Anti‐angiogenic activity of thienopyridine derivative <scp>LCB</scp>03‐0110 by targeting <scp>VEGFR</scp>‐2 and <scp>JAK</scp>/<scp>STAT</scp>3 Signalling

Kim, Byung Hak; Lee, Yoonji; Yoo, Hyun Seung; Cui, Minghua; Lee, Sungwoon; Kim, Sun Young; Cho, Jong Un; Lee, Hyangsook; Yang, Beomjoo; Kwon, Young Guen; Choi, Sun; Kim, Tae Yoon

doi:10.1111/exd.12698

Cited by 11 publications

(9 citation statements)

References 46 publications

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“…STAT3 is an essential mediator of VEGF transcription by directly binding to the VEGF promoter, thereby inducing angiogenesis. 28 , 29 Our study showed that mogroside V significantly inhibited the activation of STAT3 protein in PANC-1 cancer cells concomitantly with reducing VEGF protein levels in vivo . This finding suggests that the anti-angiogenic effects of mogroside V may be due to the ability of mogroside V to prevent STAT3 activation.…”

Section: Discussionmentioning

confidence: 62%

RETRACTED ARTICLE: A natural food sweetener with anti-pancreatic cancer properties

Dai

Dou

et al. 2016

Oncogenesis

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Mogroside V is a triterpenoid isolated from the traditional Chinese medical plant Siraitia grosvenorii. Mogroside V has a high degree of sweetness and a low calorific content. Herein, we found that mogroside V possesses tumor growth inhibitory activity in in vitro and in vivo models of pancreatic cancer by promoting apoptosis and cell cycle arrest of pancreatic cancer cells (PANC-1 cells), which may in part be mediated through regulating the STAT3 signaling pathway. These results were confirmed in vivo in a mouse xenograft model of pancreatic cancer. In xenograft tumors, Ki-67 and PCNA, the most commonly used markers of tumor cell proliferation, were downregulated after intravenous administration of mogroside V. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays showed that mogroside V treatment promoted apoptosis of pancreatic cancer cells in the xenograft tumors. Furthermore, we found that mogroside V treatment significantly reduced the expression of CD31-labeled blood vessels and of the pro-angiogenic factor vascular endothelial growth factor in the xenografts, indicating that mogroside V might limit the growth of pancreatic tumors by inhibiting angiogenesis and reducing vascular density. These results therefore demonstrate that the natural, sweet-tasting compound mogroside V can inhibit proliferation and survival of pancreatic cancer cells via targeting multiple biological targets.

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Section: Discussionmentioning

confidence: 62%

RETRACTED ARTICLE: A natural food sweetener with anti-pancreatic cancer properties

Dai

Dou

et al. 2016

Oncogenesis

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“…Clinical evidence indicates a significant correlation between active STAT3 and VEGF in gastric cancer tissues (Choi et al, 2006). Targeting STAT3/VEGF signaling has been suggested as a promising strategy for anticancer treatment (Kim et al, 2015;Po_ zarowska and Po_ zarowski, 2016).…”

Section: Introductionmentioning

confidence: 99%

C‐X‐C motif chemokine receptor 4 promotes tumor angiogenesis in gastric cancer via activation of JAK2/STAT3

Zhang

Shi

et al. 2017

Cell Biology International

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C-X-C motif chemokine receptor 4 (CXCR4) overexpression promotes gastric cancer growth and metastasis. In this study, we determined its role in regulating tumor angiogenesis. We overexpressed CXCR4 in gastric cancer cells and examined the effects of conditioned medium on endothelial cell proliferation, migration, and tube formation. The effects of CXCR4 overexpression on vascular endothelial growth factor (VEGF) expression and signal transducer and activator of transcription 3 (STAT3) activation were analyzed. In vivo xenograft studies were done to confirm the role of CXCR4 in tumor angiogenesis. Conditioned medium from CXCR4-overexpressing gastric cancer cells stimulated endothelial cell proliferation, migration, and tube formation. Such effects were blocked by addition of a neutralizing anti-VEGF antibody. CXCR4 induced VEGF production and JAK2/STAT3 activation and enhanced STAT3 binding to VEGF promoter in gastric cancer cells. Delivery of a dominant negative variant of STAT3 significantly impaired CXCR4-induced upregulation of VEGF. Overexpression of CXCR4 facilitated tumor growth and angiogenesis in SGC7901 xenograft tumors, which was associated with increased levels of phospho-STAT3. CXCR4 contributes to tumor angiogenesis in gastric cancer by inducing STAT3-dependent VEGF expression and represents a promising therapeutic target for this malignancy.

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“…Discovery Studio 3.5 (Accelrys) and GOLD [50] were used for molecular docking studies [26]. The crystal structure of VEGFR-2 tyrosine kinase obtained from Protein Data Bank (PDB entry: 3VID and 2OH4) (http://www.rcsb.org/pdb/), which contains a phosphorylated activation loop, was used for the docking study [51]. The structure 3VID was selected as an EriB similar small molecule ligand co-crystalized.…”

Section: Methodsmentioning

confidence: 99%

Eriocalyxin B, a natural diterpenoid, inhibited VEGF-induced angiogenesis and diminished angiogenesis-dependent breast tumor growth by suppressing VEGFR-2 signaling

et al. 2016

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Eriocalyxin B (EriB), a natural ent-kaurane diterpenoid isolated from the plant Isodon eriocalyx var. laxiflora, has emerged as a promising anticancer agent. The effects of EriB on angiogenesis were explored in the present study. Here we demonstrated that the subintestinal vein formation was significantly inhibited by EriB treatment (10, 15 μM) in zebrafish embryos, which was resulted from the alteration of various angiogenic genes as shown in transcriptome profiling. In human umbilical vein endothelial cells, EriB treatment (50, 100 nM) could significantly block vascular endothelial growth factors (VEGF)-induced cell proliferation, tube formation, cell migration and cell invasion. Furthermore, EriB also caused G1 phase cell cycle arrest which was correlated with the down-regulation of the cyclin D1 and CDK4 leading to the inhibition of phosphorylated retinoblastoma protein expression. Investigation of the signal transduction revealed that EriB inhibited VEGF-induced phosphorylation of VEGF receptor-2 via the interaction with the ATP-binding sites according to the molecular docking simulations. The suppression of VEGFR-2 downstream signal transduction cascades was also observed. EriB was showed to inhibit new blood vessel formation in Matrigel plug model and mouse 4T1 breast tumor model. EriB (5 mg/kg/day) treatment was able to decrease tumor vascularization and suppress tumor growth and angiogenesis. Taken together, our findings suggested that EriB is a novel inhibitor of angiogenesis through modulating VEGFR-2 signaling pathway, which could be developed as a promising anti-angiogenic agent for treatment of angiogenesis-related human diseases, such as cancer.

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Anti‐angiogenic activity of thienopyridine derivative LCB03‐0110 by targeting VEGFR‐2 and JAK/STAT3 Signalling

Cited by 11 publications

References 46 publications

RETRACTED ARTICLE: A natural food sweetener with anti-pancreatic cancer properties

RETRACTED ARTICLE: A natural food sweetener with anti-pancreatic cancer properties

C‐X‐C motif chemokine receptor 4 promotes tumor angiogenesis in gastric cancer via activation of JAK2/STAT3

Eriocalyxin B, a natural diterpenoid, inhibited VEGF-induced angiogenesis and diminished angiogenesis-dependent breast tumor growth by suppressing VEGFR-2 signaling

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