Angiogenesis Inhibitors

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 April 2011) | Viewed by 96561

Special Issue Editor


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Guest Editor
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico - Piazza G. Cesare, 11, 70124 Bari, Italy
Interests: angiogenesis; anti-angiogenesis; tumor progression; tumor vessel
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Special Issue Information

Dear Colleagues,

The idea of targeting angiogenesis to inhibit tumor growth was proposed more than three decades ago by Judah Folkman, and since then several approaches to block or disrupt tumor angiogenesis have been explored.

Antiangiogenesis remains a dynamic and evolving field in oncology. New therapeutic targets continue to emerge followed by the rapid development of new therapeutic agents to be investigated in clinical trials.

Until now, the success of antiangiogenic compounds in the clinic is rather limited when given as monotherapies. This is in contrast with many preclinical results which revealed a much higher efficacy of these agents in animal models.

Prof. Dr. Domenico Ribatti
Guest Editor

Keywords

  • angiopoietin-2 antagonists
  • antiangiogenic monoclonal antibodies
  • assays to validate antiangiogenic agents
  • avastin
  • biomarkers of response to antiangiogenic therapy
  • combination of antiangiogenic therapy with other anticancer therapies
  • endogenous inhibitors of angiogenesis
  • genetic strategies for targeting angiogenesis
  • imaging of tumor angiogenesis
  • integrins as targets for antiangiogenic therapy
  • metronomic low-dose antiangiogenic chemotherapy
  • protein tyrosine kinase inhibitors
  • targeted drug delivery to the tumor neovasculature
  • thalidomide and its IMiD derivatives
  • translating angiogenesis inhibitors to the clinic

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Published Papers (8 papers)

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Research

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476 KiB  
Article
Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca2+ Levels and eNOS Phosphorylation at Ser1179
by Stéphanie Thebault, Carmen González, Celina García, David Arredondo Zamarripa, Gabriel Nava, Luis Vaca, Fernando López-Casillas, Gonzalo Martínez De la Escalera and Carmen Clapp
Pharmaceuticals 2011, 4(7), 1052-1069; https://doi.org/10.3390/ph4071052 - 20 Jul 2011
Cited by 11 | Viewed by 8586
Abstract
Vasoinhibins, a family of antiangiogenic peptides derived from prolactin proteolysis, inhibit the vascular effects of several proangiogenic factors, including bradykinin (BK). Here, we report that vasoinhibins block the BK-induced proliferation of bovine umbilical vein endothelial cells. This effect is mediated by the inactivation [...] Read more.
Vasoinhibins, a family of antiangiogenic peptides derived from prolactin proteolysis, inhibit the vascular effects of several proangiogenic factors, including bradykinin (BK). Here, we report that vasoinhibins block the BK-induced proliferation of bovine umbilical vein endothelial cells. This effect is mediated by the inactivation of endothelial nitric oxide synthase (eNOS), as the NO donor DETA-NONOate reverted vasoinhibin action. It is an experimentally proven fact that the elevation of intracellular Ca2+ levels ([Ca2+]i) upon BK stimulation activates eNOS, and vasoinhibins blocked the BK-mediated activation of phospholipase C and the formation of inositol 1,4,5-triphosphate leading to a reduced release of Ca2+ from intracellular stores. The [Ca2+]i rise evoked by BK also involves the influx of extracellular Ca2+ via canonical transient receptor potential (TRPC) channels. Vasoinhibins likely interfere with TRPC-mediated Ca2+ entry since La3+, which is an enhancer of TRPC4 and TRPC5 channel activity, prevented vasoinhibins from blocking the stimulation by BK of endothelial cell NO production and proliferation, and vasoinhibins reduced the BK-induced increase of TRPC5 mRNA expression. Finally, vasoinhibins prevented the BK-induced phosphorylation of eNOS at Ser1179, a post-translational modification that facilitates Ca2+-calmodulin activation of eNOS. Together, our data show that vasoinhibins, by lowering NO production through the inhibition of both [Ca2+]i mobilization and eNOS phosphorylation, prevent the BK-induced stimulation of endothelial cell proliferation. Thus, vasoinhibins help to regulate BK effects on angiogenesis and vascular homeostasis. Full article
(This article belongs to the Special Issue Angiogenesis Inhibitors)
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369 KiB  
Article
Mutual Balance between Vasohibin-1 and Soluble VEGFR-1 in Endothelial Cells
by Hiroki Miyashita, Hirotada Suzuki, Akihide Ohkuchi and Yasufumi Sato
Pharmaceuticals 2011, 4(6), 782-793; https://doi.org/10.3390/ph4060782 - 31 May 2011
Cited by 9 | Viewed by 6763
Abstract
Vasohibin-1 (VASH1) is a VEGF-inducible gene of endothelial cells (ECs) that acts as a negative feedback regulator of angiogenesis. To further characterize the function of VASH1, we transfected human VASH1 gene into the mouse EC line MS1, established stable VASH1 expressing clones, and [...] Read more.
Vasohibin-1 (VASH1) is a VEGF-inducible gene of endothelial cells (ECs) that acts as a negative feedback regulator of angiogenesis. To further characterize the function of VASH1, we transfected human VASH1 gene into the mouse EC line MS1, established stable VASH1 expressing clones, and determined gene alteration by cDNA microarray analysis. Among the various angiogenesis-related genes, vascular endothelial growth factor type 1 receptor (VEGFR-1) and its alternative spliced form, soluble VEGFR1 (sVEGFR-1), were found to be the most significantly down-regulated genes. Transient overexpression of VASH1 in human umbilical vein endothelial cells confirmed the down-regulation of VEGFR-1 and sVEGFR-1. sVEGFR-1 is a decoy receptor for VEGF and inhibits angiogenesis. Interestingly, when sVEGFR-1 was overexpressed in ECs, it inhibited the expression of VASH1 in turn. These results suggest that VASH1 and sVEGFR-1, two angiogenesis inhibitors, mutually balance their expressions in ECs. Full article
(This article belongs to the Special Issue Angiogenesis Inhibitors)
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Review

