Endostatin Causes G1 Arrest of Endothelial Cells through Inhibition of Cyclin D1

Hanai, Jun‐ichi; Dhanabal, Mohan; Karumanchi, S. Ananth; Albanese, Chris; Waterman, Matthew J.F.; Chan, Barden; Ramchandran, Ramani; Pestell, Richard G.; Sukhatme, Vikas P.

doi:10.1074/jbc.m112274200

Cited by 194 publications

(121 citation statements)

References 25 publications

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“…Consistent with the present results, earlier studies show that various anti-angiogenic molecules, such as endostatin, capsaicin and curcumin, inhibit Rb phosphorylation and DNA synthesis of endothelial cells through downregulation of cyclin D1. 40,41 On the contrary, treatment of emodin in bovine aortic endothelial cells induced G2/M phase arrest of cell cycle. 38 Our experiment also showed G2/M phase arrest by emodin in HUVECs; however, its concentration was higher enough for inducing cell death.…”

Section: Discussionmentioning

confidence: 99%

Emodin inhibits vascular endothelial growth factor‐A‐induced angiogenesis by blocking receptor‐2 (KDR/Flk‐1) phosphorylation

Kwak

Park

et al. 2006

Intl Journal of Cancer

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Emodin (1,3,8‐trihydroxy‐6‐methylanthraquinone), an active component in the root and rhizome of Rheum palmatum, is a tyrosine kinase inhibitor with a number of biological activities, including antitumor effects. Here, we examine the effects of emodin on vascular endothelial growth factor (VEGF)‐A‐induced angiogenesis, both in vitro and in vivo. In vitro, emodin dose‐dependently inhibits proliferation, migration into the denuded area, invasion through a layer of Matrigel and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated with VEGF‐A. Emodin also inhibits basic fibroblast growth factor‐induced proliferation and migration of HUVECs and VEGF‐A‐induced tube formation of human dermal microvascular endothelial cells. Specifically, emodin induces the cell cycle arrest of HUVECs in the G0/G1 phase by suppressing cyclin D1 and E expression and retinoblastoma protein phosphorylation, and suppresses Matrigel invasion by inhibiting the basal secretion of matrix metalloproteinase‐2 and VEGF‐A‐stimulated urokinase plasminogen activator receptor expression. Additionally, emodin effectively inhibits phosphorylation of VEGF‐A receptor‐2 (KDR/Flk‐1) and downstream effector molecules, including focal adhesion kinase, extracellular signal‐regulated kinase 1/2, p38 mitogen‐activated protein kinase, Akt and endothelial nitric oxide synthase. In vivo, emodin strongly suppresses neovessel formation in the chorioallantoic membrane of chick and VEGF‐A‐induced angiogenesis of the Matrigel plug in mice. Our data collectively demonstrate that emodin effectively inhibits VEGF‐A‐induced angiogenesis in vitro and in vivo. Moreover, inhibition of phosphorylation of KDR/Flk‐1 and downstream effector molecules is a possible underlying mechanism of the anti‐angiogenic activity of emodin. Based on these data, we propose that an interaction of emodin with KDR/Flk‐1 may be involved in the inhibitory function of emodin toward VEGF‐A‐induced angiogenesis in vitro and responsible for its potent anti‐angiogenic in vivo. © 2006 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Emodin inhibits vascular endothelial growth factor‐A‐induced angiogenesis by blocking receptor‐2 (KDR/Flk‐1) phosphorylation

Kwak

Park

et al. 2006

Intl Journal of Cancer

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“…The results revealed that endostatin blocked the VEGF-mediated signaling pathway, inhibited the proliferation of endothelial cells, and promoted the apoptosis of endothelial cells. Hanai et al (4) found that endostatin decreased the activity of β-catenin, inhibited cyclin D1 expression and induced G1 arrest of endothelial cells. MacDonald et al (5) also reported that endostatin could remodel the blood vessels.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of endostatin combined with paclitaxel-cisplatin on breast cancer in xenograft-bearing mice

Sun

Deng

Duan

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. In the present study, we aimed to investigate the tumor-inhibiting effects of recombinant human endostatin (rhES) combined with paclitaxel-cisplatin (TP regimen) on human breast cancer in xenograft-bearing nude mice. A total of 24 mice bearing human breast cancer xenografts were administered both rhES and TP, TP alone, rhES alone or saline. The tumor growth inhibition was observed. Serum vascular endothelial growth factor (VEGF) levels and microvessel density (MVD) were determined by ELISA and immunohistochemistry, respectively. Cell apoptosis was detected using terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) staining. Survival time was observed in another 24 nude mice with the same treatment. MVD expression in the group administered rhES and TP was lower than that in the other groups (P<0.05); serum VEGF levels in the combined drug group were lower compared to the other groups; the apoptotic index increased in the combined drug group. We conclude that the effect of the TP regimen combined with rhES on breast cancer is better than that of the TP regimen alone.

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“…9 Cell surface glypicans have also been shown to be low-affinity endostatin receptors. 10 Endostatin has been implicated in several signaling pathways, such as downregulation of c-myc, 11 RhoA activity 12 and cyclin-D1, 13 blockage of VEGF signaling, 14,15 and inhibition of the wnt-signaling pathway. 16 Furthermore, endostatin has been shown to bind and inactivate metalloproteinases [17][18][19] and to regulate a spectrum of genes that suppress angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Endostatin therapy reveals a U-shaped curve for antitumor activity

et al. 2006

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Developing continuous systemic delivery of endostatin has been a goal of many laboratories. We have employed a method of gene therapy utilizing different viral constructs. Here, we report that a new serotype of adeno-associated viruses, which incorporates canine endostatin, provides dose-dependent transgene expression in the circulation after intramuscular injection in mice. Elevated levels of endostatin remained stable in the circulation for at least 4 months. In vitro assays determined that the protein expressed was biologically active. Antitumor activities of the above construct demonstrated a U-shape curve, where the maximum activity was observed within a certain critical concentration range. These data suggest that an optimum dose range may be required to achieve therapeutic efficacy in large animal models.

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Endostatin Causes G1 Arrest of Endothelial Cells through Inhibition of Cyclin D1

Cited by 194 publications

References 25 publications

Emodin inhibits vascular endothelial growth factor‐A‐induced angiogenesis by blocking receptor‐2 (KDR/Flk‐1) phosphorylation

Emodin inhibits vascular endothelial growth factor‐A‐induced angiogenesis by blocking receptor‐2 (KDR/Flk‐1) phosphorylation

Inhibitory effect of endostatin combined with paclitaxel-cisplatin on breast cancer in xenograft-bearing mice

Endostatin therapy reveals a U-shaped curve for antitumor activity

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