 Signaling in Carcinogenesis: A Focus on Cervical Cancer Therapeutics. Cells 2022; 11:cells11162528. [PMID: 36010605 PMCID: PMC9406919 DOI: 10.3390/cells11162528] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/03/2022] [Accepted: 08/11/2022] [Indexed: 11/17/2022] Open
Abstract
Chronic infection by high-risk human papillomaviruses (HPV) and chronic inflammation are factors associated with the onset and progression of several neoplasias, including cervical cancer. Oncogenic proteins E5, E6, and E7 from HPV are the main drivers of cervical carcinogenesis. In the present article, we review the general mechanisms of HPV-driven cervical carcinogenesis, as well as the involvement of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and downstream effectors in this pathology. We also review the evidence on the crosstalk between chronic HPV infection and PGE2 signaling, leading to immune response weakening and cervical cancer development. Finally, the last section updates the current therapeutic and preventive options targeting PGE2-derived inflammation and HPV infection in cervical cancer. These treatments include nonsteroidal anti-inflammatory drugs, prophylactic and therapeutical vaccines, immunomodulators, antivirals, and nanotechnology. Inflammatory signaling pathways are closely related to the carcinogenic nature of the virus, highlighting inflammation as a co-factor for HPV-dependent carcinogenesis. Therefore, blocking inflammatory signaling pathways, modulating immune response against HPV, and targeting the virus represent excellent options for anti-tumoral therapies in cervical cancer.
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Yi M, Feng X, Peng W, Teng F, Tang Y, Chen Z. Aspirin for the prevention of hepatocellular carcinoma: an updated meta-analysis with particular focus on patients with chronic liver disease. Eur J Clin Pharmacol 2022; 78:647-656. [PMID: 35032181 DOI: 10.1007/s00228-021-03247-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 10/23/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Previous studies have suggested a chemoprotective effect of aspirin in hepatocellular carcinoma (HCC), but evidence is limited for patients with chronic liver disease (CLD). Thus, we performed a meta-analysis of all observational studies, and aimed to provide a comprehensive and quantitative understanding of this topic. METHODS The PubMed/MEDLINE, Scopus, Cochrane, and Web of Science databases were systematically searched until September 2021. We pooled the hazard ratio (HR) of HCC for aspirin use versus non-use and investigated the possible dose-risk and duration-risk associations. RESULTS Ten studies involving 202,567 CLD patients were enrolled in this study. The pooled results showed a significant reduction in HCC risk in aspirin users than in non-users (HR = 0.64; 95% CI = 0.54-0.77; pheterogeneity < 0.001; I2 = 84.9%). In subgroup analyses, an aspirin dose of 100 mg/day (0.56, 0.44-0.72) showed a significant protective effect against HCC than 160 mg/day. The linear model showed a significant inverse association between the duration of aspirin use and HCC risk (exb(b) = 0.92; 95% CI = 0.90-0.94); also, a non-linear model revealed a comparable association (coef1 = 0.80, p1 < 0.001; coef2 = 1.13, p2 = 0.001). No significantly higher risk of gastrointestinal bleeding of the aspirin-treated group was detected. CONCLUSIONS The present meta-analysis suggested a significant and duration-related association between reduced HCC risk and aspirin use in a broad at-risk population. Nevertheless, aspirin therapy applied to CLD patients should be carefully monitored, although there was no significantly higher risk of gastrointestinal bleeding. REGISTRATION PROSPERO, CRD42021229892.
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Affiliation(s)
- Mengshi Yi
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xi Feng
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wei Peng
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fei Teng
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Youyin Tang
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zheyu Chen
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Biologically active lipids in the regulation of lymphangiogenesis in disease states. Pharmacol Ther 2021; 232:108011. [PMID: 34614423 DOI: 10.1016/j.pharmthera.2021.108011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/31/2021] [Accepted: 09/01/2021] [Indexed: 02/06/2023]
Abstract
Lymphatic vessels have crucial roles in the regulation of interstitial fluids, immune surveillance, and the absorption of dietary fat in the intestine. Lymphatic function is also closely related to the pathogenesis of various disease states such as inflammation, lymphedema, endometriosis, liver dysfunction, and tumor metastasis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing lymphatic vessels, is a critical determinant in the above conditions. Although the effect of growth factors on lymphangiogenesis is well-characterized, and biologically active lipids are known to affect smooth muscle contractility and vasoaction, there is accumulating evidence that biologically active lipids are also important inducers of growth factors and cytokines that regulate lymphangiogenesis. This review discusses recent advances in our understanding of biologically active lipids, including arachidonic acid metabolites, sphingosine 1-phosphate, and lysophosphatidic acid, as regulators of lymphangiogenesis, and the emerging importance of the lymphangiogenesis as a therapeutic target.
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11
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Endometriosis: Epidemiology, Classification, Pathogenesis, Treatment and Genetics (Review of Literature). Int J Mol Sci 2021; 22:ijms221910554. [PMID: 34638893 PMCID: PMC8508982 DOI: 10.3390/ijms221910554] [Citation(s) in RCA: 175] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/22/2021] [Accepted: 09/26/2021] [Indexed: 12/11/2022] Open
Abstract
Endometriosis is a “mysterious” disease and its exact cause has not yet been established. Among the etiological factors, congenital, environmental, epigenetic, autoimmune and allergic factors are listed. It is believed that the primary mechanism of the formation of endometriosis foci is retrograde menstruation, i.e., the passage of menstrual blood through the fallopian tubes into the peritoneal cavity and implantation of exfoliated endometrial cells. However, since this mechanism is also observed in healthy women, other factors must also be involved in the formation of endometriosis foci. Endometriosis is in many women the cause of infertility, chronic pain and the deterioration of the quality of life. It also represents a significant financial burden on health systems. The article presents a review of the literature on endometriosis—a disease affecting women throughout the world.
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12
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Xie S, Wang Y, Huang Y, Yang B. Mechanisms of the antiangiogenic effects of aspirin in cancer. Eur J Pharmacol 2021; 898:173989. [PMID: 33657423 DOI: 10.1016/j.ejphar.2021.173989] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 02/14/2021] [Accepted: 02/22/2021] [Indexed: 01/04/2023]
Abstract
Aspirin is an old drug extracted from willow bark and is widely used for the prevention and treatment of cardiovascular diseases. Accumulating evidence has shown that aspirin use may significantly reduce the angiogenesis of cancer; however, the mechanism of the association between angiogenesis and aspirin is complex. Although COX-1 is widely known as a target of aspirin, several studies reveal other antiangiogenic targets of aspirin, such as angiotensin II, glucose transporter 1, heparanase, and matrix metalloproteinase. In addition, some data indicates that aspirin may produce antiangiogenic effects after acting in different cell types, such as endothelial cells, platelets, pericytes, and macrophages. In this review, we concentrate on research regarding the antiangiogenic effects of aspirin in cancer, and we discuss the molecular mechanisms of aspirin and its metabolites. Moreover, we discuss some mechanisms through which aspirin treatment may normalize existing blood vessels, including preventing the disintegration of endothelial adheres junctions and the recruitment of pericytes. We also address the antiangiogenic effects and the underlying mechanisms of aspirin derivatives, which are aimed at improving safety and efficacy.
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Affiliation(s)
- Shiyuan Xie
- College of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, PR China
| | - Youqiong Wang
- College of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, PR China
| | - Yixuan Huang
- College of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, PR China
| | - Bin Yang
- College of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, PR China.
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13
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Silveira TL, Veloso ES, Gonçalves INN, Costa RF, Rodrigues MA, Cassali GD, Del Puerto HL, Pang LY, Argyle DJ, Ferreira E. Cyclooxygenase-2 expression is associated with infiltration of inflammatory cells in oral and skin canine melanomas. Vet Comp Oncol 2020; 18:727-738. [PMID: 32323423 DOI: 10.1111/vco.12601] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 02/13/2020] [Accepted: 02/18/2020] [Indexed: 12/18/2022]
Abstract
Melanoma is a fast-growing tumour in dogs and represents 7% of the total malignant neoplasms from the skin and is the most common tumour found in the oral cavity. In these tumours, high expression of cyclooxygenase-2 (COX-2) is associated with a poor prognosis. The aim of this study was to verify if the overexpression of COX-2 is related to the modulation of lymphocytes and if it is associated with the angiogenic and proliferative capacity of the melanoma. Canine melanoma samples (n = 85) were analysed by immunohistochemistry to detect the expression of S-100, Melan-A, PNL-2, COX-2, Factor VIII, Ki-67 and immune cells markers (CD3, CD4, FOXP3 and MAC387); and expression levels of MAC387, NOS and CD206 were determined by immunofluorescence. Our study showed a concurrent difference between the expression of COX-2 and inflammatory cell infiltration: Oral melanomas showed positivity for COX-2 in 34% of the cases and this expression was associated with CD3 positivity in the inflammatory infiltrate and angiogenesis; whereas cutaneous melanomas presented positivity for COX-2 in 42% of the cases and this expression was associated with positive staining for CD3, CD4, FOXP3 and MAC387. These markers are associated with inflammatory cells, angiogenesis and proliferation. Interestingly, melanomas were highly infiltrated by FOXP3+ cells, this is related to angiogenesis, whereas CD3, CD4 and MAC387 expression was only associated with cutaneous melanomas. The macrophage profile analysis showed that both oral and cutaneous melanomas with low COX-2 expression have an M1 phenoptype, whereas the cases with high COX-2 expression demonstrate a hybrid M1/M2 profile pattern. We concluded that the COX-2 is overexpressed in 42% of cutaneous melanomas and in 34% of oral melanomas, with a direct association with angiogenesis, proliferation, and intratumoral lymphocyte infiltration. We propose that COX-2 is a key regulator of immune cell infiltration and may drive tumour associated macrophage activation.
