Hypoxia‐induced vascular endothelial growth factor secretion by retinal pigment epithelial cells is inhibited by melatonin via decreased accumulation of hypoxia‐inducible factors‐1α protein

Lai, Yu‐Hung; Hu, Dan‐Ning; Rosen, Richard B.; Sassoon, Jodi; Chuang, Li‐Yeh; Wu, Kwou-Yeung; Wu, Wen-Chuan

doi:10.1111/ceo.12802

Cited by 20 publications

(14 citation statements)

References 53 publications

(198 reference statements)

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“…Endothelial cells in the tumor microenvironment serve a pivotal role in the development and progression of cancer through modulating angiogenesis (8,45). Previous studies demonstrated that pharmacological concentrations of MLT have a direct anti-angiogenic effect though the suppression of proliferation in vascular endothelial cells, as well as an indirect effect via inhibition of pro-angiogenesis cytokines, including VEGF, epidermal growth factor and insulin-like growth factor (37,41,47). VEGF is one of the most potent pro-angiogenic cytokines, which specifically triggers the proliferation of endothelial cells and increases permeability (48).…”

Section: Discussionmentioning

confidence: 99%

“…However, the underlying mechanism of MLT varies in different cancer types (36). Additionally, reports indicated that MLT decreases the expression of HIF-1α and VEGF caused by different factors in various cultivated cells, particularly hypoxia-induced accumulation of HIF-1α protein and expression of VEGF (37-39). Accumulating evidence indicates that the antitumor effect of MLT is associated with the inhibition of angiogenesis (24,40,41).…”

Section: Introductionmentioning

confidence: 99%

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Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF

Cheng

Yang

et al. 2018

Int J Mol Med

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Angiogenesis is an essential process involved in various physiological, including placentation, and pathological, including cancer and endometriosis, processes. Melatonin (MLT), a well-known natural hormone secreted primarily in the pineal gland, is involved in regulating neoangiogenesis and inhibiting the development of a variety of cancer types, including lung and breast cancer. However, the specific mechanism of its anti-angiogenesis activity has not been systematically elucidated. In the present study, the effect of MLT on viability and angiogenesis of human umbilical vein endothelial cells (HUVECs), and the production of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS), under normoxia or hypoxia was analyzed using Cell Counting kit 8, tube formation, flow cytometry, ELISA and western blot assays. It was determined that the secretion of VEGF by HUVECs was significantly increased under hypoxia, while MLT selectively obstructed VEGF release as well as the production of ROS under hypoxia. Furthermore, MLT inhibited the viability of HUVECs in a dose-dependent manner and reversed the increase in cell viability and tube formation that was induced by hypoxia/VEGF/H2O2. Additionally, treatment with an inhibitor of hypoxia inducible factor (HIF)-1α (KC7F2) and MLT synergistically reduced the release of ROS and VEGF, and inhibited cell viability and tube formation of HUVECs. These observations demonstrate that MLT may serve dual roles in the inhibition of angiogenesis, as an antioxidant and a free radical scavenging agent. MLT suppresses the viability and angiogenesis of HUVECs through the downregulation of HIF-1α/ROS/VEGF. In summary, the present data indicate that MLT may be a potential anticancer agent in solid tumors with abundant blood vessels, particularly combined with KC7F2.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF

Cheng

Yang

et al. 2018

Int J Mol Med

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“…Similar HIF-1 inhibitory effects of melatonin were observed in other cancer models, including pancreatic ductal cells, cervical cancer, and lung cancer [ 61 ]. Melatonin was also effective through HIF-1 inhibition [ 62 ].…”

Section: Melatonin and Cancer Hallmarksmentioning

confidence: 99%

“…Melatonin has an inhibitory effect on HIF1 which in turn inhibit the altered metabolism of cancer. In the previous section (sustained proliferative signaling) the inhibition of HIF1 by melatonin was discussed [ 57 , 58 , 59 , 60 , 61 , 62 ].…”

Section: Melatonin and Cancer Hallmarksmentioning

confidence: 99%

Melatonin and Cancer Hallmarks

2018

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Melatonin is a natural indoleamine produced by the pineal gland that has many functions, including regulation of the circadian rhythm. Many studies have reported the anticancer effect of melatonin against a myriad of cancer types. Cancer hallmarks include sustained proliferation, evading growth suppressors, metastasis, replicative immortality, angiogenesis, resisting cell death, altered cellular energetics, and immune evasion. Melatonin anticancer activity is mediated by interfering with various cancer hallmarks. This review summarizes the anticancer role of melatonin in each cancer hallmark. The studies discussed in this review should serve as a solid foundation for researchers and physicians to support basic and clinical studies on melatonin as a promising anticancer agent.

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“…In vivo, tissue repair is induced by hypoxia-inducible factor 1α (HIF-1α) (Semenza, 2012). The downstream factors such as stromal cell-derived factor (SDF-1α) (Krieger et al, 2016), vascular endothelial growth factor (VEGF) (Lin et al, 2012), platelet-derived growth factor b (PDGF-b) (Lai et al, 2017;Vanden Berg-Foels, 2013) and macrophage chemotactic protein-1 (MCP-1) (Artlett, 2013) recruit several cell types to participate in remodeling process (Shirozu et al, 1995;Xu et al, 2013). The mechanism of tissue repair makes in situ regeneration feasible.…”

mentioning

confidence: 99%

Strategies in cell‐free tissue‐engineered vascular grafts

Yuan

Chen

Liu

et al. 2019

J Biomedical Materials Res

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Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality in the world, among which coronary artery diseases (CAD) are the most common type of CVD. Coronary artery bypass grafting (CABG) using autologous vein and artery grafts is the typical surgical intervention for CAD patients. However, for patients whose autologous grafts are not available, there are no appropriate substitutes for vascular grafts. Investigation of tissue-engineered vascular graft (TEVG) has persisted over decades with significant advancement, utilizing different types of biomaterials.In the past two decades, a great number of studies based on cell-seeding strategies were reported. However, limitations of cell-based strategies made clinical application difficult. With the understanding of stem cells and tissue remodeling process, strategies without cell-seeding emerged as potential methods to achieve in situ regeneration.A cell-free graft may recruit host cells and guide their participation in vascular remodeling. The grafts modified by bio-active molecules showed good results in promoting in situ regeneration and exhibited potential to make the vascular grafts off-the-shelf.In this review, the strategies for cell-free TEVG manufacturing were discussed, including the materials for fabricating TEVGs, the methods of functionalization to promote in situ regeneration, the challenges researchers faced in TEVG investigation, and finally the prospects in TEVG design.

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Hypoxia‐induced vascular endothelial growth factor secretion by retinal pigment epithelial cells is inhibited by melatonin via decreased accumulation of hypoxia‐inducible factors‐1α protein

Abstract: This study suggests that melatonin may have potential value in the prevention and treatment of various retinal diseases associated with increase of VEGF, vascular leakage and angiogenesis.

Cited by 20 publications

References 53 publications

Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF

Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF

Melatonin and Cancer Hallmarks

Strategies in cell‐free tissue‐engineered vascular grafts

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