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アイテム
The mechanism of a novel radioprotector, 8-quinolinol derivative KH-3
https://repo.qst.go.jp/records/71373
https://repo.qst.go.jp/records/7137357272faa-9dfd-4de4-bb08-55b5671cfd4f
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2013-11-18 | |||||
| タイトル | ||||||
| タイトル | The mechanism of a novel radioprotector, 8-quinolinol derivative KH-3 | |||||
| 言語 | ||||||
| 言語 | jpn | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
高橋, 一平
× 高橋, 一平× 森田, 明典× 青木, 伸× 王, 冰× 細井, 義夫× 兼安, 祐子× 権丈, 雅浩× 木村, 智樹× 村上, 雄二× 永田, 靖× 王 冰× 細井 義夫 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Purpose/Objective (s): Radiation therapy for cancer often has severe side effects that limit its efficacy. Because these side effects are in part determined by p53-mediated apoptosis, temporary suppression of p53 has been suggested as a therapeutic strategy to relieve the damage of normal tissues during treatment of p53-deficient tumors. On the other hand, it is known that dissociation of a zinc ion, which is coordinated to metal ion binding site of p53, could induce p53 denaturation, hence we evaluated some zinc chelators as radioprotective p53 inhibitor. As a result, we found 5-chloro-8-quinolinol (KH-3) as a radioprotector that can protect mice from a sublethal dose of 7.5 Gy total-body irradiation (TBI). In this study, we investigated the effects and mechanism of KH-3 comparatively to a known radioprotective p53 inhibitor, PFTm. Materials /Methods: Imprinting control region (ICR) female mice, aged 8-week old, were total-body irradiated with an X-ray generator (Pantak-320S, Shimadzu) operated at 200 kV at a dose rate of 0.66 Gy/min. KH-3 (35 mg/kg) or vehicle was ip injected 30 minutes before 7.5 Gy TBI. In cell analysis, highly radiosensitive cell line MOLT-4, derived from human T-cell leukemia, was used and 10 Gy-irradiated. The suppressive effect of KH-3 and the reference compound PFTm on radiation-induced MOLT-4 apoptosis was evaluated using Annexin V-FITC or MitoTracker Red staining. To examine the specificity of KH-3 for p53-mediated apoptosis, we used MOLT-4 cells and their derivatives, namely, p53-knockdown transformant and p53 revertant which re-expressed p53 using shRNA-resistant FLAG-tagged p53-expressing plasmid. To elucidate the mechanism of action of KH-3 in p53-mediated apoptotic pathway, we mainly investigated the expression of p53 target-genes, p21 and PUMA, using quantitative real-time PCR and immunoblotting analyses. Results: For the 30-day survival study, half of the animals in the KH-3-treated group survived, whereas all the mice receiving only TBI died within 14 days (P < 0.01). Cell death analysis revealed that KH-3 had a higher inhibitory effect on cell death and lower toxicity than that of PFTm in the MOLT-4 cells. KH-3 was ineffective against the radiation-induced apoptosis of p53-knockdown transformant, but suppressed that of p53 revertant. Results indictated that suppression of radiation-induced apoptosis by KH-3 was specifically mediated through p53 signaling pathways. Furthermore, KH-3 modulated p53 target-gene expression without affecting p53 expression. In particular, p21, which has anti-apoptotic activity, was markedly up-regulated by KH-3. Conclusion: KH-3 is a novel kind of radioprotector that modulates p53 transcription. The radioprotective effect of KH-3 may be associated with its ability to up-regulate p21 expression. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | American Society for Radiation Oncology (ASTRO) Annual Meeting | |||||
| 発表年月日 | ||||||
| 日付 | 2013-09-25 | |||||
| 日付タイプ | Issued | |||||
