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.
Spiekermann
Karsten
K
Department of Medicine III, University Hospital Grosshadern, Clinical Cooperative Group Leukemia, GSF National Research Center for Environment and Health, Munich, Germany. spiekermann@gsf.de
Faber
Florian
F
Voswinckel
Robert
R
Hiddemann
Wolfgang
W
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019898:Autocrine Communication / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016895:Culture Media, Serum-Free; D004351:Drug Resistance; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000473:pathology*; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects* / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors; D000097764:ETS Translocation Variant 6 Protein; D053614:Janus Kinase 2
D016895:Culture Media, Serum-Free; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D016044:Fusion Proteins, bcr-abl; D006131:Growth Inhibitors; D007211:Indoles; D008222:Lymphokines; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D017978:Receptors, Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors; C416849:SU 5614; C426234:TEL-ABL fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C108603:TEL-JAK2 fusion protein, human; D053614:Janus Kinase 2; C491568:TEL-JAK2 fusion protein, mouse