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Giorgio Zauli - One of the best experts on this subject based on the ideXlab platform.
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Antiangiogenic Activity of the MDM2 Antagonist Nutlin-3
Circulation Research, 2007Co-Authors: Paola Secchiero, Federica Corallini, Arianna Gonelli, Raffaella Dell'eva, Marco Vitale, Silvano Capitani, Adriana Albini, Giorgio ZauliAbstract:Nutlin-3, a nongenotoxic activator of the p53 pathway, dose-dependently (range 0.1 to 10 μmol/L) inhibited the formation of capillaries in an in vivo matrigel assay, as well as the formation of capillary-like structures in an in vitro coculture system composed of endothelial cells surrounded by fibroblasts. In contrast to the chemotherapeutic agent doxorubicin, nutlin-3 showed no induction of apoptosis in vitro either in the cocultures or in isolated vascular endothelial cells, even when used at the highest concentration (10 μmol/L). However, treatment with pharmacological inhibitors of the nuclear factor κB and phosphatidylinositol 3-kinase/Akt pathways sensitized endothelial cells to nutlin-3–induced apoptosis. Although nutlin-3 and doxorubicin induced a comparable p53 accumulation in endothelial cells, nutlin-3 was significantly more efficient than doxorubicin in upregulating the p53 target genes CDKN1A/p21, MDM2, and GDF-15, as well as in inhibiting cell cycle progression. However, the predominant in vitro effect of nutlin-3 was its strong antimigratory Activity observed at concentrations significantly lower (0.1 μmol/L) than those required to inhibit endothelial cell cycle progression. Taken together, our data suggest that the Antiangiogenic Activity of nutlin-3 observed in vivo was mainly attributable to inhibition of endothelial cell migration, to some extent attributable to cell cycle arrest, and to a lesser extent attributable to induction of apoptosis.
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Antiangiogenic Activity of the mdm2 antagonist nutlin 3
Circulation Research, 2007Co-Authors: Paola Secchiero, Federica Corallini, Arianna Gonelli, Marco Vitale, Silvano Capitani, Adriana Albini, Raffaella Delleva, Giorgio ZauliAbstract:Nutlin-3, a nongenotoxic activator of the p53 pathway, dose-dependently (range 0.1 to 10 μmol/L) inhibited the formation of capillaries in an in vivo matrigel assay, as well as the formation of cap...
Paola Secchiero - One of the best experts on this subject based on the ideXlab platform.
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Antiangiogenic Activity of the MDM2 Antagonist Nutlin-3
Circulation Research, 2007Co-Authors: Paola Secchiero, Federica Corallini, Arianna Gonelli, Raffaella Dell'eva, Marco Vitale, Silvano Capitani, Adriana Albini, Giorgio ZauliAbstract:Nutlin-3, a nongenotoxic activator of the p53 pathway, dose-dependently (range 0.1 to 10 μmol/L) inhibited the formation of capillaries in an in vivo matrigel assay, as well as the formation of capillary-like structures in an in vitro coculture system composed of endothelial cells surrounded by fibroblasts. In contrast to the chemotherapeutic agent doxorubicin, nutlin-3 showed no induction of apoptosis in vitro either in the cocultures or in isolated vascular endothelial cells, even when used at the highest concentration (10 μmol/L). However, treatment with pharmacological inhibitors of the nuclear factor κB and phosphatidylinositol 3-kinase/Akt pathways sensitized endothelial cells to nutlin-3–induced apoptosis. Although nutlin-3 and doxorubicin induced a comparable p53 accumulation in endothelial cells, nutlin-3 was significantly more efficient than doxorubicin in upregulating the p53 target genes CDKN1A/p21, MDM2, and GDF-15, as well as in inhibiting cell cycle progression. However, the predominant in vitro effect of nutlin-3 was its strong antimigratory Activity observed at concentrations significantly lower (0.1 μmol/L) than those required to inhibit endothelial cell cycle progression. Taken together, our data suggest that the Antiangiogenic Activity of nutlin-3 observed in vivo was mainly attributable to inhibition of endothelial cell migration, to some extent attributable to cell cycle arrest, and to a lesser extent attributable to induction of apoptosis.
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Antiangiogenic Activity of the mdm2 antagonist nutlin 3
Circulation Research, 2007Co-Authors: Paola Secchiero, Federica Corallini, Arianna Gonelli, Marco Vitale, Silvano Capitani, Adriana Albini, Raffaella Delleva, Giorgio ZauliAbstract:Nutlin-3, a nongenotoxic activator of the p53 pathway, dose-dependently (range 0.1 to 10 μmol/L) inhibited the formation of capillaries in an in vivo matrigel assay, as well as the formation of cap...
Juergen Mestan - One of the best experts on this subject based on the ideXlab platform.