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Affiliation(s)
- Tatiany L Silveira
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Emerson S Veloso
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Ivy N N Gonçalves
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Renato F Costa
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Michele A Rodrigues
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Geovanni D Cassali
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Helen L Del Puerto
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Lisa Y Pang
- The Roslin Institute, The University of Edinburgh, Edinburgh, Scotland
| | - David J Argyle
- The Roslin Institute, The University of Edinburgh, Edinburgh, Scotland
| | - Enio Ferreira
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil
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14
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Sart S, Tomasi RFX, Barizien A, Amselem G, Cumano A, Baroud CN. Mapping the structure and biological functions within mesenchymal bodies using microfluidics. SCIENCE ADVANCES 2020; 6:eaaw7853. [PMID: 32181333 PMCID: PMC7056316 DOI: 10.1126/sciadv.aaw7853] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 12/12/2019] [Indexed: 05/02/2023]
Abstract
Organoids that recapitulate the functional hallmarks of anatomic structures comprise cell populations able to self-organize cohesively in 3D. However, the rules underlying organoid formation in vitro remain poorly understood because a correlative analysis of individual cell fate and spatial organization has been challenging. Here, we use a novel microfluidics platform to investigate the mechanisms determining the formation of organoids by human mesenchymal stromal cells that recapitulate the early steps of condensation initiating bone repair in vivo. We find that heterogeneous mesenchymal stromal cells self-organize in 3D in a developmentally hierarchical manner. We demonstrate a link between structural organization and local regulation of specific molecular signaling pathways such as NF-κB and actin polymerization, which modulate osteo-endocrine functions. This study emphasizes the importance of resolving spatial heterogeneities within cellular aggregates to link organization and functional properties, enabling a better understanding of the mechanisms controlling organoid formation, relevant to organogenesis and tissue repair.
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Affiliation(s)
- Sébastien Sart
- LadHyX and Department of Mechanics, Ecole Polytechnique, CNRS–UMR 7646, 91128 Palaiseau, France
- Physical Microfluidics and Bioengineering, Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France
| | - Raphaël F.-X. Tomasi
- LadHyX and Department of Mechanics, Ecole Polytechnique, CNRS–UMR 7646, 91128 Palaiseau, France
- Physical Microfluidics and Bioengineering, Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France
| | - Antoine Barizien
- LadHyX and Department of Mechanics, Ecole Polytechnique, CNRS–UMR 7646, 91128 Palaiseau, France
- Physical Microfluidics and Bioengineering, Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France
| | - Gabriel Amselem
- LadHyX and Department of Mechanics, Ecole Polytechnique, CNRS–UMR 7646, 91128 Palaiseau, France
| | - Ana Cumano
- Unit for Lymphopoiesis, Department of Immunology–INSERM U1223, Institut Pasteur, 75015 Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, 75018 Paris, France
| | - Charles N. Baroud
- LadHyX and Department of Mechanics, Ecole Polytechnique, CNRS–UMR 7646, 91128 Palaiseau, France
- Physical Microfluidics and Bioengineering, Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France
- Corresponding author.
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15
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Castillo MFR, Cohen A, Edberg D, Hoppensteadt D, Fareed J, Martin B, Halaris A. Vascular endothelial growth factor in bipolar depression: A potential biomarker for diagnosis and treatment outcome prediction. Psychiatry Res 2020; 284:112781. [PMID: 31986357 DOI: 10.1016/j.psychres.2020.112781] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 01/07/2020] [Accepted: 01/10/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Vascular Endothelial Growth Factor (VEGF) has been implicated in the neurotrophic model of depression. We explored the potential role of VEGF in the pathophysiology of bipolar depression and potential utility as a diagnostic or outcome predictive biomarker. METHODS In a double-blind study, treatment-resistant bipolar depressed patients received Escitalopram and were randomized to receive add-on Celecoxib (26 participants) or Placebo (21 participants). There were 32 healthy controls. Plasma levels of VEGF were determined at three timepoints over eight weeks. RESULTS Bipolar patients had significantly higher VEGF levels at baseline compared to healthy controls. Logistic regression analysis revealed that the AUC is 0.67 and the VEGF cut point is 8.21. At all timepoints, patients receiving Celecoxib had comparable VEGF levels to those receiving Placebo. VEGF levels did not change significantly over time. Baseline VEGF was a poor predictor of treatment response with an AUC of 0.53. CONCLUSIONS The increased VEGF in bipolar depression agrees with similar findings in major depressive disorder. A high VEGF level tended to accurately predict bipolar disorder, with apparent differential VEGF expression. Baseline VEGF did not predict treatment response, and levels did not change with treatment. Plasma VEGF may have diagnostic utility and guide personalized treatment.
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Affiliation(s)
- Monica Feliz R Castillo
- Department of Psychiatry and Behavioral Neurosciences, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
| | - Arielle Cohen
- Department of Psychiatry and Behavioral Neurosciences, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
| | - David Edberg
- Department of Psychiatry and Behavioral Neurosciences, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
| | - Debra Hoppensteadt
- Hemostasis and Thrombosis Research Laboratories, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
| | - Jawed Fareed
- Hemostasis and Thrombosis Research Laboratories, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
| | - Brendan Martin
- Clinical Research Office, Biostatistics Collaborative Core, Loyola University Chicago, Maywood, Illinois, USA
| | - Angelos Halaris
- Department of Psychiatry and Behavioral Neurosciences, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA.
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16
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Transferrin-Modified Nanoliposome Codelivery Strategies for Enhancing the Cancer Therapy. J Pharm Sci 2019; 109:2426-2436. [PMID: 31760084 DOI: 10.1016/j.xphs.2019.11.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/22/2019] [Accepted: 11/12/2019] [Indexed: 02/07/2023]
Abstract
Chemotherapy remains one of the most effective treatments for many cancers in a clinic. At present, various targets have been used to modify the PEGylated liposomes for doxorubicin (Dox) delivery, but the antitumor effect of Dox is not satisfactory. Therefore, combination chemotherapeutics has been considered as a promising method to improve tumor treatment. These years, RAF/MEK/ERK-mediated cell signaling pathway has been discovered to inhibit the growth of tumors. Thus, Sorafenib tosylate (Sor) was used in this study, which directly inhibited tumor cell proliferation through blocking RAF/MEK/ERK-mediated cell signaling pathway and indirectly inhibited tumor cell growth through blocking angiogenesis by VEGFR and PDGF. In this article, we develop a "combination delivery system" to deliver the hydrophobic drug (Sor) in phospholipid bilayer and hydrophilic drug (Dox) in inner cores for enhancing the antitumor effect. Moreover, in vitro experiments verified whether the physicochemical properties of carriers were stable and transferrin-modified liposomes displayed the highest uptake. The results of in vivo experiments showed that the codelivery system inhibited the tumor growth more effectively than monotherapy. Overall, this combination delivery system for delivering the hydrophobic and hydrophilic drugs simultaneously may offer a novel strategy for breast cancer treatment and provide a reference for the possibility of clinical usage.
