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Inhibition of HIF-1α by the anticancer drug TAS106 enhances X-ray-induced apoptosis in vitro and in vivo

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Title: Inhibition of HIF-1α by the anticancer drug TAS106 enhances X-ray-induced apoptosis in vitro and in vivo
Other Titles: TAS106 radiosensitises tumour cells via HIF-1α inhibition
Authors: Yasui, H. Browse this author
Ogura, A. Browse this author
Asanuma, T. Browse this author
Matsuda, A. Browse this author →KAKEN DB
Kasiwakura, I. Browse this author
Kuwabara, M. Browse this author
Inanami, O. Browse this author →KAKEN DB
Keywords: anticancer drug
apoptosis
HIF-1α
hypoxia
radiosensitisation
X-irradiation
Issue Date: 4-Nov-2008
Publisher: Nature Publishing Group
Journal Title: British Journal of Cancer
Volume: 99
Issue: 9
Start Page: 1442
End Page: 1452
Publisher DOI: 10.1038/sj.bjc.6604720
PMID: 18854835
Abstract: In a previous study, we showed that a novel anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd) increased the anti-tumour efficacy of X-irradiation. However, its effects on hypoxic cells in tumours remain unclarified. Herein we show that TAS106 enhances the induction of apoptosis in X-irradiated human gastric adenocarcinoma MKN45 and MKN28 cells under hypoxia in vitro. At the same time, the accumulation of HIF-1α observed under hypoxia was shown to be decreased to the level of normoxia in the presence of 0.1 μM TAS106. To study the function of HIF-1α protein in apoptosis of hypoxic cells, we employed an HIF-1α reductive approach using its specific antisense oligodeoxynucleotide. The reduction of HIF-1α gene expression dramatically enhanced X-ray-induced apoptosis in hypoxic cells. In in vivo experiments in which MKN45 cells were transplanted into severe combined immunodeficient (SCID) mice, TAS106 (0.5 mg/kg) suppressed HIF-1α expression and subsequently reduced the area of the hypoxic region in the tumour, and enhanced the induction of apoptosis in the hypoxic region when combined with 2 Gy of X-irradiation. These results suggest the possibility that TAS106 acts as a potent radiosensitiser via the inhibition of HIF-1α expression and can be a useful agent against radiotherapy-resistant hypoxic cells in solid tumours.
Type: article (author version)
URI: http://hdl.handle.net/2115/38343
Appears in Collections:獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 稲波 修

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