The protein tyrosine kinase inhibitor SU5614 inhibits VEGF-induced endothelial cell sprouting and induces growth arrest and apoptosis by inhibition of c-kit in AML cells

Objective Angiogenesis, the process of new blood vessel formation, is a critical process during growth and metastasis of solid tumors and might also represent a promising therapeutical target in patients with acute myeloid leukemia (AML). Methods In this study, we analyzed the expression of vascular endothelial growth factor receptors (VEGFR)-1/2 and its ligand VEGF in AML cell lines and characterized the inhibitory activity of the protein tyrosine kinase (PTK) inhibitor SU5614 on human endothelial and leukemic cells. Results Intracellular VEGF expression was detected in 9 of 10 leukemic cell lines. In contrast, VEGFR-1 and VEGFR-2 expression was restricted to 6 and 2 out of 10 cell lines, respectively. Although SU5614 was a potent inhibitor of the VEGF-induced endothelial cell sprouting in vitro, the sensitivity of leukemic cells toward the growth inhibitory activity of the compound was determined by the c-kit, but not by the VEGFR-1/2 expression. SU5614 induced growth arrest and apoptosis in c-kit–expressing Kasumi-1, UT-7, and M-07e cells and inhibited the stem cell factor (SCF)-induced tyrosine phosphorylation of c-kit. The sensitivity of Kasumi-1 cells towards the growth inhibitory activity of SU5614 was caused by an autocrine production of SCF, but not by transforming mutations of c-kit. Conclusions Our data provide strong evidence that SU5614 has a dual mode of action, and by direct inhibition of c-kit in AML cells and by inhibition of VEGFR-2 in endothelial cells, it might represent a novel treatment option for patients with c-kit+ AML.