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17
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Sekiguchi K, Ito Y, Hattori K, Inoue T, Hosono K, Honda M, Numao A, Amano H, Shibuya M, Unno N, Majima M. VEGF Receptor 1-Expressing Macrophages Recruited from Bone Marrow Enhances Angiogenesis in Endometrial Tissues. Sci Rep 2019; 9:7037. [PMID: 31065021 PMCID: PMC6504918 DOI: 10.1038/s41598-019-43185-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 04/08/2019] [Indexed: 01/08/2023] Open
Abstract
Angiogenesis is critical in maintenance of endometrial tissues. Here, we examined the role of VEGF receptor 1 (VEGFR1) signaling in angiogenesis and tissue growth in an endometriosis model. Endometrial fragments were implanted into the peritoneal wall of mice, and endometrial tissue growth and microvessel density (MVD) were determined. Endometrial fragments from wild-type (WT) mice grew slowly with increased angiogenesis determined by CD31+ MVD, peaking on Day 14. When tissues from WT mice were transplanted into VEGFR1 tyrosine kinase-knockout mice, implant growth and angiogenesis were suppressed on Day 14 compared with growth of WT implants in a WT host. The blood vessels in the implants were not derived from the host peritoneum. Immunostaining for VEGFR1 suggested that high numbers of VEGFR1+ cells such as macrophages were infiltrated into the endometrial tissues. When macrophages were deleted with Clophosome N, both endometrial tissue growth and angiogenesis were significantly suppressed. Bone marrow chimera experiments revealed that growth and angiogenesis in endometrial implants were promoted by host bone marrow-derived VEGFR1+/CD11b+ macrophages that accumulated in the implants, and secreted basic fibroblast growth factor (bFGF). A FGF receptor kinase inhibitor, PD173047 significantly reduced size of endometrial tissues and angiogenesis. VEGFR1 signaling in host-derived cells is crucial for growth and angiogenesis in endometrial tissue. Thus, VEGFR1 blockade is a potential treatment for endometriosis.
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Affiliation(s)
- Kazuki Sekiguchi
- Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.,Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.,Department of Obstetrics and Gynecology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoshiya Ito
- Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.,Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Kyoko Hattori
- Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.,Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.,Department of Obstetrics and Gynecology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Tomoyoshi Inoue
- Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.,Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Kanako Hosono
- Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.,Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Masako Honda
- Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.,Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.,Department of Obstetrics and Gynecology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Akiko Numao
- Department of Obstetrics and Gynecology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hideki Amano
- Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.,Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Masabumi Shibuya
- Gakubunkan Institute of Physiology and Medicine, Jobu University, Takasaki, Gunma, Japan
| | - Nobuya Unno
- Department of Obstetrics and Gynecology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Masataka Majima
- Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. .,Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.
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18
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Horikirizono H, Ishigaki K, Amaha T, Iizuka K, Nagumo T, Tamura K, Seki M, Edamura K, Asano K. Inhibition of growth of canine-derived vascular endothelial cells by non-steroidal anti-inflammatory drugs and atrial natriuretic peptide. J Vet Med Sci 2019; 81:776-779. [PMID: 30930345 PMCID: PMC6541854 DOI: 10.1292/jvms.18-0575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
This study investigated the direct effects of non-steroidal anti-inflammatory drugs (NSAIDs) and atrial natriuretic peptide (ANP) on canine-derived vascular endothelial cells (VECs). VECs
were isolated and cultured from canine arteries and veins. The mRNA expressions of vascular endothelial growth factor receptor 2, cyclooxygenase-2, and natriuretic peptide receptor 1 were
detected in the cultured VECs. The viability of the cultured VECs was reduced in a dose-dependent manner by meloxicam, carprofen, and robenacoxib. By contrast, dose escalations of ANP had
only marginal influence on the viability of cultured VECs. NSAIDs may potentially serve as not only analgesic agents against cancerous and perioperative pain but also as adjuvant
anti-angiogenic drugs in dogs with malignant tumors.
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Affiliation(s)
- Hiro Horikirizono
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
| | - Kumiko Ishigaki
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
| | - Takao Amaha
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
| | - Keigo Iizuka
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
| | - Takahiro Nagumo
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
| | - Kei Tamura
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
| | - Mamiko Seki
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
| | - Kazuya Edamura
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
| | - Kazushi Asano
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
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19
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Poirier M, Awale M, Roelli MA, Giuffredi GT, Ruddigkeit L, Evensen L, Stooss A, Calarco S, Lorens JB, Charles RP, Reymond JL. Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT-β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2. ChemMedChem 2018; 14:224-236. [PMID: 30520265 DOI: 10.1002/cmdc.201800554] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Indexed: 12/11/2022]
Abstract
By screening a focused library of kinase inhibitor analogues in a phenotypic co-culture assay for angiogenesis inhibition, we identified an aminotriazine that acts as a cytostatic nanomolar inhibitor. However, this aminotriazine was found to be completely inactive in a whole-kinome profiling assay. To decipher its mechanism of action, we used the online target prediction tool PPB2 (http://ppb2.gdb.tools), which suggested lysophosphatidic acid acyltransferase β (LPAAT-β) as a possible target for this aminotriazine as well as several analogues identified by structure-activity relationship profiling. LPAAT-β inhibition (IC50 ≈15 nm) was confirmed in a biochemical assay and by its effects on cell proliferation in comparison with a known LPAAT-β inhibitor. These experiments illustrate the value of target-prediction tools to guide target identification for phenotypic screening hits and significantly expand the rather limited pharmacology of LPAAT-β inhibitors.
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Affiliation(s)
- Marion Poirier
- Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland
| | - Mahendra Awale
- Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland
| | - Matthias A Roelli
- Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3000, Bern 9, Switzerland
| | - Guy T Giuffredi
- Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland
| | - Lars Ruddigkeit
- Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland
| | - Lasse Evensen
- Department of Biomedicine, Centre for Cancer Biomarkers (CCBIO), University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway
| | - Amandine Stooss
- Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3000, Bern 9, Switzerland
| | - Serafina Calarco
- Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3000, Bern 9, Switzerland
| | - James B Lorens
- Department of Biomedicine, Centre for Cancer Biomarkers (CCBIO), University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway
| | - Roch-Philippe Charles
- Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3000, Bern 9, Switzerland
| | - Jean-Louis Reymond
- Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland
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20
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Asghari S, Valizadeh A, Aghebati-Maleki L, Nouri M, Yousefi M. Endometriosis: Perspective, lights, and shadows of etiology. Biomed Pharmacother 2018; 106:163-174. [DOI: 10.1016/j.biopha.2018.06.109] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 05/31/2018] [Accepted: 06/18/2018] [Indexed: 12/24/2022] Open
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21
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Lei CS, Hou YC, Pai MH, Lin MT, Yeh SL. Effects of quercetin combined with anticancer drugs on metastasis-associated factors of gastric cancer cells: in vitro and in vivo studies. J Nutr Biochem 2018; 51:105-113. [DOI: 10.1016/j.jnutbio.2017.09.011] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 08/07/2017] [Accepted: 09/11/2017] [Indexed: 02/07/2023]
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Zhang L, Li S, Li L, Chen Z, Yang Y. COX‑2 inhibition in the endothelium induces glucose metabolism normalization and impairs tumor progression. Mol Med Rep 2017; 17:2937-2944. [PMID: 29257333 PMCID: PMC5783508 DOI: 10.3892/mmr.2017.8270] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 12/12/2017] [Indexed: 01/24/2023] Open
Abstract
Previous antitumor angiogenesis strategies have focused on targeting angiogenic signals. Encouragingly, the metabolism of tumor endothelial cells (TECs) has gained attention as a therapeutic target in recent years. There is consensus that, in terms of antitumor angiogenesis, the promotion of tumor vascular regression and normalization of the remaining blood vessels are equally important. Presently, tumor vessel normalization (TVN) is an emerging antitumor treatment. The present study focused on the normalization of TEC metabolism. The results demonstrated that TECs have a hyperglycolytic metabolism. Parixibox, a cyclooxygenase-2 (COX-2) blocker, successively reduces the expression of vascular endothelial growth factor (VEGF) in the tumor microenvironment. VEGF further influences the expression of 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3, a key glycolysis gene. Pharmacological blockade of COX-2 restored the glucose metabolism level (particularly glycolysis) in TECs, which may be an important basic process in TVN. Therefore, COX-2, which acts on abnormal tumor vessels, is expected to become a novel target for tumor treatment.
