The antiangiogenic agent Neovastat (AE-941) induces endothelial cell apoptosis

Neovastat (AE-941), a naturally occurring multifunctional antiangiogenic agent, has been shown to inhibit key components of the angiogenic process, including matrix metalloproteinases and vascular endothelial growth factor-mediated signaling events. In this study, we report the presence of a proapop...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2002-08, Vol.1 (10), p.795-802
Main Authors: Boivin, Dominique, Gendron, Sébastien, Beaulieu, Edith, Gingras, Denis, Béliveau, Richard
Format: Article
Language:English
Subjects:
3T3 Cells
Amino Acid Chloromethyl Ketones - metabolism
Angiogenesis Inhibitors - pharmacology
Animals
Aorta - cytology
Apoptosis
Blotting, Western
Caspase 3
Caspase 8
Caspase 9
Caspases - metabolism
Cattle
Cell Death
Cell Line
Cell Survival
Cells, Cultured
Chromatin - metabolism
COS Cells
Cysteine Proteinase Inhibitors - pharmacology
Cytochrome c Group - metabolism
Cytosol - metabolism
DNA - metabolism
DNA Fragmentation
Dose-Response Relationship, Drug
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - pathology
Enzyme Inhibitors - pharmacology
Humans
Immunoblotting
In Situ Nick-End Labeling
Mice
Mitochondria - metabolism
Poly(ADP-ribose) Polymerases - metabolism
Proto-Oncogene Proteins c-bcl-2 - metabolism
Time Factors
Tissue Extracts - pharmacology
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha - metabolism
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Summary:Neovastat (AE-941), a naturally occurring multifunctional antiangiogenic agent, has been shown to inhibit key components of the angiogenic process, including matrix metalloproteinases and vascular endothelial growth factor-mediated signaling events. In this study, we report the presence of a proapoptotic activity within this compound. Neovastat treatment of bovine aortic endothelial cells caused cell death with characteristics of apoptosis, including chromatin condensation and DNA fragmentation. Neovastat markedly induced caspase-3, caspase-8, and caspase-9 activities, at similar levels to those measured in cells treated with tumor necrosis factor-alpha. Activation of caspases by Neovastat appears to be essential for its proapoptotic effects because all apoptotic features were blocked by zVAD-fmk, a broad-spectrum caspase inhibitor. The activation of caspases was correlated with the cleavage of the nuclear substrate poly(ADP-ribose) polymerase, and by a concomitant release of cytochrome c from mitochondria to the cytoplasm. Neovastat-induced apoptosis appears to be specific to endothelial cells because treatment of other cell types such as U-87, COS-7, NIH-3T3, and SW1353 did not result in increased caspase-3 activity. These results demonstrate that Neovastat contains a proapoptotic factor that specifically induces the activation of caspases in endothelial cells and the resulting apoptosis of these cells.
ISSN:1535-7163
1538-8514