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