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789 KiB  
Review
Proteolytically Derived Endogenous Angioinhibitors Originating from the Extracellular Matrix
by Chandra Shekhar Boosani and Yakkanti A. Sudhakar
Pharmaceuticals 2011, 4(12), 1551-1577; https://doi.org/10.3390/ph4121551 - 2 Dec 2011
Cited by 16 | Viewed by 8506
Abstract
Angiogenesis, a neovascularization process induced from the existing parent blood vessels, is a prerequisite for many physiological and pathological conditions. Under physiological conditions it is regulated by a balance between endogenous angioinhibitors and angioactivators, and an imbalance between them would lead to pathological [...] Read more.
Angiogenesis, a neovascularization process induced from the existing parent blood vessels, is a prerequisite for many physiological and pathological conditions. Under physiological conditions it is regulated by a balance between endogenous angioinhibitors and angioactivators, and an imbalance between them would lead to pathological conditions such as cancer, age-related macular degeneration (AMD), diabetic retinopathy, cardiovascular diseases, etc. Several proteolytically generated endogenous molecules have been identified which exhibit angioinhibition and/or antitumor activities. These angioinhibitors interact with endothelial and tumor cells by binding to distinct integrins and initiate many of their intracellular signaling mechanisms regulating the cell survival and or apoptotic pathways. The present review will focus on the extracellular matrix derived angioinhibitors, and their mechanisms of actions that point to the clinical significance and therapeutic implications. Full article
(This article belongs to the Special Issue Angiogenesis Inhibitors)
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404 KiB  
Review
Endogenous Matrix-Derived Inhibitors of Angiogenesis
by Malin Sund, Pia Nyberg and Hans Petter Eikesdal
Pharmaceuticals 2010, 3(10), 3021-3039; https://doi.org/10.3390/ph3103021 - 28 Sep 2010
Cited by 9 | Viewed by 8989
Abstract
Endogenous inhibitors of angiogenesis are proteins or fragments of proteins that are formed in the body, which can inhibit the angiogenic process. These molecules can be found both in the circulation and sequestered in the extracellular matrix (ECM) surrounding cells. Many matrix-derived inhibitors [...] Read more.
Endogenous inhibitors of angiogenesis are proteins or fragments of proteins that are formed in the body, which can inhibit the angiogenic process. These molecules can be found both in the circulation and sequestered in the extracellular matrix (ECM) surrounding cells. Many matrix-derived inhibitors of angiogenesis, such as endostatin, tumstatin, canstatin and arresten, are bioactive fragments of larger ECM molecules. These substances become released upon proteolysis of the ECM and the vascular basement membrane (VBM) by enzymes of the tumor microenvironment. Although the role of matrix-derived angiogenesis inhibitors is well studied in animal models of cancer, their role in human cancers is less established. In this review we discuss the current knowledge about these molecules and their potential use as cancer therapeutics and biomarkers. Full article
(This article belongs to the Special Issue Angiogenesis Inhibitors)
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1390 KiB  
Review
Thrombospondin-1 as a Paradigm for the Development of Antiangiogenic Agents Endowed with Multiple Mechanisms of Action
by Marco Rusnati, Chiara Urbinati, Silvia Bonifacio, Marco Presta and Giulia Taraboletti
Pharmaceuticals 2010, 3(4), 1241-1278; https://doi.org/10.3390/ph3041241 - 23 Apr 2010
Cited by 28 | Viewed by 15991
Abstract
