Ablation of microvessels in vivo upon dimerization of iCaspase-9
Open Access
- 1 April 2002
- journal article
- research article
- Published by Springer Nature in Gene Therapy
- Vol. 9 (7), 444-451
- https://doi.org/10.1038/sj.gt.3301671
Abstract
Anti-angiogenic therapies based on targeted disruption of the tumor microvascular network have been proposed for cancer treatment. Inhibitors of the endothelial cell pro-survival pathway mediated by VEGF were shown to activate caspases and cause microvascular regression, but the efficacy of this strategy can be hindered by the engagement of redundant survival pathways. Alternatively, if direct activation of an apical pro-apoptotic caspase is sufficient to disrupt microvessels in vivo, such a strategy could potentially override upstream endothelial cell survival inputs and disrupt tumor neovascular networks. Here, we fused caspase-9 to a mutated FKBP12 domain to express an inducible caspase-9 molecule (iCaspase-9) that can be activated by a cell-permeable dimerizer drug, and transduced this construct into primary endothelial cells. We found that drug-induced dimerization of iCaspase-9 is sufficient to activate endogenous caspase-3 and trigger apoptosis even when endothelial cells are treated with the pro-survival factors VEGF or bFGF. A single intraperitoneal injection of the dimerizer drug induced apoptosis of endothelial cells expressing iCaspase-9 and elimination of human microvessels engineered in immunodeficient mice. These results demonstrate that the activation of iCaspase-9 disrupts microvessels in vivo, and suggest a novel anti-angiogenic strategy based on the expression and controlled activation of an inducible death gene in neovascular endothelial cells.Keywords
This publication has 32 references indexed in Scilit:
- A Targetable, Injectable Adenoviral Vector for Selective Gene Delivery to Pulmonary Endothelium in VivoMolecular Therapy, 2000
- Molecular Adaptors for Vascular-Targeted Adenoviral Gene DeliveryHuman Gene Therapy, 2000
- Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicityJCI Insight, 2000
- Angiopoietin-1 Inhibits Endothelial Cell Apoptosis via the Akt/Survivin PathwayJournal of Biological Chemistry, 2000
- Improved Artificial Death Switches Based on Caspases and FADDHuman Gene Therapy, 1999
- Vascular Endothelial Growth Factor (VEGF)-Mediated Angiogenesis Is Associated with Enhanced Endothelial Cell Survival and Induction of Bcl-2 ExpressionThe American Journal of Pathology, 1999
- WD-40 Repeat Region Regulates Apaf-1 Self-association and Procaspase-9 ActivationPublished by Elsevier ,1998
- Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosisNature, 1995
- Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis.The Journal of Experimental Medicine, 1994
- Role of protein kinase C in the inhibition by fibroblast growth factor of apoptosis in serum-depleted endothelial cellsBiochemical and Biophysical Research Communications, 1990