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aee788 a dual family epidermal growth factor receptor erbb2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and Antiangiogenic Activity
Cancer Research, 2004Co-Authors: Peter Traxler, Peter R Allegrini, Ralf Brandt, Josef Brueggen, Robert Cozens, Doriano Fabbro, Konstantina Grosios, Heidi Lane, Paul M J Mcsheehy, Juergen MestanAbstract:Aberrant epidermal growth factor receptor (EGFR) and ErbB2 expression are associated with advanced disease and poor patient prognosis in many tumor types (breast, lung, ovarian, prostate, glioma, gastric, and squamous carcinoma of head and neck). In addition, a constitutively active EGFR type III deletion mutant has been identified in non-small cell lung cancer, glioblastomas, and breast tumors. Hence, members of the EGFR family are viewed as promising therapeutic targets in the fight against cancer. In a similar vein, vascular endothelial growth factor (VEGF) receptor kinases are also promising targets in terms of an Antiangiogenic treatment strategy. AEE788, obtained by optimization of the 7H-pyrrolo[2,3-d]pyrimidine lead scaffold, is a potent combined inhibitor of both epidermal growth factor (EGF) and VEGF receptor tyrosine kinase family members on the isolated enzyme level and in cellular systems. At the enzyme level, AEE788 inhibited EGFR and VEGF receptor tyrosine kinases in the nm range (IC(50)s: EGFR 2 nm, ErbB2 6 nm, KDR 77 nm, and Flt-1 59 nm). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC(50)s: 11 and 220 nm, respectively). AEE788 demonstrated antiproliferative Activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor- and VEGF-stimulated human umbilical vein endothelial cells. These properties, combined with a favorable pharmacokinetic profile, were associated with a potent antitumor Activity in a number of animal models of cancer, including tumors that overexpress EGFR and or ErbB2. Oral administration of AEE788 to tumor-bearing mice resulted in high and persistent compound levels in tumor tissue. Moreover, AEE788 efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. Strikingly, AEE788 also inhibited VEGF-induced angiogenesis in a murine implant model. Antiangiogenic Activity was also apparent by measurement of tumor vascular permeability and interstitial leakage space using dynamic contrast enhanced magnetic resonance imaging methodology. Taken together, these data indicate that AEE788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. Consequently, AEE788 is currently in Phase I clinical trials in oncology.
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aee788 a dual family epidermal growth factor receptor erbb2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and Antiangiogenic Activity
Cancer Research, 2004Co-Authors: Peter Traxler, Peter R Allegrini, Ralf Brandt, Josef Brueggen, Robert Cozens, Doriano Fabbro, Konstantina Grosios, Heidi Lane, Paul M J Mcsheehy, Juergen MestanAbstract:Aberrant epidermal growth factor receptor (EGFR) and ErbB2 expression are associated with advanced disease and poor patient prognosis in many tumor types (breast, lung, ovarian, prostate, glioma, gastric, and squamous carcinoma of head and neck). In addition, a constitutively active EGFR type III deletion mutant has been identified in non-small cell lung cancer, glioblastomas, and breast tumors. Hence, members of the EGFR family are viewed as promising therapeutic targets in the fight against cancer. In a similar vein, vascular endothelial growth factor (VEGF) receptor kinases are also promising targets in terms of an Antiangiogenic treatment strategy. AEE788, obtained by optimization of the 7 H -pyrrolo[2,3- d ]pyrimidine lead scaffold, is a potent combined inhibitor of both epidermal growth factor (EGF) and VEGF receptor tyrosine kinase family members on the isolated enzyme level and in cellular systems. At the enzyme level, AEE788 inhibited EGFR and VEGF receptor tyrosine kinases in the nm range (IC 50 s: EGFR 2 nm, ErbB2 6 nm, KDR 77 nm, and Flt-1 59 nm). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC 50 s: 11 and 220 nm, respectively). AEE788 demonstrated antiproliferative Activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor- and VEGF-stimulated human umbilical vein endothelial cells. These properties, combined with a favorable pharmacokinetic profile, were associated with a potent antitumor Activity in a number of animal models of cancer, including tumors that overexpress EGFR and or ErbB2. Oral administration of AEE788 to tumor-bearing mice resulted in high and persistent compound levels in tumor tissue. Moreover, AEE788 efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. Strikingly, AEE788 also inhibited VEGF-induced angiogenesis in a murine implant model. Antiangiogenic Activity was also apparent by measurement of tumor vascular permeability and interstitial leakage space using dynamic contrast enhanced magnetic resonance imaging methodology. Taken together, these data indicate that AEE788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. Consequently, AEE788 is currently in Phase I clinical trials in oncology.
Kh Lam - One of the best experts on this subject based on the ideXlab platform.
