Recent Advances in Antiangiogenic Agents with VEGFR as Target

Zhang, J; Shan, Yuanyuan; Pan, Xiaoyan; He, Lingnan

doi:10.2174/138955711797068355

Cited by 23 publications

(14 citation statements)

References 97 publications

(129 reference statements)

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“…In contrast, coumestrol inhibited 100% of the kinase activity of CK2, 36% of DYRK1a, 40% of GSK3b and 47% of JAK2. Although coumestrol had a relatively high inhibition of 59% against vascular endothelial growth factor receptor 3 (VEGFR3), this inhibition might be compromised because VEGFR3 is a proven drug target [23]. Overall, our results suggest that coumestrol selectively inhibits kinase activity of CK2 in a cell-free manner.…”

Section: Resultsmentioning

confidence: 90%

Coumestrol from the national cancer Institute’s natural product library is a novel inhibitor of protein kinase CK2

Liu

Hsieh

Yang

et al. 2013

BMC Pharmacol Toxicol

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BackgroundCasein kinase 2 (CK2) is involved in various cellular events such as proliferation, apoptosis, and the cell cycle. CK2 overexpression is associated with multiple human cancers and may therefore be a promising target for cancer therapy. To identity novel classes of inhibitors for CK2, we screened a natural product library obtained from National Cancer Institute.MethodsThe quantitative luminescent kinase assay ADP-Glo™ was used to screen CK2 inhibitors from the natural product library. The same assay was used to determine cell-free dose-dependent response of CK2 inhibitors and conduct a kinetic study. Docking was performed to predict the binding patterns of selected CK2 inhibitors. Western blot analysis was used to evaluate Akt phosphorylation specific to CK2 and apoptosis effect. The cell viability assay CellTiter-Glo® was used to evaluate the inhibition effects of CK2 inhibitors on cancer cells.ResultsWe identified coumestrol as a novel reversible ATP competitive CK2 inhibitor with an IC50 value of 228 nM. Coumestrol is a plant-derived compound that belongs to the class of phytoestrogens, natural compounds that mimic the biological activity of estrogens. In our study, coumestrol showed high selectivity among 13 kinases. The hydrogen bonds formed between coumestrol and the amino acids in the ATP binding site were first reviewed by a molecular docking study that suggested a possible interaction of coumestrol with the hinge region of ATP site of CK2. In addition, coumestrol inhibited cancer cell growth partially through down-regulation of CK2-specific Akt phosphorylation. Finally, coumestrol exerted strong inhibition effects on the growth of three cancer cell lines.ConclusionOur study shows that coumestrol, a novel ATP competitive and cell permeable CK2 inhibitor with submicromolar IC50, had inhibition effects on the growth of three cancer cell lines and may represent a promising class of CK2 inhibitors.

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Section: Resultsmentioning

confidence: 90%

Coumestrol from the national cancer Institute’s natural product library is a novel inhibitor of protein kinase CK2

Liu

Hsieh

Yang

et al. 2013

BMC Pharmacol Toxicol

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“…The VEGF/VEGFR pathway becomes an attractive target for anticancer drug design. 9 Ligands binding VEGFRs in the cell membrane induces receptor dimerization and activation of the latter, and autophosphorylation of specific tyrosine residues within the dimeric complex. 10, 11 VEGF primarily binds to three transmembrane receptors with intracellular TK activity: VEGFR1 (Flt-1), VEGFR2 (Flk-1) and VEGFR3 (Flt-4).…”

mentioning

confidence: 99%

A novel angiogenesis inhibitor impairs lovo cell survival via targeting against human VEGFR and its signaling pathway of phosphorylation

et al. 2012

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Colorectal cancer represents the fourth commonest malignancy, and constitutes a major cause of significant morbidity and mortality among other diseases. However, the chemical therapy is still under development. Angiogenesis plays an important role in colon cancer development. We developed HMQ18–22 (a novel analog of taspine) with the aim to target angiogenesis. We found that HMQ18–22 significantly reduced angiogenesis of chicken chorioallantoic membrane (CAM) and mouse colon tissue, and inhibited cell migration and tube formation as well. Then, we verified the interaction between HMQ18–22 and VEGFR2 by AlphaScreen P-VEGFR assay, screened the targets on angiogenesis by VEGF Phospho Antibody Array, validated the target by western blot and RNAi in lovo cells. We found HMQ18–22 could decrease phosphorylation of VEGFR2(Tyr1214), VEGFR1(Tyr1333), Akt(Tyr326), protein kinase Cα (PKCα) (Tyr657) and phospholipase-Cγ-1 (PLCγ-1) (Tyr771). Most importantly, HMQ18–22 inhibited proliferation of lovo cell and tumor growth in a human colon tumor xenografted model of athymic mice. Compared with normal lovo cells proliferation, the inhibition on proliferation of knockdown cells (VEGFR2, VEGFR1, Akt, PKCα and PLCγ-1) by HMQ18–22 decreased. These results suggested that HMQ18–22 is a novel angiogenesis inhibitor and can be a useful therapeutic candidate for colon cancer intervention.

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“…This strategy resulted in the first clinically approved small molecule-like drugs that targeted tumoral angiogenesis: sunitinib and sorafenib [14,15]. VEGFR-2 inhibition is still being actively studied; it is considered an important strategy for angiogenesis inhibition [16] and towards the discovery of new anticancer drugs [17]. Many other angiogenesis therapeutic targets are currently being studied.…”

Section: An Overview Of Angiogenesismentioning

confidence: 99%

Antiangiogenic compounds: well-established drugs versus emerging natural molecules

et al. 2018

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a b s t r a c tAngiogenesis is the natural and physiologic process of growing blood vessels from pre-existing ones. Pathological angiogenesis occurs when the precise balance of all the molecular pathways that regulate angiogenesis is disrupted, and this process is a critical step in many diseases, including cancer. A limited number of antiangiogenic synthetic drugs have been developed. However, due to toxicity and side effects issues, the search for alternative to existing drugs is ongoing. In this sense, natural molecules obtained from plants or macrofungi, have demonstrated extraordinary potential in the treatment of angiogenesisrelated pathologies, specially taking into consideration its absence or very low toxicity, when compared to synthetic drugs. Using natural compounds as potential angiogenesis modulators is thus a promising field of research, supporting the creation of novel therapies able to reduce the use of drugs and associated side effects. In this review, the current status of antiangiogenic drugs and the wide variety of natural extracts and molecules with antiangiogenic capacities, as well as the angiogenesis molecular pathways and therapeutic targets, are presented. Finally, the challenges that need to be overcome in order to increase the use of natural compounds for clinical purposes are discussed.

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Recent Advances in Antiangiogenic Agents with VEGFR as Target

Cited by 23 publications

References 97 publications

Coumestrol from the national cancer Institute’s natural product library is a novel inhibitor of protein kinase CK2

Coumestrol from the national cancer Institute’s natural product library is a novel inhibitor of protein kinase CK2

A novel angiogenesis inhibitor impairs lovo cell survival via targeting against human VEGFR and its signaling pathway of phosphorylation

Antiangiogenic compounds: well-established drugs versus emerging natural molecules

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