The tetrapeptide Arg-Leu-Tyr-Glu inhibits VEGF-induced angiogenesis

Baek, Yi Yong; Lee, Dong Hoon; So, Ju Hoon; Kim, Cheol-Hee; Jeoung, Dooil; Lee, Hansoo; Choe, Jongseon; Won, Moo Ho; Ha, Kwon Soo; Kwon, Young Guen; Kim, Young Myeong

doi:10.1016/j.bbrc.2015.05.073

Cited by 11 publications

(23 citation statements)

References 23 publications

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“…Since RLYE inhibits in vitro angiogenic behaviors, such as proliferation, migration, and tube-like structure formation, of HUVECs treated with VEGF-A [19], we hypothesize that RLYE can inhibit tumor growth and metastasis via inhibition of tumor angiogenesis. To confirm this hypothesis, we first examined the effects of RLYE on angiogenesis ex vivo and in vivo .…”

Section: Resultsmentioning

confidence: 99%

“…RLYE treatment markedly suppressed the total surface density of capillaries induced by VEGF-A (Figure 1B). However, the peptide RLME that has no antiangiogenic activity [19] did not inhibit VEGF-induced angiogenesis in the CAM model (Figure 1B). We further confirmed the antiangiogenic capability of RLYE in an animal model using intravital microscopy.…”

Section: Resultsmentioning

confidence: 99%

“…RLYE has been shown to inhibit the angiogenic signal cascades in HUVECs stimulated with VEGF-A at a maximum inhibitory molar ratio of 11:1 of RLYE to monomeric VEGF [19], which is different from the approximately 1:1 molar ratio of bevacizumab [38]. This suggests that the peptide does not directly bind to VEGF-A, which is different from the mode of action of bevacizumab.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study showed that RLYE has potent antiangiogenic activity with IC 50 of 0.06-0.08 nM against VEGF-A [19]. This activity is more potent than those of clinically used antiangiogenic cancer drugs including bevacizumab (IC 50 = 0.15 nM for VEGF-A), ramucirumab (IC 50 = 1-2 nM for VEGFR-2), and the tyrosine receptor kinase inhibitor sunitinib (IC 50 = 80 nM for VEGFR-2) in endothelial cell culture conditions [36, 38, 42].…”

Section: Discussionmentioning

confidence: 99%

“…Thereafter, a single kringle 5 of plasminogen was shown to be more effective in anti-endothelial cell proliferation than angiostatin [17], and the tetrapeptide Lys-Leu-Tyr-Asp (KLYD) derived from the kringle 5 was revealed to have a potent inhibitory effect on endothelial cell proliferation [18]. We recently demonstrated that Arg-Leu-Tyr-Glu (RLYE) can more effectively inhibit VEGF-induced angiogenic activity in vitro than KLYD [19]. However, its underlying mechanism of action is unclear, as are the pharmacological effects on tumor angiogenesis, tumor blood vessel leakage, and tumor progression in an animal model.…”

Section: Introductionmentioning

confidence: 99%

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Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism

et al. 2016

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The tetrapeptide Arg-Leu-Tyr-Glu (RLYE) is known to inhibit vascular endothelial growth factor-A (VEGF-A)-induced angiogenesis in vitro. Herein, we examined its underlying mechanism and antitumor activity associated with vascular remodeling. RLYE inhibited VEGF-A-induced angiogenesis in a mouse model and suppressed VEGF-A-induced angiogenic signal cascades in human endothelial cells. However, RLYE showed no inhibitory effect on VEGF-A-induced proliferation and migration of multiple myeloma cells expressing VEGF receptor (VEGFR)-1, but not VEGFR-2. In addition, RLYE showed no inhibitory effect on angiogenic activities induced by VEGF-B, basic fibroblast growth factor, epithermal growth factor, sphingosine-1-phosphate, and placental growth factor. RLYE bound specifically to VEGFR-2 at the VEGF-A binding site, thereby blocking VEGF-A-VEGFR-2 binding and VEGF-A-induced VEGFR-2 internalization. The RLYE peptide inhibited tumor growth and metastasis via suppression of tumor angiogenesis in tumor-bearing mice. Moreover, RLYE showed a synergistic effect of the cytotoxic agent irinotecan on tumor cell apoptosis and tumor progression via tumor vessel normalization due to stabilization of VE-cadherin-mediated adherens junction, improvement of pericyte coverage, and inhibition of vascular leakage in tumors. Our results suggest that RLYE can be used as an antiangiogenic and tumor blood vessel remodeling agent for inhibition of tumor growth and metastasis by antagonizing VEGFR-2, with the synergistic anti-cancer effect via enhancement of drug delivery and therapeutic efficacy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism

