title: TS-1 enhances the effect of radiotherapy by suppressing radiation-induced hypoxia-inducible factor-1 activation and inducing endothelial cell apoptosis.
abstract: 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 gamma-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.
authors.affiliation: Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zeng
authors.forename: Guangfei
authors.initials: G
authors.lastname: Ou
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itasaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Xuejun
authors.initials: X
authors.lastname: Xie
authors.forename: Keiko
authors.initials: K
authors.lastname: Shibuya
authors.forename: Shinae
authors.initials: S
authors.lastname: Kizaka-Kondoh
authors.forename: Akiyo
authors.initials: A
authors.lastname: Morinibu
authors.forename: Kazumi
authors.initials: K
authors.lastname: Shinomiya
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiraoka
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004338:Drug Combinations; D042783:Endothelial Cells / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010094:Oxonic Acid / Q000627:therapeutic use*; D005641:Tegafur / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid