Blocking angiogenesis and tumorigenesis with GFA-116, a synthetic molecule that inhibits binding of vascular endothelial growth factor to its receptor

Jiazhi Sun, Michelle A. Blaskovich, Rishi K. Jain, Frederic Delarue, Daniel Paris, Steven Brem, Marguerite Wotoczek-Obadia, Qing Lin, Domenico Coppola, Kihang Choi, Michael Mullan, Andrew Hamilton, Saïd M. Sebti

Research output: Contribution to journalArticle

Abstract

A small synthetic library of cyclohexapeptidomimetic calixarenes was prepared to identify disrupters of vascular endothelial growth factor (VEGF) binding to its receptor that inhibits angiogenesis. From this library, we discovered GFA-116, which potently inhibits 125I-VEGF binding to Flk-1 in Flk-1-overexpressing NIH 3T3 cells and human prostate tumor cells with an IC 50 of 750 nM. This inhibition is highly selective for VEGF in that 125I-platelet-derived growth factor binding to its receptor is not affected. GFA-116 inhibits VEGF-stimulated Flk-1 tyrosine phosphorylation and subsequent activation of Erk1/2 mitogen-activated protein kinases. Furthermore, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor-dependent stimulation of Erk1/2 phosphorylation are not affected at concentrations as high as 10 μM. In vitro, GFA-116 inhibits angiogenesis as measured by inhibition of migration and formation of capillary-like structures by human endothelial cells as well as suppression of microvessel outgrowth in rat aortic rings and rat cornea angiogenesis. In vivo, GFA-116 (50 mpk/day) inhibits tumor growth and angiogenesis as measured by CD31 staining of A-549 human lung tumors in nude mice. Furthermore, GFA-116 is also effective at inhibiting tumor growth and metastasis to the lung of B16-F10 melanoma cells injected into immunocompetent mice. Taken together, these results demonstrate that a synthetic molecule capable of disrupting the binding of VEGF to its receptor selectively inhibits VEGF-dependent signaling and suppresses angiogenesis and tumorigenesis.

Original languageEnglish (US)
Pages (from-to)3586-3592
Number of pages7
JournalCancer Research
Volume64
Issue number10
DOIs
StatePublished - May 15 2004

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Vascular Endothelial Growth Factor A
Carcinogenesis
Platelet-Derived Growth Factor
Neoplasms
Calixarenes
Phosphorylation
NIH 3T3 Cells
Lung
Experimental Melanomas
Fibroblast Growth Factors
Mitogen-Activated Protein Kinase 1
Growth
Microvessels
Epidermal Growth Factor
Nude Mice
Cornea
Libraries
Tyrosine
GFA 116
Prostate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Blocking angiogenesis and tumorigenesis with GFA-116, a synthetic molecule that inhibits binding of vascular endothelial growth factor to its receptor. / Sun, Jiazhi; Blaskovich, Michelle A.; Jain, Rishi K.; Delarue, Frederic; Paris, Daniel; Brem, Steven; Wotoczek-Obadia, Marguerite; Lin, Qing; Coppola, Domenico; Choi, Kihang; Mullan, Michael; Hamilton, Andrew; Sebti, Saïd M.

In: Cancer Research, Vol. 64, No. 10, 15.05.2004, p. 3586-3592.

Research output: Contribution to journalArticle

Sun, J, Blaskovich, MA, Jain, RK, Delarue, F, Paris, D, Brem, S, Wotoczek-Obadia, M, Lin, Q, Coppola, D, Choi, K, Mullan, M, Hamilton, A & Sebti, SM 2004, 'Blocking angiogenesis and tumorigenesis with GFA-116, a synthetic molecule that inhibits binding of vascular endothelial growth factor to its receptor', Cancer Research, vol. 64, no. 10, pp. 3586-3592. https://doi.org/10.1158/0008-5472.CAN-03-2673
Sun, Jiazhi ; Blaskovich, Michelle A. ; Jain, Rishi K. ; Delarue, Frederic ; Paris, Daniel ; Brem, Steven ; Wotoczek-Obadia, Marguerite ; Lin, Qing ; Coppola, Domenico ; Choi, Kihang ; Mullan, Michael ; Hamilton, Andrew ; Sebti, Saïd M. / Blocking angiogenesis and tumorigenesis with GFA-116, a synthetic molecule that inhibits binding of vascular endothelial growth factor to its receptor. In: Cancer Research. 2004 ; Vol. 64, No. 10. pp. 3586-3592.
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AU - Brem, Steven

AU - Wotoczek-Obadia, Marguerite

AU - Lin, Qing

AU - Coppola, Domenico

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AU - Hamilton, Andrew

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