Abstract
CSC3436 has been identified as a potent antitumor agent. This study investigated the effects of CSC3436 and mechanisms by which it exerts its antiangiogenic and vascular disrupting properties. Using an in vivo matrigel plug assay and zebrafish assay, we found that CSC3436 significantly inhibits microvessel formation. CSC3436 also suppresses endothelial cells migration and tube formation. Flow cytometry that CSC3436 inhibits growth of human endothelial cells（HUVEC、EA.hy926）by induction of apoptotic cell death in a concentration–dependent manner. We were able to correlate CSC3436– induced apoptosis in endothelial cells with the cleavage of procaspase-3, -8, and-9, as well as with the cleavage of PARP by Western blotting assay. Such sensitization was achieved through up-regulation of death receptor 5. CSC3436 was also capable of increasing the expression level of p53, and most importantly, the induction of DR5 by CSC3436 was abolished by p53 small interfering RNA. The results of this study indicate that CSC3436 exhibits vascular targeting activity associated with the induction of DR5-mediated endothelial cell apoptosis through p53 up-regulation, which suggests its potential as an antivascular and antitumor therapeutic agent.
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