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Affiliation(s)
- Longhui Zhang
- Obstetrics and Gynecology Department, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Sufen Li
- Obstetrics and Gynecology Department, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Lan Li
- Obstetrics and Gynecology Department, Chong Qing Health Center for Women and Children, Chongqing 400010, P.R. China
| | - Zhengqiong Chen
- Obstetrics and Gynecology Department, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Ying Yang
- Obstetrics and Gynecology Department, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
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23
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The anti-tumor effect of aspirin: What we know and what we expect. Biomed Pharmacother 2017; 95:656-661. [DOI: 10.1016/j.biopha.2017.08.085] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 08/19/2017] [Accepted: 08/23/2017] [Indexed: 12/12/2022] Open
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24
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Farooq U, Naz S, Zehra B, Khan A, Ali SA, Ahmed A, Sarwar R, Bukhari SM, Rauf A, Ahmad I, Mabkhot YN. Isolation and characterization of three new anti-proliferative Sesquiterpenes from Polygonum barbatum and their mechanism via apoptotic pathway. BMC Cancer 2017; 17:694. [PMID: 29061136 PMCID: PMC5654143 DOI: 10.1186/s12885-017-3667-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 09/28/2017] [Indexed: 11/23/2022] Open
Abstract
Background The emergence of chemoresistant cancers and toxicity related to existing chemotherapeutic agents, demand the search for new pharmacophore with enhanced anti-cancer activity and least toxicity. For this purpose, three new sesquiterpenes were isolated from ethyl acetate fraction of the aerial parts of the plant Polygonum barbatum and evaluated for their anti-cancer potential. Methods The structural elucidation and characterization of the isolated compounds 1–3 were performed using various spectroscopic techniques such as mass, UV, IR, and extensive 1D/2D–NMR spectroscopy. Furthermore, the compounds 1–3 were subjected to screening of anti-cancer activity against different cell lines followed by brief analysis of apoptotic and anti-angiogenic potentials of the potent hit against non-small cell lung carcinoma cell line. Results All the compounds 1–3 were subjected to anti-proliferative potential against non-small cell lung carcinoma (NCI-H460), breast cancer (MCF-7), cervical cancer (HeLa) and normal mouse fibroblast (NIH-3 T3) cell lines. Among these, compound 3 was found to be more cytotoxic against NCI-H460 and MCF-7 cells (IC50 = 17.86 ± 0.72 and 11.86 ± 0.46 μM respectively). When compared with the standard drug cisplatin compound 3 was found to have more potent activity against NCI-H460 (IC50 = 19 ± 1.24 μM) as compared to MCF-7 cell lines (IC50 = 9.62 ± 0.5 μM). Compound 3 induced apoptosis in NCI-H460 cells in a dose dependent manner. It significantly downregulated, the expression of anti-apoptotic (BCL-2 L1 and p53) and increased the expression of pro-apoptotic (BAK and BAX) genes. Besides apoptosis, it also significantly reduced the cell migration and downregulated the angiogenic genes (i.e. VEGF and COX-2), thereby, inhibiting angiogenesis in NCI-H460 cells. Conclusion Compound 3 possesses potent anti-proliferative potential as well as induced apoptosis and inhibited the cell migration of the cancerous cells by altering the gene expression, responsible for it.
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Affiliation(s)
- Umar Farooq
- Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, KPK, 22060, Pakistan.
| | - Sadia Naz
- Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, KPK, 22060, Pakistan
| | - Binte Zehra
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Ajmal Khan
- Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, KPK, 22060, Pakistan.
| | - Syed Abid Ali
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Ayaz Ahmed
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
| | - Rizwana Sarwar
- Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, KPK, 22060, Pakistan
| | - Syed Majid Bukhari
- Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, KPK, 22060, Pakistan
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar, Khyber Pakhtunkhwa, 23561, Pakistan
| | - Izhar Ahmad
- Department of Botany, Islamia College Peshawar, Peshawar, Pakistan
| | - Yahia Nasser Mabkhot
- Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh, 11451, Saudi Arabia
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Chen H, Cai W, Chu ESH, Tang J, Wong CC, Wong SH, Sun W, Liang Q, Fang J, Sun Z, Yu J. Hepatic cyclooxygenase-2 overexpression induced spontaneous hepatocellular carcinoma formation in mice. Oncogene 2017; 36:4415-4426. [PMID: 28346420 PMCID: PMC5543258 DOI: 10.1038/onc.2017.73] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 02/07/2017] [Accepted: 02/07/2017] [Indexed: 12/12/2022]
Abstract
Cyclooxygenase (COX)-2 is upregulated in hepatocellular carcinoma (HCC). However, the direct causative effect of COX-2 in spontaneous HCC formation remains unknown. We thus investigate the role and molecular pathogenesis of COX-2 in HCC by using liver-specific COX-2 transgenic (TG) mice. We found spontaneous HCC formation with elevated inflammatory infiltrates and neovessels in male TG mice (3/21, 14.3%), but not in any of male WT mice (0/19). Reduced representation bisulfite sequencing (RRBS) and gene expression microarrays were performed in the HCC tumor and non-HCC liver tissues to investigate the molecular mechanisms of COX-2-driven HCC. By RRBS, DNA promoter hypermethylation was identified in HCC from TG mice. Induction of promoter hypermethylation was associated with reduced tet methylcytosine dioxygenase 1 (TET1) expression by COX-2. TET1 could catalyze the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) and prevents DNA hypermethylation. In keeping with this, loss of 5hmC was demonstrated in COX-2-induced HCC. Consistently, COX-2 overexpression in human HCC cell lines could reduce both TET1 expression and 5hmc levels. Integrative analyses of DNA methylation and gene expression profiles further identified significantly downregulated genes including LTBP1, ADCY5 and PRKCZ by promoter methylation in COX-2-induced HCC. Reduced expression of LTBP1, ADCY5 and PRKCZ by promoter hypermethylation was further validated in human HCCs. Bio-functional investigation revealed that LTBP1 inhibited cell proliferation in HCC cell lines, suggesting its potential role as a tumor suppressor in HCC. Gene expression microarrays revealed that signaling cascades (AKT (protein kinase B), STK33 (Serine/Threonine kinase 33) and MTOR (mechanistic target of rapamycin) pathways) were enriched in COX-2-induced HCC. In conclusion, this study demonstrated for the first time that enhanced COX-2 expression in hepatocytes is sufficient to induce HCC through inducing promoter hypermethylation by reducing TET1, silencing tumor-suppressive genes and activating key oncogenic pathways. Inhibition of COX-2 represents a mechanism-based target for HCC prevention.
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Affiliation(s)
- H Chen
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - W Cai
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
| | - E S H Chu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - J Tang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - C-C Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - S H Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - W Sun
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Q Liang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - J Fang
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Z Sun
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
| | - J Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
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Pandey VK, Amin PJ, Shankar BS. COX-2 inhibitor prevents tumor induced down regulation of classical DC lineage specific transcription factor Zbtb46 resulting in immunocompetent DC and decreased tumor burden. Immunol Lett 2017; 184:23-33. [PMID: 28161224 DOI: 10.1016/j.imlet.2017.01.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 01/16/2017] [Accepted: 01/30/2017] [Indexed: 12/26/2022]
Abstract
The interaction between the immune and tumor cells in the microenvironment is an important factor deciding the progression of cancer. Though many of the soluble mediators in the microenvironment that mediate immunosuppression are known, the mechanism by which the tumor affects the distal progenitors is not known. We report that the tumor derived prostanoids down regulated classical dendritic cells DC (cDC) lineage specific transcription factor Zbtb46 in the progenitor cells which affects its differentiation. Prostanoids also induced ERK/CREB/IL-10 signaling pathway in DC that is more important for maturation of DC. This was observed under in vitro as well as in vivo conditions leading to phenotypic and functional impairment of DC. siRNA mediated knockdown of Zbtb46 and not exogenous IL-10 mimicked the effects of tumor conditioned medium (TCM) on suppression of maturation markers. Treatment of tumor cells with COX-2 inhibitor NS-398 averted TCM induced phenotypic impairment of DC in vitro. Treatment of tumor bearing mice with NS-398 prevented tumor induced down regulation of Zbtb46 resulting in immunocompetent DC which in turn led to a decrease in tumor burden. The effects of NS-398 was indeed through immunomodulation was corroborated by no such response in SCID mice. Our study provides novel insight into the distal regulation of progenitor cells by tumor and the importance of Zbtb46 expression in anti-tumor immunity. These results identify Zbtb46 expression as an indicator of immunocompetent DC in tumor and also highlights that COX-2 inhibitors could be useful in cancer immunotherapy.
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Affiliation(s)
- Vipul K Pandey
- Immunology Section, Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India
| | - Prayag J Amin
- Immunology Section, Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India
| | - Bhavani S Shankar
- Immunology Section, Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India.