et al. 2016

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Interleukin 8 mediates bcl‐xL‐induced enhancement of human melanoma cell dissemination and angiogenesis in a zebrafish xenograft model

Gabellini

Gómez-Abenza

Ibáñez-Molero

et al. 2017

Intl Journal of Cancer

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The protein bcl-xL is able to enhance the secretion of the proinflammatory chemokine interleukin 8 (CXCL8) in human melanoma lines. In this study, we investigate whether the bcl-xL/CXCL8 axis is important for promoting melanoma angiogenesis and aggressiveness in vivo, using angiogenesis and xenotransplantation assays in zebrafish embryos. When injected into wild-type embryos, bcl-xL-overexpressing melanoma cells showed enhanced dissemination and angiogenic activity compared with control cells. Human CXCL8 protein elicited a strong proangiogenic activity in zebrafish embryos and zebrafish Cxcr2 receptor was identified as the mediator of CXCL8 proangiogenic activity using a morpholino-mediated gene knockdown. However, human CXCL8 failed to induce neutrophil recruitment in contrast to its zebrafish homolog. Interestingly, the greater aggressiveness of bcl-xL-overexpressing melanoma cells was mediated by an autocrine effect of CXCL8 on its CXCR2 receptor, as confirmed by an shRNA approach. Finally, correlation studies of gene expression and survival analyses using microarray and RNA-seq public databases of human melanoma biopsies revealed that bcl-xL expression significantly correlated with the expression of CXCL8 and other markers of melanoma progression. More importantly, a high level of co-expression of bcl-xL and CXCL8 was associated with poor prognosis in melanoma patients. In conclusion, these data demonstrate the existence of an autocrine CXCL8/CXCR2 signaling pathway in the bcl-xL-induced melanoma aggressiveness, encouraging the development of novel therapeutic approaches for high bcl-xL-expressing melanoma.

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A new material for tissue engineered vagina reconstruction: Acellular porcine vagina matrix

Zhang

et al. 2017

J Biomedical Materials Res

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Acellular matrix materials have been widely used to repair various tissues and organs. According to the plastic principle, when a part of the body is lost, it should be replaced with a similar material. Therefore, the use of a homologous organ-specific acellular vaginal tissue in vagina reconstruction repair surgery may show good results. However, the acellular vagina matrix (AVM) form large vertebrates is difficult to isolate. In this study, we described a multistep method to prepare porcine AVM and evaluated the efficacy of acellularization. We also investigated the biomechanical properties, biological activity elements, and biocompatibility of the porcine AVM. We then used this material to reconstruct a rat vagina and performed further morphologic and functional analyses. Small intestinal submucosa (SIS), which is a commonly used acellular matrix material, was used in a control group. Histological examination, DNA content analysis, and agarose gel electrophoresis revealed that the decellularization procedure was effective. The AVM had acceptable biomechanical properties and sufficient growth factor production (VEGF, FGF, TGF-β1, and PDGF-BB) compared with that of the SIS. Subcutaneous transplantation in rats showed that the AVM had good biocompatibility. The tissue-engineered vagina using the AVM more resembled normal-appearing tissue than did that using SIS following morphologic and functional analyses. The AVM has great potential for application in vaginal reconstructive surgery. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1949-1959, 2017.

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The tetrapeptide Arg-Leu-Tyr-Glu inhibits VEGF-induced angiogenesis

Cited by 11 publications

References 23 publications

Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism

Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism

Interleukin 8 mediates bcl‐xL‐induced enhancement of human melanoma cell dissemination and angiogenesis in a zebrafish xenograft model

A new material for tissue engineered vagina reconstruction: Acellular porcine vagina matrix

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