The Src family kinase inhibitor, dasatinib, inhibits angiogenesis in vitro and in vivo

摘要: AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 270 Src family tyrosine kinases (SFKs) have essential roles in regulating multiple events involved angiogenesis. We investigated the effects of dasatinib (BMS-354825), an orally bioavailable dual Src/Abl kinase inhibitor, on angiogenesis using both vitro and vivo models. Our results show that inhibited VEGF- or bFGF-induced human endothelial cell (HUVEC) survival, migration tube formation with IC50 values low nM range. Dasatinib-mediated HUVEC apoptosis was due to its ability abrogate adhesion, consistent a mechanism involving anoikis. These biological responses were associated inhibition Src/FAK/p130CAS/paxillin signaling pathway following treatment Moreover, potent inhibitor ex chick aortic ring assay. Using two-photon confocal microscopy, we examined effect tumor directly . Results dramatically suppresses prostate cancer xenograft model. Taken together, these findings suggest anti-tumor activity may be at least partially anti-angiogenic activity. This study also provides rationale for clinical development as therapeutic cancer.