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Chen X, Wang Q, Zhan L, Shu A. Effects and mechanisms of docosahexaenoic acid on the generation of angiopoietin-2 by rat brain microvascular endothelial cells under an oxygen- and glucose-deprivation environment. SPRINGERPLUS 2016; 5:1518. [PMID: 27652091 PMCID: PMC5017979 DOI: 10.1186/s40064-016-3067-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 08/12/2016] [Indexed: 01/06/2023]
Abstract
Objective The aim of this study was to investigate the effects of docosahexaenoic acid (DHA) on the generation of angiopoietin-2 (Ang-2) by rat brain microvascular endothelial cells under an oxygen- and glucose-deprivation environment (OGD), and its relationship, if any, with cyclooxygenase 2 (COX-2) expression. Methods Annexin V and propidium iodide apoptosis assay was used to detect apoptosis. Enzyme linked immunosorbent assay was used to detect Ang-2, vascular endothelial growth factor (VEGF), prostaglandin E2 (PGE2), and prostaglandin I2 (PGI2) content. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect Ang-2 and VEGF mRNA expression. Western blot was used to detect expression of COX-2 protein. Results DHA reduced the apoptosis rate (P = 0.026) and decreased the secretion of Ang-2, VEGF, PGE2, and PGI2 (P = 0.006, P = 0.000, P = 0.002, P = 0.004 respectively). The relative expression of Ang2 and Vegf mRNA, as well as COX-2 expression, also decreased (P = 0.000, P = 0.005, P = 0.007 respectively). These effects were antagonized by GW9662 (peroxisome proliferator-activated receptor-γ antagonist). COX-2 protein expression levels were positively correlated with Ang2 and Vegf mRNA expression levels (γ = 0.69, P = 0.038 and γ = 0.76, P = 0.032, respectively). Ang-2 and VEGF mRNA levels were positively correlated with Ang-2 (γ = 0.84, P = 0.012) and VEGF (γ = 0.71, P = 0.036) secretion levels respectively. Conclusion DHA reduced apoptosis induced by an OGD environment, thus decreasing Ang-2 and VEGF synthesis. This phenomenon was associated with a decrease in COX-2 protein expression, PGE2 and PGI2 secretion, and generation regulation via intracellular transcriptional pathways.
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Affiliation(s)
- Xiaobo Chen
- Department of Anesthesiology, Three Gorges University People's Hospital, The First People's Hospital of Yichang, No. 2 Jiefang Road, Yichang, 443000 Hubei China
| | - Qiang Wang
- Department of Anesthesiology, Three Gorges University People's Hospital, The First People's Hospital of Yichang, No. 2 Jiefang Road, Yichang, 443000 Hubei China
| | - Leyun Zhan
- Department of Anesthesiology, Three Gorges University People's Hospital, The First People's Hospital of Yichang, No. 2 Jiefang Road, Yichang, 443000 Hubei China
| | - Aihua Shu
- Department of Anesthesiology, Three Gorges University People's Hospital, The First People's Hospital of Yichang, No. 2 Jiefang Road, Yichang, 443000 Hubei China
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REDUCTION OF VITREOUS PROSTAGLANDIN E2 LEVELS AFTER TOPICAL ADMINISTRATION OF INDOMETHACIN 0.5%, BROMFENAC 0.09%, AND NEPAFENAC 0.1%. Retina 2016; 36:1227-31. [DOI: 10.1097/iae.0000000000000860] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Abstract
OBJECTIVE Eighty percent of pancreatic ductal adenocarcinomas (PDAs) overexpress mucin 1 (MUC1), a transmembrane mucin glycoprotein. MUC1(high) PDA patients also express high levels of cyclooxygenase 2 (COX-2) and show poor prognosis. The cytoplasmic tail of MUC1 (MUC1-CT) partakes in oncogenic signaling, resulting in accelerated cancer progression. Our aim was to understand the regulation of Cox-2 expression by MUC1. METHODS Levels of COX-2 and MUC1 were determined in MUC1(-/-), MUC1(low), and MUC1(high) PDA cells and tumors using reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. Proliferative and invasive potential was assessed using MTT and Boyden chamber assays. Chromatin immunoprecipitation was performed to evaluate binding of MUC1-CT to the promoter of COX-2 gene. RESULTS Significantly higher levels of COX-2 mRNA and protein were detected in MUC1(high) versus MUC1(low/null) cells, which were recapitulated in vivo. In addition, deletion of MUC1 gene and transient knockdown of MUC1 led to decreased COX-2 level. Also, MUC1-CT associated with the COX-2 promoter at ∼1000 base pairs upstream of the transcription start site, the same gene locus where nuclear factor κB p65 associates with the COX-2 promoter. CONCLUSIONS Data supports a novel regulation of COX-2 gene by MUC1 in PDA, the intervention of which may lead to a better therapeutic targeting in PDA patients.
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Ko SY, Blatch GL, Dass CR. Netrin-1 as a potential target for metastatic cancer: focus on colorectal cancer. Cancer Metastasis Rev 2015; 33:101-13. [PMID: 24338005 DOI: 10.1007/s10555-013-9459-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Despite advanced screening technology and cancer treatments available today, metastasis remains an ongoing major cause of cancer-related deaths worldwide. Typically, colorectal cancer is one of the cancers treatable by surgery in conjunction with chemotherapy when it is detected at an early stage. However, it still ranks as the second highest modality and mortality of cancer types in western countries, and this is mostly due to a recurrence of metastatic colorectal cancer post-resection of the primary malignancy. Colorectal cancer metastases predominantly occur in the liver and lung, and yet the molecular mechanisms that regulate these organ-specific colorectal cancer metastases are largely unknown. Therefore, the identification of any critical molecule, which triggers malignancy in colorectal cancer, would be an excellent target for treatment. Netrin-1 was initially discovered as a chemotropic neuronal guidance molecule, and has been marked as a regulator for many cancers including colorectal cancer. Here, we summarise key findings of the role of netrin-1 intrinsic to colorectal cancer cells, extrinsic to the tumour microenvironment and angiogenesis, and consequently, we evaluate netrin-1 as a potential target molecule for metastasis.
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Affiliation(s)
- Suh Youn Ko
- College of Health and Biomedicine, Victoria University, St Albans, 3021, Australia
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Oba K, Hosono K, Amano H, Okizaki SI, Ito Y, Shichiri M, Majima M. Downregulation of the proangiogenic prostaglandin E receptor EP3 and reduced angiogenesis in a mouse model of diabetes mellitus. Biomed Pharmacother 2014; 68:1125-33. [PMID: 25465154 DOI: 10.1016/j.biopha.2014.10.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 10/18/2014] [Indexed: 11/18/2022] Open
Abstract
Vascular complications such as foot ulcers are a hallmark of diabetes mellitus (DM), although the molecular mechanisms that underlie vascular dysfunction remain unclear. Herein, we show that angiogenesis, which is indispensable to the healing of ulcers, is suppressed in polyurethane sponge implants in mice with DM and reduced proangiogenic signaling. DM was induced in male C57BL/6 mice by intraperitoneal injection of streptozotocin (100mg/kg). Polyurethane sponge disks were implanted into subcutaneous tissues on the backs of mice, and angiogenesis and expression of related factors were analyzed in sponge granulation tissues. Densities of platelet endothelial cell adhesion molecule-1 (PECAM-1)-positive vascular structures and PECAM-1 expression in sponge granulation tissues were increased over time in control mice and reduced in diabetic mice. The reductions in diabetic mice were accompanied by reduced expression of inducible cyclo-oxygenase-2 and microsomal prostaglandin E synthase-1. The prostaglandin E receptor subtype EP3 was downregulated in sponge granulation tissues in diabetic mice, whereas EP1, EP2, and EP4 were not. The expression of the proangiogenic growth factor vascular endothelial growth factor (VEGF)-A and the chemokine stromal cell-derived factor-1 (SDF-1) were both reduced in diabetic mice. Treatment of diabetic mice with a selective agonist of EP3, ONO-AE 248 (30 nmol/site/day, topical injection), reversed suppression of angiogenesis in diabetic mice. These results indicate that proangiogenic EP3 signaling is suppressed in diabetic mice with reduced expression of VEGF and SDF-1. Stimulation of EP3 signaling restored angiogenesis in a sponge implant model in mice with DM. This suggests that topical application of an EP3 agonist could be a novel strategy to treat foot ulcers in patients with DM.
