ATL‐1, an analogue of aspirin‐triggered lipoxin A4, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor

Cezar-de-Mello, P F T; Vieira, Andreza Maia; Nascimento-Silva, Vany; Villela, Christina Gaspar; Barja‐Fidalgo, Christina; Fierro, Iolanda M.

doi:10.1038/sj.bjp.0707650

Cited by 61 publications

(45 citation statements)

References 66 publications

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“…Furthermore, the ability of LTD 4 to transactivate growth factor receptor tyrosine kinases and initiate mitogenic signaling is well established (7), and we propose that the VEGF receptor is the locus of the effect of LXA 4 via ALXR on HUVEC proliferation in response to LTD 4 . Analogous conclusions implicating ALXR have been made by others based on mimicry by other ALXR agonists, for example, ATL, the annexin-derived peptide Ac2-26, and relative sensitivity to the ALXR antagonists and the CysLT antagonists (15,31,43,44). The consequences of such modulation of VEGF receptor activation are seen proximally in the modulation of PLC-␥, MAPK, and Akt activation and physiologically in modulation of cell proliferation and angiogenesis.…”

Section: Discussionmentioning

confidence: 90%

“…Work by Fierro and colleagues has shown the stable synthetic analog of ATL, 15-epi-16-(para-fluoro)-phenoxy-LXA 4 (ATL-1), inhibits VEGF-and LTD 4 -stimulated angiogenesis in vitro and in vivo (29 -31). Additionally, ATL-1 has been shown to regulate the proteolytic activity necessary to digest basement membrane (30) and to modulate endothelial cell migration (31), key events in the angiogenic process (32).…”

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confidence: 99%

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Lipoxin A4: Anti-Inflammatory and Anti-Angiogenic Impact on Endothelial Cells

Baker

O'Meara²,

Scannell³

et al. 2009

The Journal of Immunology

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Lipoxins (LX) are a class of eicosanoid that possesses a wide spectrum of antiinflammatory and proresolution bioactions. Here we have investigated the impact of the endogenously produced eicosanoid LXA4 on endothelial cell inflammatory, proliferative, and antigenic responses. Using HUVECs we demonstrate that LXA4 inhibits vascular endothelial growth factor (VEGF)-stimulated inflammatory responses including IL-6, TNF-α, IFN-γ and IL-8 secretion, as well as endothelial ICAM-1 expression. Interestingly, LXA4 up-regulated IL-10 production from HUVECs. Consistent with these antiinflammatory and proresolution responses to LXA4, we demonstrate that LXA4 inhibited leukotriene D4 and VEGF-stimulated proliferation and angiogenesis as determined by tube formation of HUVECs. We have explored the underlying molecular mechanisms and demonstrate that LXA4 pretreatment is associated with the decrease of VEGF-stimulated VEGF receptor 2 (KDR/FLK-1) phosphorylation and downstream signaling events including activation of phospholipase C-γ, ERK1/2, and Akt.

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

Lipoxin A4: Anti-Inflammatory and Anti-Angiogenic Impact on Endothelial Cells

Baker

O'Meara²,

Scannell³

et al. 2009

The Journal of Immunology

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“…This discrepancy between in vivo and in vitro studies might be caused by enhanced VEGF level in H22-bearing mice, which would in turn evoke endothelial cell proliferation. A lot of articles confirmed that LXA 4 could inhibit VEGF-stimulated proliferation of HUVEC (12,13,(41)(42)(43).…”

Section: Discussionmentioning

confidence: 98%

“…Because VEGF is a well-known potent inducer of angiogenesis (12,13), in this study, after confirming the expression of LXA 4 receptor in H22 cells by Western blotting (seen in Supplementary Fig. S1), we first tested the effect of exogenous LXA 4 on VEGF secretion in H22 cells.…”

Section: Resultsmentioning

confidence: 99%

Lipoxin A4 and Its Analogue Suppress the Tumor Growth of Transplanted H22 in Mice: The Role of Antiangiogenesis