Uncontrolled neovascularization occurs in several angiogenesis-dependent diseases, including cancer. Neovascularization is tightly controlled by the balance between angiogenic growth factors and antiangiogenic agents. The various natural angiogenesis inhibitors identified so far affect neovascularization by different mechanisms of action. Thrombospondin-1 (TSP-1) is a matricellular [...] Read more.
Uncontrolled neovascularization occurs in several angiogenesis-dependent diseases, including cancer. Neovascularization is tightly controlled by the balance between angiogenic growth factors and antiangiogenic agents. The various natural angiogenesis inhibitors identified so far affect neovascularization by different mechanisms of action. Thrombospondin-1 (TSP-1) is a matricellular modular glycoprotein that acts as a powerful endogenous inhibitor of angiogenesis. It acts both indirectly, by sequestering angiogenic growth factors and effectors in the extracellular environment, and directly, by inducing an antiangiogenic program in endothelial cells following engagement of specific receptors including CD36, CD47, integrins and proteoglycans (all involved in angiogenesis ). In view of its central, multifaceted role in angiogenesis, TSP-1 has served as a source of antiangiogenic tools, including TSP-1 fragments, synthetic peptides and peptidomimetics, gene therapy strategies, and agents that up-regulate TSP-1 expression. This review discusses TSP-1-based inhibitors of angiogenesis, their mechanisms of action and therapeutic potential, drawing our experience with angiogenic growth factor-interacting TSP-1 peptides, and the possibility of exploiting them to design novel antiangiogenic agents. Full article
(This article belongs to the Special Issue Angiogenesis Inhibitors)
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2001 KiB  
Review
Platelet-Derived Growth Factor (PDGF)/PDGF Receptors (PDGFR) Axis as Target for Antitumor and Antiangiogenic Therapy
by Marius Raica and Anca Maria Cimpean
Pharmaceuticals 2010, 3(3), 572-599; https://doi.org/10.3390/ph3030572 - 11 Mar 2010
Cited by 213 | Viewed by 19656
Abstract
Angiogenesis in normal and pathological conditions is a multi-step process governed by positive and negative endogenous regulators. Many growth factors are involved in different steps of angiogenesis, like vascular endothelial growth factors (VEGF), fibroblast growth factor (FGF)-2 or platelet-derived growth factors (PDGF). From [...] Read more.
Angiogenesis in normal and pathological conditions is a multi-step process governed by positive and negative endogenous regulators. Many growth factors are involved in different steps of angiogenesis, like vascular endothelial growth factors (VEGF), fibroblast growth factor (FGF)-2 or platelet-derived growth factors (PDGF). From these, VEGF and FGF-2 were extensively investigated and it was shown that they significantly contribute to the induction and progression of angiogenesis. A lot of evidence has been accumulated in last 10 years that supports the contribution of PDGF/PDGFR axis in developing angiogenesis in both normal and tumoral conditions. The crucial role of PDGF-B and PDGFR-β in angiogenesis has been demonstrated by gene targeting experiments, and their expression correlates with increased vascularity and maturation of the vascular wall. PDGF and their receptors were identified in a large variety of human tumor cells. In experimental models it was shown that inhibition of PDGF reduces interstitial fluid pressure in tumors and enhances the effect of chemotherapy. PDGFR have been involved in the cardiovascular development and their loss leads to a disruption in yolk sac blood vessels development. PDGFRβ expression by pericytes is necessary for their recruitment and integration in the wall of tumor vessels. Endothelial