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Affiliation(s)
- Kazuhito Oba
- Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan; Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Kanako Hosono
- Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Hideki Amano
- Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Shin-Ichiro Okizaki
- Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan; Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Yoshiya Ito
- Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Masayoshi Shichiri
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Masataka Majima
- Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
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Ogawa F, Amano H, Eshima K, Ito Y, Matsui Y, Hosono K, Kitasato H, Iyoda A, Iwabuchi K, Kumagai Y, Satoh Y, Narumiya S, Majima M. Prostanoid induces premetastatic niche in regional lymph nodes. J Clin Invest 2014; 124:4882-94. [PMID: 25271626 DOI: 10.1172/jci73530] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 08/21/2014] [Indexed: 01/17/2023] Open
Abstract
The lymphatic system is an important route for cancer dissemination, and lymph node metastasis (LNM) serves as a critical prognostic determinant in cancer patients. We investigated the contribution of COX-2-derived prostaglandin E2 (PGE2) in the formation of a premetastatic niche and LNM. A murine model of Lewis lung carcinoma (LLC) cell metastasis revealed that COX-2 is expressed in DCs from the early stage in the lymph node subcapsular regions, and COX-2 inhibition markedly suppressed mediastinal LNM. Stromal cell-derived factor-1 (SDF-1) was elevated in DCs before LLC cell infiltration to the lymph nodes, and a COX-2 inhibitor, an SDF-1 antagonist, and a CXCR4 neutralizing antibody all reduced LNM. Moreover, LNM was reduced in mice lacking the PGE2 receptor EP3, and stimulation of cultured DCs with an EP3 agonist increased SDF-1 production. Compared with WT CD11c+ DCs, injection of EP3-deficient CD11c+ DCs dramatically reduced accumulation of SDF-1+CD11c+ DCs in regional LNs and LNM in LLC-injected mice. Accumulation of Tregs and lymph node lymphangiogenesis, which may influence the fate of metastasized tumor cells, was also COX-2/EP3-dependent. These results indicate that DCs induce a premetastatic niche during LNM via COX-2/EP3-dependent induction of SDF-1 and suggest that inhibition of this signaling axis may be an effective strategy to suppress premetastatic niche formation and LNM.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Carcinoma, Lewis Lung/immunology
- Carcinoma, Lewis Lung/metabolism
- Carcinoma, Lewis Lung/secondary
- Celecoxib
- Cell Line, Tumor
- Chemokine CXCL12/metabolism
- Cyclooxygenase 2/metabolism
- Cyclooxygenase 2 Inhibitors/pharmacology
- Dendritic Cells/immunology
- Dinoprostone/physiology
- Drug Screening Assays, Antitumor
- Gene Knockout Techniques
- Lung Neoplasms/immunology
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Lymph Nodes/immunology
- Lymph Nodes/pathology
- Lymphangiogenesis
- Lymphatic Metastasis
- Male
- Mice, Knockout
- Neoplasm Transplantation
- Pyrazoles/pharmacology
- Receptors, CXCR4/metabolism
- Receptors, Prostaglandin E, EP3 Subtype/genetics
- Receptors, Prostaglandin E, EP3 Subtype/metabolism
- Signal Transduction
- Sulfonamides/pharmacology
- T-Lymphocytes, Regulatory/immunology
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LIU GONG, YU MINGYANG, HUANG XU, ZHU DONG, CHENG SHIHUAN, MA RENSHI, GU GUISHAN. Synergistic effect of celecoxib in tumor necrosis factor-related apoptosis-inducing ligand treatment in osteosarcoma cells. Mol Med Rep 2014; 10:2198-202. [DOI: 10.3892/mmr.2014.2409] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 06/06/2014] [Indexed: 11/05/2022] Open
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Madka V, Mohammed A, Li Q, Zhang Y, Patlolla JMR, Biddick L, Lightfoot S, Wu XR, Steele V, Kopelovich L, Rao CV. Chemoprevention of urothelial cell carcinoma growth and invasion by the dual COX-LOX inhibitor licofelone in UPII-SV40T transgenic mice. Cancer Prev Res (Phila) 2014; 7:708-16. [PMID: 24795386 PMCID: PMC4310686 DOI: 10.1158/1940-6207.capr-14-0087] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Epidemiologic and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual COX-lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3 to 5-fold more than did those of the wild-type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6%-80.2%, P < 0.0001 in males; by 36.9%-55.3%, P < 0.0001 in females) compared with the control group. The licofelone diet led to the development of significantly fewer invasive tumors in these transgenic mice. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; P < 0.01) and female mice (41%-44%; P < 0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, and caspase3) with a decrease in proliferation, inflammation, and angiogenesis markers (proliferating cell nuclear antigen, COX-2, 5-LOX, prostaglandin E synthase 1, FLAP, and VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC.
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Affiliation(s)
- Venkateshwar Madka
- Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Altaf Mohammed
- Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Qian Li
- Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Yuting Zhang
- Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Jagan M R Patlolla
- Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Laura Biddick
- Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Stan Lightfoot
- Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Xue-Ru Wu
- Department of Urology, NYU Medical Center, New York, New York; and
| | - Vernon Steele
- Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland
| | - Levy Kopelovich
- Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland
| | - Chinthalapally V Rao
- Authors' Affiliations: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
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Kang JX, Liu A. The role of the tissue omega-6/omega-3 fatty acid ratio in regulating tumor angiogenesis. Cancer Metastasis Rev 2013; 32:201-10. [PMID: 23090260 DOI: 10.1007/s10555-012-9401-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Angiogenesis is a necessary step in tumor growth and metastasis. It is well established that the metabolites of omega-6 and omega-3 fatty acids, which must be obtained through the diet and cannot be synthesized de novo in mammals, have differential effects on cellular processes. Omega-6 fatty acid (n-6 FA)-derived metabolites promote angiogenesis by increasing growth factor expression whereas omega-3 fatty acids (n-3 FA) have anti-angiogenic and antitumor properties. However, most studies thus far have failed to account for the role of the n-6 FA/n-3 FA ratio in angiogenesis and instead examined the absolute levels of n-6 and n-3 FA. This review highlights the biochemical interactions between n-6 and n-3 FA and focuses on how the n-6/n-3 FA ratio in tissues modulates tumor angiogenesis. We suggest that future work should consider the n-6/n-3 FA ratio to be a key element in experimental design and analysis. Furthermore, we recommend that clinical interventions should aim to both reduce n-6 metabolites and simultaneously increase n-3 FA intake.
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Karimzadeh L, Nabiuni M, Kouchesfehani HM, Adham H, Bagheri A, Sheikholeslami A. Effect of bee venom on IL-6, COX-2 and VEGF levels in polycystic ovarian syndrome induced in Wistar rats by estradiol valerate. J Venom Anim Toxins Incl Trop Dis 2013; 19:32. [PMID: 24330637 PMCID: PMC4029518 DOI: 10.1186/1678-9199-19-32] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 12/06/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Polycystic ovarian syndrome (PCOS) is a low-grade inflammatory disease characterized by hyperandrogenemia, hirsutism, chronic anovulation and vascular disorder. Interleukin-6 (IL-6), cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are triggered by inflammatory stimuli and lead to angiogenesis and pathogenesis of the ovary. Honeybee venom (HBV) contains an array of biologically active components possessing various pharmaceutical properties. This study was designed to assess the possibility of HBV application as an anti-inflammatory therapeutic agent to suppress levels of the main inflammatory mediators IL-6, COX-2 and VEGF.To induce PCOS, 1 mg of estradiol valerate (EV) per 100 g of body weight was subcutaneously (SC) injected into eight-week-old rats. After 60 days, 0.5 mg/kg of HBV was administered Intraperitoneal (IP) for 14 consecutive days, and the results of PCOS treatment were investigated. Rats were then anesthetized with CO2, and the ovaries were surgically removed. Serum IL-6 was detected by the ELISA kit. Immunoexpression of COX-2 and VEGF were examined in three groups: EV-induced PCOS, HBV-treated PCOS and control animals. RESULTS Thickness of theca layer, number and diameter of cysts and levels of IL-6 significantly decreased in HBV group relative to PCOS group. The immunohistochemical analysis showed an increase in COX-2 and VEGF expression in PCOS group whereas HBV-treated rats presented weak and irregular immunostaining. CONCLUSIONS Our results suggest that the beneficial effect of HBV may be mediated through its inhibitory effect on serum IL-6 level and ovarian COX-2 and VEGF expression.
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Affiliation(s)
| | - Mohammad Nabiuni
- Department of Cell and Molecular Biology, School of Biological Sciences, Kharazmi University, Karaj, Iran.
