A nucleoside anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106), sensitizes cells to radiation by suppressing BRCA2 expression
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概要
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Background: A novel anticancer drug 1-(3-C-ethynyl-b-D-ribo-pentofuranosyl)cytosine (ECyd, TAS106) has been shown to radiosensitize tumor cells and to improve the therapeutic efficiency of X-irradiation. However, the effect of TAS106 on cellular DNA repair capacity has not been elucidated. Our aim in this study was to examine whether TAS106 modified the repair capacity of DNA double-strand breaks (DSBs) in tumor cells. Methods: Various cultured cell lines treated with TAS106 were irradiated and then survival fraction was examined by the clonogenic survival assays. Repair of sublethal damage (SLD), which indicates DSBs repair capacity, was measured as an increase of surviving cells after split dose irradiation with an interval of incubation. To assess the effect of TAS106 on the DSBs repair activity, the time courses of g-H2AX and 53BP1 foci formation were examined by using immunocytochemistry. The expression of DNA-repair-related proteins was also examined by Western blot analysis and semi-quantitative RT-PCR analysis. Results: In clonogenic survival assays, pretreatment of TAS106 showed radiosensitizing effects in various cell lines. TAS106 inhibited SLD repair and delayed the disappearance of g-H2AX and 53BP1 foci, suggesting that DSB repair occurred in A549 cells. Western blot analysis demonstrated that TAS106 down-regulated the expression of BRCA2 and Rad51, which are known as keys among DNA repair proteins in the homologous recombination (HR) pathway. Although a significant radiosensitizing effect of TAS106 was observed in the parental V79 cells, pretreatment with TAS106 did not induce any radiosensitizing effects in BRCA2-deficient V-C8 cells. Conclusions: Our results indicate that TAS106 induces the down-regulation of BRCA2 and the subsequent abrogation of the HR pathway, leading to a radiosensitizing effect. Therefore, this study suggests that inhibition of the HR pathway may be useful to improve the therapeutic efficiency of radiotherapy for solid tumors.
著者
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Inanami Osamu
弘前大学 保健学研究科放射線生命科学
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Inanami Osamu
Laboratory Of Radiation Biology Graduate School Of Veterinary Medicine Hokkaido University
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Inanami Osamu
Lab. Radiat. Biol. Grad. Sch. Vet. Med. Hokkaido Univ.
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Matsuda Akira
Laboratory Of Medicinal Chemistry Faculty Of Pharmaceutical Sciences Hokkaido University
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Yamamori Tohru
Laboratory Of Radiation Biology Department Of Environmental Veterinary Sciences Graduate School Of V
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Meike Shunsuke
Laboratory Of Radiation Biology Department Of Environmental Veterinary Sciences Graduate School Of V
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Eitaki Masato
Laboratory Of Radiation Biology Department Of Environmental Veterinary Sciences Graduate School Of V
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Yasui Hironobu
Laboratory Of Radiation Biology Department Of Environmental Veterinary Sciences Graduate School Of V
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