Chen

Hao

et al. 2010

Molecular Cancer Therapeutics

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Tumor angiogenesis plays an essential role in carcinogenesis, cancer progression, and metastasis. Some studies indicate that lipoxins, endogenous anti-inflammatory lipid mediators, might be involved in tumor angiogenesis; however, the governing mechanisms are still unknown. In the present study, we examined the effects of exogenous lipoxin A 4 (LXA 4 ) in mouse hepatocarcinoma cell line (H22) and H22-bearing mice model. It was found that in H22 cells, LXA 4 inhibited the production of vascular endothelial growth factor and reduced hypoxia-inducible factor-1α level. In addition, its analogue, BML-111, blocked the expression of vascular endothelial growth factor in serum and tumor sections from H22-bearing mice. H&E staining and immunostaining with antibodies against CD34 revealed that BML-111 suppressed tumor-related angiogenesis in vivo, but LXA 4 could not influence the proliferation of primary cultured human umbilical vein endothelial cells. The tumor growth was also inhibited by BML-111. We also found that BML-111 enhanced the in situ apoptosis while inhibiting macrophage infiltration in tumor tissue. The results provide new evidence that LXA 4 suppresses the growth of transplanted H22 tumor in mice through inhibiting tumor-related angiogenesis. Mol Cancer Ther; 9(8); 2164-74. ©2010 AACR.

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“…Recently, Cezar-de-Mello et al [33] have reported that ATL, an analogue of aspirin-triggered lipoxin A 4 , inhibited VEGF-induced HUVEC angiogenesis through several steps including inhibition of MMP-9 expression and activity, the transcription factor NF-B, phosphoinositide 3 kinases and extracellar signal-regulated kinase-2. This may help us to understand more about the effect of LXA 4 on angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Effects of Lipoxin A4 on CoCl2-Induced Angiogenesis and Its Possible Mechanisms in Human Umbilical Vein Endothelial Cells

Liu

et al. 2009

Pharmacology

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Lipoxin A₄ (LXA₄), a ‘stop signal’ for inflammation, is endogenously produced by eicosanoids, mainly via cell-to-cell interactions. At present, its influence on hypoxic angiogenesis, which is responsible for tumor growth and metastasis, has not been determined. Hypoxia regulates a variety of transcription factors including hypoxia-inducible factor (HIF)-1α, which plays a role in the expression of vascular endothelial growth factor (VEGF) and is considered a target for anti-angiogenic therapy. In this study, we utilized cobalt chloride (CoCl₂) to mimic hypoxia in vitro. Data suggested that LXA₄ decreased the expression and nucleus translocation of HIF-1α in a dose-dependent manner in CoCl₂-treated human umbilical vein endothelial cells (HUVEC). Furthermore, we confirmed that LXA₄ suppressed VEGF expression, tube formation and migration activity of HUVEC under hypoxia induced by CoCl₂. These results suggest that LXA₄ may have inhibitory effects on tumor angiogenesis through downregulation of the expression and nucleus translocation of HIF-1α. In summary, this study provides the first evidence for the anti-angiogenic role of LXA₄ on hypoxic human endothelial cells, which may have therapeutic value for cancer and other angiogenesis-associated diseases.

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ATL‐1, an analogue of aspirin‐triggered lipoxin A₄, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor

Cited by 61 publications

References 66 publications

Lipoxin A4: Anti-Inflammatory and Anti-Angiogenic Impact on Endothelial Cells

Lipoxin A4: Anti-Inflammatory and Anti-Angiogenic Impact on Endothelial Cells

Lipoxin A4 and Its Analogue Suppress the Tumor Growth of Transplanted H22 in Mice: The Role of Antiangiogenesis

Effects of Lipoxin A<sub>4</sub> on CoCl<sub>2</sub>-Induced Angiogenesis and Its Possible Mechanisms in Human Umbilical Vein Endothelial Cells

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