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Kumar BNP, Rajput S, Dey KK, Parekh A, Das S, Mazumdar A, Mandal M. Celecoxib alleviates tamoxifen-instigated angiogenic effects by ROS-dependent VEGF/VEGFR2 autocrine signaling. BMC Cancer 2013; 13:273. [PMID: 23731702 PMCID: PMC3681557 DOI: 10.1186/1471-2407-13-273] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 05/31/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Tamoxifen (TAM) is widely used in the chemotherapy of breast cancer and as a preventive agent against recurrence after surgery. However, extended TAM administration for breast cancer induces increased VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy. Celecoxib (CXB), a selective COX-2 inhibitor, suppresses VEGF gene expression by targeting the VEGF promoter responsible for its inhibitory effect. For this study, we had selected CXB as non-steroidal anti-inflammatory drug in combination with TAM for suppressing VEGF expression and simultaneously reducing doses of both the drugs. METHODS The effects of CXB combined with TAM were examined in two human breast cancer cell lines in culture, MCF7 and MDA-MB-231. Assays of proliferation, apoptosis, angiogenesis, metastasis, cell cycle distribution, and receptor signaling were performed. RESULTS Here, we elucidated how the combination of TAM and CXB at nontoxic doses exerts anti-angiogenic effects by specifically targeting VEGF/VEGFR2 autocrine signaling through ROS generation. At the molecular level, TAM-CXB suppresses VHL-mediated HIF-1α activation, responsible for expression of COX-2, MMP-2 and VEGF. Besides low VEGF levels, TAM-CXB also suppresses VEGFR2 expression, confirmed through quantifying secreted VEGF levels, luciferase and RT-PCR studies. Interestingly, we observed that TAM-CXB was effective in blocking VEGFR2 promoter induced expression and further 2 fold decrease in VEGF levels was observed in combination than TAM alone in both cell lines. Secondly, TAM-CXB regulated VEGFR2 inhibits Src expression, responsible for tumor progression and metastasis. FACS and in vivo enzymatic studies showed significant increase in the reactive oxygen species upon TAM-CXB treatment. CONCLUSIONS Taken together, our experimental results indicate that this additive combination shows promising outcome in anti-metastatic and apoptotic studies. In a line, our preclinical studies evidenced that this additive combination of TAM and CXB is a potential drug candidate for treatment of breast tumors expressing high levels of VEGF and VEGFR2. This ingenious combination might be a better tailored clinical regimen than TAM alone for breast cancer treatment.
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Affiliation(s)
- B N Prashanth Kumar
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal PIN-721302, India
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Holmes CE, Jasielec J, Levis JE, Skelly J, Muss HB. Initiation of aspirin therapy modulates angiogenic protein levels in women with breast cancer receiving tamoxifen therapy. Clin Transl Sci 2013; 6:386-90. [PMID: 24127927 PMCID: PMC5350889 DOI: 10.1111/cts.12070] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Aspirin has a range of antineoplastic properties linked to inhibition of cyclooxygenase enzymes in tumor cells, platelet inhibition and to inhibition of angiogenesis. We undertook a prospective study to determine the influence of a 45-day course of aspirin therapy on circulating and intraplatelet levels of selected proangiogenic (vascular endothelial growth factor [VEGF]) and antiangiogenic (thrombospondin-1 [TSP-1]) proteins, and platelet protein release in women diagnosed with breast cancer who were receiving tamoxifen therapy. Initiation of aspirin therapy increases serum and intraplatelet levels of TSP-1 without a corresponding increase in VEGF levels. Following aspirin therapy, VEGF levels decreased (relative to pretreatment levels) while TSP-1 returned to pretreatment levels. Plasma TSP-1 and VEGF levels did not change on aspirin therapy. Aspirin use also decreased thrombin receptor mediated release of TSP-1 and VEGF from platelets. The selective impact on platelet angiogenic protein content and release supports one mechanism by which aspirin can modify the angiogenic balance in women receiving tamoxifen therapy. Aspirin therapy appears to favor an overall antiangiogenic balance in women with breast cancer who are receiving tamoxifen therapy.
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Affiliation(s)
- Chris E Holmes
- Department of Medicine, University of Vermont, Burlington, Vermont, USA
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Kwon SH, Jeong SW, Jang JY, Lee JE, Lee SH, Kim SG, Kim YS, Cho YD, Kim HS, Kim BS, Jin SY. Cyclooxygenase-2 and vascular endothelial growth factor in chronic hepatitis, cirrhosis and hepatocellular carcinoma. Clin Mol Hepatol 2012; 18:287-94. [PMID: 23091809 PMCID: PMC3467432 DOI: 10.3350/cmh.2012.18.3.287] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Revised: 08/06/2012] [Accepted: 08/09/2012] [Indexed: 01/05/2023] Open
Abstract
Background/Aims Cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are up-regulated in hepatocellular carcinoma (HCC). To investigate the levels of COX-2 and VEGF expression in chronic hepatitis (CH), cirrhosis, and HCC. Methods The immunohistochemical expressions of COX-2 and VEGF were evaluated in tissues from patients with CH (n=95), cirrhosis (n=38), low-grade HCC (LG-HCC; n=6), and high-grade HCC (HG-HCC; n=29). Results The COX-2 expression scores in CH, cirrhosis, LG-HCC, and HG-HCC were 3.3±1.9 (mean±SD), 4.2±1.7, 5.5±1.0, and 3.4±2.4, respectively (CH vs. cirrhosis, P=0.016; CH vs. LG-HCC, P=0.008; LG-HCC vs. HG-HCC, P=0.004), and the corresponding VEGF expression scores were 0.9±0.8, 1.5±0.7, 1.8±0.9, and 1.6±1.1 (CH vs. cirrhosis, P<0.001; CH vs. LG-HCC, P=0.011; LG-HCC vs. HG-HCC, P=0.075). Both factors were correlated with the fibrosis stage in CH and cirrhosis (COX-2: r=0.427, P<0.001; VEGF: r=0.491, P<0.001). There was a significant correlation between COX-2 and VEGF in all of the tissue samples (r=0.648, P<0.001), and between high COX-2 and VEGF expression scores and survival (COX-2: P=0.001; VEGF: P<0.001). Conclusions The expressions of both COX-2 and VEGF are significantly higher in cirrhosis and LG-HCC than in CH. High COX-2 and high VEGF expressions are associated with a high survival rate.
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Affiliation(s)
- Soon Ha Kwon
- Division of Gastroenterology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea
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Fujita M, Kohanbash G, Fellows-Mayle W, Hamilton RL, Komohara Y, Decker SA, Ohlfest JR, Okada H. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res 2011; 71:2664-74. [PMID: 21324923 DOI: 10.1158/0008-5472.can-10-3055] [Citation(s) in RCA: 313] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Epidemiologic studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAID) and reduced glioma risks in humans. Most NSAIDs function as COX-2 inhibitors that prevent production of prostaglandin E₂ (PGE₂). Because PGE₂ induces expansion of myeloid-derived suppressor cells (MDSC), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME). In mouse models of glioma, treatment with the COX-2 inhibitors acetylsalicylic acid (ASA) or celecoxib inhibited systemic PGE₂ production and delayed glioma development. ASA treatment also reduced the MDSC-attracting chemokine CCL2 (C-C motif ligand 2) in the TME along with numbers of CD11b(+)Ly6G(hi)Ly6C(lo) granulocytic MDSCs in both the bone marrow and the TME. In support of this evidence that COX-2 blockade blocked systemic development of MDSCs and their CCL2-mediated accumulation in the TME, there were defects in these processes in glioma-bearing Cox2-deficient and Ccl2-deficient mice. Conversely, these mice or ASA-treated wild-type mice displayed enhanced expression of CXCL10 (C-X-C motif chemokine 10) and infiltration of cytotoxic T lymphocytes (CTL) in the TME, consistent with a relief of MDSC-mediated immunosuppression. Antibody-mediated depletion of MDSCs delayed glioma growth in association with an increase in CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma development. Finally, Cxcl10-deficient mice exhibited reduced CTL infiltration of tumors, establishing that CXCL10 limited this pathway of immunosuppression. Taken together, our findings show that the COX-2 pathway promotes gliomagenesis by directly supporting systemic development of MDSCs and their accumulation in the TME, where they limit CTL infiltration.
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Affiliation(s)
- Mitsugu Fujita
- Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
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Isono M, Suzuki T, Hosono K, Hayashi I, Sakagami H, Uematsu S, Akira S, DeClerck YA, Okamoto H, Majima M. Microsomal prostaglandin E synthase-1 enhances bone cancer growth and bone cancer-related pain behaviors in mice. Life Sci 2011; 88:693-700. [PMID: 21324324 DOI: 10.1016/j.lfs.2011.02.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Revised: 01/17/2011] [Accepted: 01/28/2011] [Indexed: 11/19/2022]
Abstract
AIMS Nonsteroidal anti-inflammatory drugs are a therapeutic modality for chronic cancer pain arising from bone metastases. Chronic administration of a cyclooxygenase (COX)-2 inhibitor is effective to bone cancer-related pain. However, adverse cardiovascular effects have limited COX-2 inhibitor therapy, and elucidation of better targets for blocking prostaglandin (PG) biosynthesis is necessary. Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that catalyzes isomerization of the endoperoxide PGH(2) to PGE(2). To investigate the validity of mPGES-1 as a therapeutic target, we evaluated bone cancer pain-related behaviors in mPGES-1 knockout (PGES-1-/-) mice. MAIN METHODS Lewis lung carcinoma cells (LLCCs) were injected into the intramedullary space of the femur of wild-type (WT) and PGES-1-/- mice. Pain-related behaviors were evaluated. KEY FINDINGS PGES-1-/- mice exhibited reduced tumor growth in bone marrow compared to WT. The expression of pro-calcitonin gene-related peptide (CGPR) in the dorsal root ganglia of L(1-5) was significantly higher in WT mice at day 14, whereas it was unchanged in mPGES-1 mice. In the observation of pain-related behaviors, mPGES-1-/- mice exhibited significantly fewer spontaneous flinches and their onset was several days later than WT. The appearance of other pain-related behaviors in mPGES-1-/- mice was also delayed as compared to WT. LLCC-injected WT mice treated with a COX-2 inhibitor, celecoxib, exhibited similar temporal changes to mPGES1-/-. SIGNIFICANCE The present results suggest that mPGES-1 plays a crucial role in the enhancement of bone cancer growth and bone cancer pain, and that inhibition of mPGES-1 may have clinical utility in the management of bone cancer pain.
