4-isothiocyanate-2, 2, 6, 6-tetramethyl piperidinooxyl inhibits angiogenesis by suppressing VEGFR2 and Tie2 phosphorylation

• Published in: Oncology letters Vol. 12; no. 4; pp. 2828 - 2834
• Main Authors: Liu, Yuanyuan, Gao, Jing, Huang, Shuangsheng, Hu, Lamei, Wang, Zhiqiang, Wang, Zheyuan, Chen, Xiao, Zhang, Xiaoyu, Li, Wenguang
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.10.2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: 2; 4-isothiocyanate-2; 6; 6-tetramethyl piperidinooxyl; Angiogenesis; Cell adhesion & migration; Cell culture; Cytokines; Epidermal growth factor; Gene expression; Genetic aspects; Health aspects; Kinases; Lung cancer; Neovascularization; Oncology; Phosphorylation; reactive oxygen species; Studies; Thiocyanates; Tie2; Vascular endothelial growth factor; vascular endothelial growth factor receptor 2; United States > US; 2; vascular endothelial growth factor receptor 2; Tie2; 6; angiogenesis; reactive oxygen species; 6-tetramethyl piperidinooxyl; 4-isothiocyanate-2
• ISSN: 1792-1074; 1792-1082
• DOI: 10.3892/ol.2016.4948

Reactive oxygen species (ROS) are involved in the signaling pathway and are triggered by angiogenic factors, including vascular endothelial growth factor and angiopoietins. 4-isothiocyanate-2, 2, 6, 6-tetramethyl piperidinooxyl (4-ISO-Tempo) is one of the nitroxides that exhibits antioxidant activity. However, the anti-angiogenic effect of 4-ISO-Tempo remains unknown. The aim of this study was to investigate the effect of 4-ISO-Tempo on tumor proliferation and angiogenesis as well as its underlying mechanisms. Our results revealed that 4-ISO-Tempo significantly inhibited the viability of neoplastic and endothelial cells. Furthermore, the effective concentration of 4-ISO-Tempo on human microvascular endothelial cell 1 (HMEC-1) was lower than that on human lung adenocarcinoma A549 and human colon cancer SW620 cells. This suggested that endothelial cells were more sensitive to 4-ISO-Tempo than tumor cells. Furthermore, we demonstrated that 4-ISO-Tempo also suppressed secretion of matrix metalloproteinase (MMP)-2 and MMP-9, and migration and tube formation of HMEC-1 cells. The mechanism is attributed to the decreasing ROS generation and further phosphorylation of vascular endothelial growth factor receptor 2 and Tie2. Our findings suggest that 4-ISO-Tempo should be investigated for its usefulness in anti-angiogenesis therapies.