Open AccessTS‐1 enhances the effect of radiotherapy by suppressing radiation‐induced hypoxia‐inducible factor‐1 activation and inducing endothelial cell apoptosis
Author(s) -
Zeng Lihua,
Ou Guangfei,
Itasaka Satoshi,
Harada Hiroshi,
Xie Xuejun,
Shibuya Keiko,
KizakaKondoh Shinae,
Morinibu Akiyo,
Shinomiya Kazumi,
Hiraoka Masahiro
Publication year - 2008
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.00943.x
Subject(s) - radiation therapy , radiosensitivity , cancer research , apoptosis , vascular endothelial growth factor , hypoxia (environmental) , tumor hypoxia , hypoxia inducible factors , medicine , angiogenesis , genetic enhancement , in vivo , chemoradiotherapy , pathology , chemistry , biology , vegf receptors , gene , biochemistry , microbiology and biotechnology , organic chemistry , oxygen
The therapeutic effect of concurrent chemoradiotherapy with TS‐1 has been confirmed in various solid tumors; however, the detailed mechanism of action has not yet been fully elucidated. In the present study, we identified hypoxia‐inducible factor‐1 (HIF‐1) as one of the targets of TS‐1 in chemoradiotherapy. In growth delay assays using a tumor xenograft of non‐small‐cell lung carcinoma, H441, TS‐1 treatment enhanced the therapeutic effect of single γ‐ray radiotherapy (14 Gy) and significantly delayed tumor growth by 1.58‐fold compared to radiotherapy alone ( P < 0.01). An optical in vivo imaging experiment using a HIF‐1‐dependent 5HRE‐luc reporter gene revealed that TS‐1 treatment suppressed radiation‐induced activation of HIF‐1 in the tumor xenografts. The suppression led to apoptosis of endothelial cells resulting in both a significant decrease in microvessel density ( P < 0.05; vs radiation therapy alone) and a significant increase in apoptosis of tumor cells ( P < 0.01; vs radiation therapy alone) in tumor xenografts. All of these results indicate that TS‐1 enhances radiation‐induced apoptosis of endothelial cells by suppressing HIF‐1 activity, resulting in an increase in radiosensitivity of the tumor cells. Our findings strengthen the importance of both HIF‐1 and its downstream gene, such as vascular endothelial cell growth factor, as therapeutic targets to enhance the effect of radiotherapy. ( Cancer Sci 2008; 99: 2327–2335)