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Affiliation(s)
- Masako Isono
- Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan
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Hosono K, Suzuki T, Tamaki H, Sakagami H, Hayashi I, Narumiya S, Alitalo K, Majima M. Roles of prostaglandin E2-EP3/EP4 receptor signaling in the enhancement of lymphangiogenesis during fibroblast growth factor-2-induced granulation formation. Arterioscler Thromb Vasc Biol 2011; 31:1049-58. [PMID: 21311040 DOI: 10.1161/atvbaha.110.222356] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE2 receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation. METHODS AND RESULTS Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced lymphangiogenesis in a dose-dependent manner, whereas topical PGE2 enhanced lymphangiogenesis. Topical injection of fluorescein isothiocyanate-dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE2. An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts. CONCLUSIONS Our findings suggest that COX-2 and EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis.
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Affiliation(s)
- Kanako Hosono
- Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, 228-8555, Japan
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Nakamura M, Yamaguchi S, Motoyoshi K, Negishi M, Saito-Taki T, Matsumoto K, Hayashi I, Majima M, Kitasato H. Anti-tumor effects of prostaglandin D2 and its metabolites, 15-deoxy-Δ12, 14-PGJ2, by peroxisome proliferator-activated receptor (PPAR) γ-dependent and -independent pathways. Inflamm Regen 2011. [DOI: 10.2492/inflammregen.31.189] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Katoh H, Hosono K, Suzuki T, Watanabe M, Majima M. EP3/EP4 signaling regulates tumor microenvironment formation by bone marrow-derived fibroblasts. Inflamm Regen 2011. [DOI: 10.2492/inflammregen.31.316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Numao A, Hosono K, Suzuki T, Hayashi I, Uematsu S, Akira S, Ogino Y, Kawauchi H, Unno N, Majima M. The inducible prostaglandin E synthase mPGES-1 regulates growth of endometrial tissues and angiogenesis in a mouse implantation model. Biomed Pharmacother 2010; 65:77-84. [PMID: 21247731 DOI: 10.1016/j.biopha.2010.12.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2010] [Accepted: 12/06/2010] [Indexed: 11/26/2022] Open
Abstract
Endometriosis is one of the most common gynecological diseases in women of reproductive age. Although cyclooxygenase (COX)-2 inhibitors are effective in the treatment of endometriosis, the adverse cardiovascular effects associated with these inhibitors have limited their use. Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme downstream of COX-2 in prostaglandin E(2) biosynthesis. Previously, we developed mPGES-1 knockout mice (mPGES-1(-/-)) and have identified for the first time the roles of ectopic lesion- and host-associated mPGES-1 in angiogenesis and the growth of endometrial tissues. When mPGES-1(-/-) endometrial fragments were implanted into wild type (WT) mice (mPGES-1(-/-)→WT), or WT fragments implanted into mPGES-1(-/-) mice (WT→mPGES-1(-/-)), the growth of the implants was suppressed at days 14 and 28 after implantation, compared toWT→WT transplantation. An even greater degree of suppression was observed in mPGES-1(-/-) endometrial fragments implanted into mPGES-1(-/-) mice (mPGES-1(-/-)→mPGES-1(-/-)). After WT-WT implantation, mPGES-1 expression was localized at the border of the implanted endometrial tissues. Microvessel density, determined by CD31 immunostaining, was markedly suppressed in the mPGES-1(-/-) endometrial fragments implanted into mPGES-1(-/-) mice, with some suppression also observed in the mPGES-1(-/-)→WT and WT→mPGES-1(-/-) groups. The expression of vascular endothelial growth factor (VEGF-A) was significantly reduced in mPGES-1(-/-) endometrial tissues implanted into mPGES-1(-/-) mice at days 14 and 28, in comparison to the WT→WT group. These results suggested that mPGES-1 enhanced angiogenesis and growth of the endometrial implant, and indicate that mPGES-1 may be a good therapeutic target for endometriosis.
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Affiliation(s)
- Akiko Numao
- Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
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Queiroga FL, Pires I, Parente M, Gregório H, Lopes CS. COX-2 over-expression correlates with VEGF and tumour angiogenesis in canine mammary cancer. Vet J 2010; 189:77-82. [PMID: 20675158 DOI: 10.1016/j.tvjl.2010.06.022] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2009] [Revised: 06/23/2010] [Accepted: 06/29/2010] [Indexed: 12/22/2022]
Abstract
This study was designed to investigate the possible roles of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in canine mammary cancer angiogenesis. Immunohistochemistry was performed on 70 tumours (28 benign and 42 malignant) in order to detect COX-2 and VEGF expression. Microvessel density (MVD) was determined by CD31 immunolabelling to assess tumour angiogenesis. There was a significantly higher expression of COX-2 (P<0.001), VEGF (P<0.001) and MVD (P<0.001) in malignant compared to benign tumours. In the malignant group, the MVD of COX-2 positive tumours was significantly higher than that of COX-2 negative tumours (P=0.026). A similar association was observed for VEGF (P<0.001) positive tumours. The results from this study suggested that over-expression of COX-2 and VEGF may contribute to increased angiogenesis and aggression in malignant tumours.
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Affiliation(s)
- Felisbina L Queiroga
- CECAV, Department of Veterinary Sciences, Universidade de Trás-os-Montes e Alto Douro, 5001-801 Vila Real, Portugal.
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Kamata H, Hosono K, Suzuki T, Ogawa Y, Kubo H, Katoh H, Ito Y, Uematsu S, Akira S, Watanabe M, Majima M. mPGES-1-expressing bone marrow-derived cells enhance tumor growth and angiogenesis in mice. Biomed Pharmacother 2010; 64:409-16. [DOI: 10.1016/j.biopha.2010.01.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Accepted: 01/29/2010] [Indexed: 10/19/2022] Open
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Long H, Wu QM, Li H. Significance of vascular endothelial growth factor expression and microvessel density in gastric cancer. Shijie Huaren Xiaohua Zazhi 2010; 18:557-562. [DOI: 10.11569/wcjd.v18.i6.557] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the correlations among vascular endothelial growth factor (VEGF) expression, microvessel density (MVD) and multiple pathological parameters in gastric cancer and analyze the significance of VEGF expression and MVD in patients with gastric cancer.
METHODS: A total of 169 patients with gastric cancer were retrospectively analyzed. The expression of VEGF and CD34 in gastric cancer specimens was detected by immunohistochemistry. The correlations among VEGF expression, MVD, and prognostic parameters were then analyzed.
RESULTS: A positive correlation was noted between VEGF expression and MVD in gastric carcinoma (P = 0.0053). Both VEGF expression and MVD were associated with tumor invasion, lymph node metastasis and TNM stage. The five-year disease-free survival and overall survival were lower in patients with tumors positive for VEGF than in those with tumors negative for VEGF (38.8% vs 57.1% and 35.3% vs 54.8%, respectively; both P < 0.01). The five-year disease-free survival and overall survival were lower in patients with tumors having high MVD score (> 5) than in patients with tumors having low MVD score (35.3% vs 53.9% and 23.5% vs 49.3%, both P < 0.05).
CONCLUSION: VEGF expression is closely associated with tumor angiogenesis and progression in gastric cancer. VEGF expression, MDV and tumor site are valuable parameters for predicting the prognosis of gastric cancer.
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Yang H, Park SH, Choi HJ, Moon Y. The integrated stress response-associated signals modulates intestinal tumor cell growth by NSAID-activated gene 1 (NAG-1/MIC-1/PTGF- ). Carcinogenesis 2010; 31:703-11. [PMID: 20130018 DOI: 10.1093/carcin/bgq008] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Hyun Yang
- Department of Microbiology and Immunology and Medical Research Institute, Pusan National University School of Medicine, Yangsan 626-813, Korea
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Recruited bone marrow cells expressing the EP3 prostaglandin E receptor subtype enhance angiogenesis during chronic inflammation. Biomed Pharmacother 2010; 64:93-100. [DOI: 10.1016/j.biopha.2009.04.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Accepted: 04/15/2009] [Indexed: 11/18/2022] Open
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