Inhibition of HIF-1alpha by the anticancer drug TAS106 enhances X-ray-induced apoptosis in vitro and in vivo.
In a previous study, we showed that a novel anticancer drug, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd) increased the antitumour efficacy of X-irradiation. However, its effects on hypoxic cells in tumours remain unclarified. Here, 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-1alpha observed under hypoxia was shown to be decreased to the level of normoxia in the presence of 0.1 microM TAS106. To study the function of HIF-1alpha protein in apoptosis of hypoxic cells, we employed an HIF-1alpha reductive approach using its specific antisense oligodeoxynucleotide. The reduction of HIF-1alpha 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(-1)) suppressed HIF-1alpha 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 through the inhibition of HIF-1alpha expression and can be a useful agent against radiotherapy-resistant hypoxic cells in solid tumours.
Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Sapporo 060-0818, Japan.
H
H
Yasui
A
A
Ogura
T
T
Asanuma
A
A
Matsuda
I
I
Kashiwakura
M
M
Kuwabara
O
O
Inanami
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014541:Uridine Kinase / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D014964:X-Ray Therapy
D000970:Antineoplastic Agents; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016376:Oligonucleotides, Antisense; D011838:Radiation-Sensitizing Agents; D042461:Vascular Endothelial Growth Factor A; C483834:UCK2 protein, human; D014541:Uridine Kinase