cells of tumor-associated blood vessels can express PDGFR. Based on these data, it was suggested the potential benefit of targeting PDGFR in the treatment of solid tumors. The molecular mechanisms of PDGF/PDGFR-mediated angiogenesis are not fully understood, but it was shown that tyrosine kinase inhibitors reduce tumor growth and angiogenesis in experimental xenograft models, and recent data demonstrated their efficacy in chemoresistant tumors. The in vivo effects of PDGFR inhibitors are more complex, based on the cross-talk with other angiogenic factors. In this review, we summarize data regarding the mechanisms and significance of PDGF/PDGFR expression in normal conditions and tumors, focusing on this axis as a potential target for antitumor and antiangiogenic therapy. Full article
(This article belongs to the Special Issue Angiogenesis Inhibitors)
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219 KiB  
Review
The Chick Embryo Chorioallantoic Membrane as an In Vivo Assay to Study Antiangiogenesis
by Domenico Ribatti
Pharmaceuticals 2010, 3(3), 482-513; https://doi.org/10.3390/ph3030482 - 8 Mar 2010
Cited by 59 | Viewed by 16257
Abstract
Antiangiogenesis, e.g., inhibition of blood vessel growth, is being investigated as a way to prevent the growth of tumors and other angiogenesis-dependent diseases. Pharmacological inhibition interferes with the angiogenic cascade or the immature neovasculature with synthetic or semi-synthetic substances, endogenous inhibitors or biological [...] Read more.
Antiangiogenesis, e.g., inhibition of blood vessel growth, is being investigated as a way to prevent the growth of tumors and other angiogenesis-dependent diseases. Pharmacological inhibition interferes with the angiogenic cascade or the immature neovasculature with synthetic or semi-synthetic substances, endogenous inhibitors or biological antagonists.The chick embryo chorioallantoic membrane (CAM) is an extraembryonic membrane, which serves as a gas exchange surface and its function is supported by a dense capillary network. Because its extensive vascularization and easy accessibility, CAM has been used to study morphofunctional aspects of the angiogenesis process in vivo and to study the efficacy and mechanism of action of pro- and anti-angiogenic molecules. The fields of application of CAM in the study of antiangiogenesis, including our personal experience, are illustrated in this review article. Full article
(This article belongs to the Special Issue Angiogenesis Inhibitors)
103 KiB  
Review
The Vasohibin Family
by Yasufumi Sato
Pharmaceuticals 2010, 3(2), 433-440; https://doi.org/10.3390/ph3020433 - 5 Feb 2010
Cited by 10 | Viewed by 10140
Abstract
Angiogenesis is regulated by the local balance between angiogenesis stimulators and inhibitors. A number of endogenous angiogenesis inhibitors have been found in the body. The origin of these inhibitors is mostly extrinsic to the vasculature. Recently, however, vascular endothelial cells themselves have been [...] Read more.
Angiogenesis is regulated by the local balance between angiogenesis stimulators and inhibitors. A number of endogenous angiogenesis inhibitors have been found in the body. The origin of these inhibitors is mostly extrinsic to the vasculature. Recently, however, vascular endothelial cells themselves have been found to produce angiogenesis inhibitors including vasohibin-1. These intrinsic inhibitors are thought to regulate angiogenesis by an auto-regulatory or negative-feedback mechanism. This review will focus on vasohibin-1 produced by vascular endothelial cells and on its homologue, vasohibin-2. Full article
(This article belongs to the Special Issue Angiogenesis Inhibitors)
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