SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation.
OBJECTIVE
Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecle indolinone that specifically inhibits this family of kinases.


METHODS
Human umbilical vein endothelial cells were used to study the effects of SFK inhibition. Western blot analysis was performed to determine the effect of SFK inhibition on the PI3K/Akt pathway and caspase cleavage. Apoptosis was studied by propidium iodide staining of nuclei. Angiogenesis was examined using capillary tubule formation in Matrigel. Tumor response was further studied in vivo using Lewis lung carcinoma cells implanted into the dorsal skin fold of mice in the window model and in the hind limb in the tumor volume model.


RESULTS
Clonogenic survival of endothelial cells was decreased after the combined therapy of SU6656 and radiation compared with radiotherapy alone. Furthermore, SFK inhibition by SU6656 attenuated radiation-induced Akt phosphorylation and increased radiation-induced apoptosis and vascular endothelium destruction. In vivo, SU6656 administered before irradiation significantly enhanced radiation-induced destruction of blood vessels within the tumor windows and enhanced tumor growth delay when administered during fractionated irradiation.


CONCLUSIONS
This study demonstrates the potential use of SFK inhibition to enhance the effects of ionizing radiation during radiotherapy.
Cuneo
Kyle C
KC
Vanderbilt University School of Medicine, Nashville, TN 37232-5671, USA.
Geng
Ling
L
Tan
Jiahuai
J
Brousal
Jeffrey
J
Shinohara
Eric T
ET
Osusky
Katherine
K
Fu
Allie
A
Shyr
Yu
Y
Wu
Huiyun
H
Hallahan
Dennis E
DE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000532:radiotherapy; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D058534:Class I Phosphatidylinositol 3-Kinases; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014471:Umbilical Veins; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011838:Radiation-Sensitizing Agents; C416927:SU 6656; D013449:Sulfonamides; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases