Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

Guo, Shanchun; Colbert, Laronna S.; McGlothen, Tanisha; Gonzalez-Perez, Ruben R.

doi:10.5772/27370

Cited by 10 publications

(8 citation statements)

References 276 publications

(295 reference statements)

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“…Apart from this, UHRF1, which encode a protein that regulates DNA and histone methylation, and NR1H4 (Nuclear Receptor Subfamily 1 Group H Member 4), which encode ligand-activated transcription factor, are also found to be linked with inflammation (Fiorucci et al, 2010;Wang et al, 2018), oxidative stress (Gai et al, 2017;J. K. Kim J. K. et al, 2020), and angiogenesis (Guo and Mo, 2020). Interestingly, in the present study, NR1H4 was also found to be one of the targets of down-regulated miRNA identified in a plasma sample of NPDR cases and thus can act as a preferred candidate in studies concerned with identification of circulatory prognostic biomarker for DR.…”

Section: Mmp9mentioning

confidence: 99%

Integrative Computational Approach Revealed Crucial Genes Associated With Different Stages of Diabetic Retinopathy

et al. 2020

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The increased incidence of diabetic retinopathy (DR) and the legacy effect associated with it has raised a great concern toward the need to find early diagnostic and treatment strategies. Identifying alterations in genes and microRNAs (miRNAs) is one of the most critical steps toward understanding the mechanisms by which a disease progresses, and this can be further used in finding potential diagnostic and prognostic biomarkers and treatment methods. We selected different datasets to identify altered genes and miRNAs. The integrative analysis was employed to find potential candidate genes (differentially expressed and aberrantly methylated genes that are also the target of altered miRNAs) and early genes (genes showing altered expression and methylation pattern during early stage of DR) for DR. We constructed a protein-protein interaction (PPI) network to find hub genes (potential candidate genes showing a greater number of interactions) and modules. Gene ontologies and pathways associated with the identified genes were analyzed to determine their role in DR progression. A total of 271 upregulated-hypomethylated genes, 84 downregulated-hypermethylated genes, 11 upregulated miRNA, and 30 downregulated miRNA specific to DR were identified. 40 potential candidate genes and 9 early genes were also identified. PPI network analysis revealed 7 hub genes (number of interactions >5) and 1 module (score = 5.67). Gene ontology and pathway analysis predicted enrichment of genes in oxidoreductase activity, binding to extracellular matrix, immune responses, leukocyte migration, cell adhesion, PI3K-Akt signaling pathway, ECM receptor interaction, etc., and thus their association with DR pathogenesis. In conclusion, we identified 7 hub genes and 9 early genes that could act as a potential prognostic, diagnostic, or therapeutic target for DR, and a few early genes could also play a role in metabolic memory phenomena.

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Section: Mmp9mentioning

confidence: 99%

Integrative Computational Approach Revealed Crucial Genes Associated With Different Stages of Diabetic Retinopathy

et al. 2020

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“…sunitinib, cabozantinib, and sorafenib 8 . VEGFR-2 has an advantage of the weak expression in the healthy tissue and overexpression is reported in several types of cancer namely, breast cancer, prostate cancer, colon cancer, cervical cancer, NSCLC, kidney clear cell cancer, brain glioma, bladder carcinoma, pancreatic cancer, oral cancer, skin melanoma oesophageal cancer, and ovarian cancer 9 , 10 . In addition, it was reported that the selective blockage of VEGFR-2 rather than of both receptors (VEGFR-1 and VEGFR-2), ideally overcomes the disadvantageous haematologic consequences that occurred in malignancy due to the elevated VEGF levels 11 .…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies

Taghour

Elkady

Eldehna

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC 50 values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.

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“…Vascular endothelial growth factor (VEGF) expression, through the expression of the cell-surface kinase VEGFR-2 (KDR/Flk-1), is strongly associated with both angiogenesis and tumor aggressiveness [5,8]. KDR is overexpressed in different types of cancers, such as breast cancer [9,10], cervical cancer [11,12], non-small cell lung cancer (NSCLC) [11,13,14], hepatocellular carcinoma (HCC) [5,11,15], and renal carcinoma [5,11,16]. VEGF overexpression has been observed in solid tumors, which initiates the activation of VEGFR-2 [4].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of a Novel VEGFR-2 Inhibitor Based on a 1,2,5-Oxadiazole-2-Oxide Scaffold with MAPK Signaling Pathway Inhibition

et al. 2022

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Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3 ,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 cell one-dose screening revealed that compounds 12a–c and 14a had the best MGI%, among the tested compounds. The target fluorinated compound 12b, as the most active one, showed better anticancer activity compared to the reference drug sorafenib, with IC50 values of 11.5, 11.6, and 13 µM against the HepG-2, A2780CP, and MDA-MB-231 cell lines, respectively. Furthermore, compound 12b (IC50 = 0.092 µM) had VEGFR-2-inhibitory activity comparable to that of the standard inhibitor sorafenib (IC50 = 0.049 µM). Furthermore, the ability of compound 12b in modulating MAPK signaling pathways was investigated. It was found to decrease the level of total ERK and its phosphorylated form, as well as leading to the down-regulation of metalloproteinase MMP-9 and the over-expression of p21 and p27, thus leading to subG1 cell-cycle arrest and, thus, the induction of apoptosis. Additionally, compound 12b decreased the rate of wound healing in the absence of serum, in comparison to DMSO-treated cells, providing a significant impact on metastasis inhibition. The quantitative RT-PCR results for E-cadherin and N-cadherin showed lower expression of the neuronal N-cadherin and increased expression of epithelial E-cadherin, indicating the ability of 12b to suppress metastasis. Furthermore, 12b-treated HepG2 cells expressed a low level of anti-apoptotic Bcl-2 and over-expressed proapoptotic Bax genes, respectively. Using the DAF-FM DA fluorescence probe, compound 12b produced NO intracellularly as efficiently as the reference drug JS-K. In silico molecular docking studies showed a structural similarity through an overlay of 12b with sorafenib. Interestingly, the drug-likeness properties of compound 12b met the expectations of Pfizer’s rule for the design of new drug candidates. Therefore, this study presents a novel anticancer lead compound that is worthy of further investigation and activity improvement.

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Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

Cited by 10 publications

References 276 publications

Integrative Computational Approach Revealed Crucial Genes Associated With Different Stages of Diabetic Retinopathy

Integrative Computational Approach Revealed Crucial Genes Associated With Different Stages of Diabetic Retinopathy

Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies

Design, Synthesis, and Biological Evaluation of a Novel VEGFR-2 Inhibitor Based on a 1,2,5-Oxadiazole-2-Oxide Scaffold with MAPK Signaling Pathway Inhibition

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