COX-2 in Radiotherapy: A Potential Target for Radioprotection and Radiosensitization

Cheki, Mohsen; Yahyapour, Rasoul; Farhood, Bagher; Rezaeyan, Abolhasan; Shabeeb, Dheyauldeen; Amini, Peyman; Rezapoor, Saeed; Najafi, Masoud

doi:10.2174/1874467211666180219102520

Cited by 71 publications

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“…Also, some studies have proposed several agents which inhibit inflammatory and profibrotic pathways to protect or mitigate lung pneumonitis and fibrosis. 25-28 Evidences have shown that inflammatory and profibrotic cytokines play a key role in chronic consequences of exposure to IR in lung tissue. 29 Amongst several cytokines, IL-1, IL-4, IL-6, IL-13, TNF-α and TGF-β are the most effective cytokines in promoting late effects of radiation injury in various organs such as the lung.…”

Section: Resultsmentioning

confidence: 99%

Metformin Protects against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression

et al. 2018

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Purpose: Lung tissue is one of the most sensitive organs to ionizing radiation (IR). Early and late side effects of exposure to IR can limit the radiation doses delivered to tumors that are within or adjacent to this organ. Pneumonitis and fibrosis are the main side effects of radiotherapy for this organ. IL-4 and IL-13 have a key role in the development of pneumonitis and fibrosis. Metformin is a potent anti-fibrosis and redox modulatory agent that has shown radioprotective effects. In this study, we aimed to evaluate possible upregulation of these cytokines and subsequent cascades such as IL4-R1, IL-13R1, Dual oxidase 1 (DUOX1) and DUOX2. In addition, we examined the potential protective effect of metformin in these cytokines and genes, as well as histopathological changes in rat’s lung tissues.Methods: 20 rats were divided into 4 groups: control; metformin treated; radiation + metformin; and radiation. Irradiation was performed with a 60Co source delivering 15 Gray (Gy) to the chest area. After 10 weeks, rats were sacrificed and their lung tissues were removed for histopathological, real-time PCR and ELISA assays.Results: Irradiation of lung was associated with an increase in IL-4 cytokine level, as well as the expression of IL-4 receptor-a1 (IL4ra1) and DUOX2 genes. However, there was no change in the level of IL-13 and its downstream gene including IL-13 receptor-a2 (IL13ra2). Moreover, histopathological evaluations showed significant infiltration of lymphocytes and macrophages, fibrosis, as well as vascular and alveolar damages. Treatment with metformin caused suppression of upregulated genes and IL-4 cytokine level, associated with amelioration of pathological changes.Conclusion: Results of this study showed remarkable pathological damages, an increase in the levels of IL-4, IL4Ra1 and Duox2, while that of IL-13 decreased. Treatment with metformin showed ability to attenuate upregulation of IL-4–DUOX2 pathway and other pathological damages to the lung after exposure to a high dose of IR.

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Section: Resultsmentioning

confidence: 99%

Metformin Protects against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression

et al. 2018

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“…COX-2 is a key enzyme catalyzing the metabolism of arachidonic acid into prostaglandins and finally contributes to cellular inflammation and carcinogenesis, also involved in RIBE, both in vitro and in vivo [ 23 , 24 ]. Increased COX-2 expression and/or activation in distant non-targeted tissues will cause oxidative DNA damage and elevated cancer risk [ 25 ]. It has been found that COX-2 plays a key role in EMT of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Epithelial–mesenchymal transition in non-targeted lung tissues of Kunming mice exposed to X-rays is suppressed by celecoxib

Pei

Sun

et al. 2018

Journal of Radiation Research

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Lung cancer is one of the highest health risks caused by ionizing radiation, which induces both direct effects and non-targeted effects. However, whether radiation-induced non-targeted effects result in epithelial–mesenchymal transition, a critical process during tumorigenesis, in non-targeted lung tissues remains unknown. In the present study, Kunming mice were subjected to whole-body, cranial or local abdominal irradiation of single-dose or fractionated 4 Gy X-rays, and the expressions of epithelial–mesenchymal transition markers in non-targeted lung tissues were assessed by both qRT-PCR and immunofluorescent staining. It was found that the epithelial marker was downregulated while the mesenchymal markers were upregulated significantly in non-targeted lung tissues of the irradiated mice. Local abdominal irradiation was more efficient in inducing epithelial–mesenchymal transition than whole-body or cranial irradiation when the fractionated irradiation method was adopted. In addition, the intraperitoneal administration of celecoxib suppressed epithelial–mesenchymal transition in the non-targeted lung tissues. In conclusion, our findings suggest that epithelial–mesenchymal transition is induced in non-targeted lung tissues, but can be suppressed by inhibition of cyclooxygenase-2 by celecoxib.

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“…A large number of studies have confirmed that chronic free radical production by irradiated or adjacent nonirradiated cells plays a key role in radiation toxicity [90,91]. Studies have proposed that ROS/NO producing enzymes such as mitochondria, membrane, endoplasmic reticulum and lysosomes in cells, are involved in this process [92]. Modulation of free radical production in these enzymes and organelles have been proposed for amelioration of radiation toxicity [93].…”

Section: Melatonin Modulates Redox Activity Following Exposure To Irmentioning

confidence: 99%

Mechanisms for Radioprotection by Melatonin; Can it be Used as a Radiation Countermeasure?

Amini

Mirtavoos-Mahyari

Motevaseli

et al. 2019

CMP

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COX-2 in Radiotherapy: A Potential Target for Radioprotection and Radiosensitization

Abstract: In this review, we describe the role of COX-2 in radiation normal tissue injury as well as irradiated bystander and non-targeted cells. In addition, mechanisms of COX-2 induced tumor resistance to radiotherapy and the potential role of COX-2 inhibition are discussed.

Cited by 71 publications

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Metformin Protects against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression

Metformin Protects against Radiation-Induced Pneumonitis and Fibrosis and Attenuates Upregulation of Dual Oxidase Genes Expression

Epithelial–mesenchymal transition in non-targeted lung tissues of Kunming mice exposed to X-rays is suppressed by celecoxib

Mechanisms for Radioprotection by Melatonin; Can it be Used as a Radiation Countermeasure?

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