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Antiangiogenic Activity of 2-formyl-8-hydroxy-quinolinium chloride
Elsevier Masson, 2016Co-Authors: Kh Lam, Lee Kkh, Kok Shl, Wong Rsm, Fy Lau, Cheng Gym, Wy Wong, Sw Tong, Kw Chan, Chan RykAbstract:Tumour growth is closely related to the development of new blood vessels to supply oxygen and nutrients to cancer cells. Without the neovascular formation, tumour volumes cannot increase and undergo metastasis. Antiangiogenesis is one of the most promising approaches for antitumour therapy. The exploration of new Antiangiogenic agents would be helpful in antitumour therapy. Quinoline is an aromatic nitrogen compound characterized by a double-ring structure which exhibits a benzene ring fused to pyridine at two adjacent carbon atoms. The high stability of quinoline makes it preferable in a variety of therapeutic and pharmaceutical applications, including antitumour treatment. This work is to examine the potential Antiangiogenic Activity of the synthetic compound 2-Formyl-8-hydroxy-quinolinium chloride. We found that 2-Formyl-8-hydroxy-quinolinium chloride could inhibit the growth of human umbilical vein endothelial cells in vitro. Using the diethylnitrosamine-induced hepatocarcinogenesis model, 2-Formyl-8-hydroxy-quinolinium chloride showed strong Antiangiogenic Activity. Furthermore, 2-Formyl-8-hydroxy-quinolinium chloride could inhibit the growth of large Hep3B xenografted tumour from the nude mice. We assume that 2-Formyl-8-hydroxy-quinolinium chloride could be a potential Antiangiogenic and antitumour agent and it is worthwhile to further study its underlying working mechanism.Department of Applied Biology and Chemical Technolog
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Resveratrol derivative, trans-3,5,4 '-trimethoxystilbene, exerts Antiangiogenic and vascular-disrupting effects in zebrafish through the downregulation of vegfr2 and cell-cycle modulation
Wiley-Liss, 2010Co-Authors: Alex D, Kh Lam, Ec Leong, Zj Zhang, Yan Gth, Sh Cheng, Cw Leong, Sw Chan, Lee SmyAbstract:Angiogenesis plays an important role in the development of neoplastic diseases such as cancer. Resveratrol and its derivatives exert Antiangiogenic effects, but the mechanisms of their actions remain unclear. The aim of this study was to evaluate the Antiangiogenic Activity of resveratrol and its derivative trans-3,5,4'-trimethoxystilbene in vitro using human umbilical vein endothelial cells (HUVECS) and in vivo using transgenic zebrafish, and to clarify their mechanisms Of action in zebrafish by gene expression analysis of the vascular endothelial growth factor (VEGF) receptor (VEGFR2/KDR) and cell-cycle analysis. trans-3,5,4'-Trimethoxystilbene showed significantly more potent Antiangiogenic Activity than that of resveratrol in both assays. In zebrafish, trans-3-5-4'-trimethoxystilbene caused intersegmental vessel regression and downregulated VEGFR2 mRNA expression. Trans-3,5,4'-trimethoxystilbene also induced G2/M cell-cycle arrest, most specifically in endothelial cells of zebrafish embryos. We propose that the Antiangiogenic and vascular-targeting activities of trans-3,5,4'-trimethoxystilbene result front the downregulation of VEGFR2 expression and cell-cycle arrest at G2/M phase.Department of Applied Biology and Chemical Technolog
Federica Corallini - One of the best experts on this subject based on the ideXlab platform.
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Antiangiogenic Activity of the MDM2 Antagonist Nutlin-3
Circulation Research, 2007Co-Authors: Paola Secchiero, Federica Corallini, Arianna Gonelli, Raffaella Dell'eva, Marco Vitale, Silvano Capitani, Adriana Albini, Giorgio ZauliAbstract:Nutlin-3, a nongenotoxic activator of the p53 pathway, dose-dependently (range 0.1 to 10 μmol/L) inhibited the formation of capillaries in an in vivo matrigel assay, as well as the formation of capillary-like structures in an in vitro coculture system composed of endothelial cells surrounded by fibroblasts. In contrast to the chemotherapeutic agent doxorubicin, nutlin-3 showed no induction of apoptosis in vitro either in the cocultures or in isolated vascular endothelial cells, even when used at the highest concentration (10 μmol/L). However, treatment with pharmacological inhibitors of the nuclear factor κB and phosphatidylinositol 3-kinase/Akt pathways sensitized endothelial cells to nutlin-3–induced apoptosis. Although nutlin-3 and doxorubicin induced a comparable p53 accumulation in endothelial cells, nutlin-3 was significantly more efficient than doxorubicin in upregulating the p53 target genes CDKN1A/p21, MDM2, and GDF-15, as well as in inhibiting cell cycle progression. However, the predominant in vitro effect of nutlin-3 was its strong antimigratory Activity observed at concentrations significantly lower (0.1 μmol/L) than those required to inhibit endothelial cell cycle progression. Taken together, our data suggest that the Antiangiogenic Activity of nutlin-3 observed in vivo was mainly attributable to inhibition of endothelial cell migration, to some extent attributable to cell cycle arrest, and to a lesser extent attributable to induction of apoptosis.
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Antiangiogenic Activity of the mdm2 antagonist nutlin 3
Circulation Research, 2007Co-Authors: Paola Secchiero, Federica Corallini, Arianna Gonelli, Marco Vitale, Silvano Capitani, Adriana Albini, Raffaella Delleva, Giorgio ZauliAbstract:Nutlin-3, a nongenotoxic activator of the p53 pathway, dose-dependently (range 0.1 to 10 μmol/L) inhibited the formation of capillaries in an in vivo matrigel assay, as well as the formation of cap...