title: Effect of sunitinib combined with ionizing radiation on endothelial cells.
abstract: The aims of present study were to evaluate the efficacy of combining sunitinib with ionizing radiation (IR) on endothelial cells in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) were exposed to IR with or without sunitinib pretreatment. Apoptosis assay and cell cycle distribution were analyzed by flow cytometry. Clonogenic survival assay at 3 Gy dose with or without sunitinib was performed. The activity of phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway was detected by Western immunoblot. Lewis lung carcinoma mouse model was built to examine the effect of combination therapy on endothelial cells in vivo. Microvasculature changes were detected by immunohistochemistry using anti-CD31 antibody. Our results showed combination therapy of sunitinib and IR significantly increased apoptosis of endothelial cells and inhibited colony formation compared to sunitinib or radiotherapy alone. It also resulted in cell cycle redistribution (decreasing cells in S phase and increasing cells in G2/M phase). The activity of PI3K/Akt signal pathway was inhibited, which could be the potential mechanisms that account for the enhanced radiation response induced by sunitinib. In vivo analysis showed that combination therapy significantly decreased microvasculature formation. The results demonstrated that combination therapy of sunitinib and IR has the potential to increase the cytotoxic effects on endothelial cells.
authors.affiliation: Department of Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors.forename: Hai-Ping
authors.initials: HP
authors.lastname: Zhang
authors.forename: Koichi
authors.initials: K
authors.lastname: Takayama
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Jiao
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Jie-Jun
authors.initials: JJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000532:radiotherapy*; D011758:Pyrroles / Q000008:administration & dosage*; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D011758:Pyrroles; D011838:Radiation-Sensitizing Agents; D000077210:Sunitinib