WEKO3
アイテム
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As a result of further screening, we found an 8-quinolinol derivative KH-3 as a radioprotector that has an ability to modulate p53 transcription resulting in the up-regulation of p21, and that can protect mice from a sublethal dose of 7.5 Gy total-body irradiation (TBI), but not of a higher dose of TBI (8.0 Gy). These data indicate that KH-3 is effective only in a narrow range of radiation dose that causes sublethal hematopoietic syndrome in mouse TBI. In this study, we further investigated the effects and mechanism of KH-3, including RNA interference-mediated silencing analysis of p21. In addition, p53 and p21 have been reported as resistant factors in radiation-induced gastrointestinal (GI) syndrome in mice. The fact raises the possibility that KH-3 protects mice from GI syndrome by up-regulating p21. We then tested the possibility using the technique of abdominal subtotal-body irradiation (SBI) to avoid the hematopoietic syndrome.\n\\n Materials /Methods: 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, and WST-8 colorimetric assay. To examine the specificity of KH-3 for p21 in the p53-mediated apoptosis, we used MOLT-4 cells and its p21-knockdown transformant. In mouse SBI model, ICR female mice, aged 8-week old, were irradiated with a gamma-ray generator with shielding lead walls at least 3.0 cm thick. KH-3 (60 mg/kg) or vehicle was ip injected 30 minutes before 18 or 24 Gy SBI, and the mice were anesthetized 5-10 minutes before SBI. The abdomen of the anesthetized mice was exposed to gamma rays at a dose rate of 0.70 Gy/min.\n\\n Results: RNA interference-mediated silencing of p21 revealed that KH-3 was ineffective against the radiation-induced apoptosis of p21-knockdown transformant, indictating that suppression of radiation-induced apoptosis by KH-3 was specifically mediated through p53-p21 signaling pathways. For the 30-day survival study, survival rates of mice in KH-3-treated groups were 90% (18 Gy-SBI) and 40% (24-Gy SBI) respectively, whereas those of the control vehicle-injected groups were 40% (18 Gy-SBI) and 0% (24-Gy SBI) respectively. The dose-reduction factor (DRF) of KH-3 in the SBI was about 1.3.\n \n Conclusion: KH-3 is a novel kind of radioprotector that upregulates p53-p21 pathway and protects mice from GI death. 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KH-3, a Transcriptional Modulator of p53, Protects Mice from Radiation-Induced Gastrointestinal Syndrome
https://repo.qst.go.jp/records/71575
https://repo.qst.go.jp/records/71575b15bb12b-e917-41f0-86a3-e6c80971f242
Item type | 会議発表用資料 / Presentation(1) | |||||
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公開日 | 2015-01-13 | |||||
タイトル | ||||||
タイトル | KH-3, a Transcriptional Modulator of p53, Protects Mice from Radiation-Induced Gastrointestinal Syndrome | |||||
言語 | ||||||
言語 | eng | |||||
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× 笹谷, めぐみ× 有安, 真也× 神谷, 研二× 細井, 義夫× 稲葉, 俊哉× 王 冰 |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | Purpose/Objective(s): In a previous study, we reported that some zinc (II) chelators suppress radiation-induced p53-dependent apoptosis through inhibition of p53-dependent apoptotic pathways. As a result of further screening, we found an 8-quinolinol derivative KH-3 as a radioprotector that has an ability to modulate p53 transcription resulting in the up-regulation of p21, and that can protect mice from a sublethal dose of 7.5 Gy total-body irradiation (TBI), but not of a higher dose of TBI (8.0 Gy). These data indicate that KH-3 is effective only in a narrow range of radiation dose that causes sublethal hematopoietic syndrome in mouse TBI. In this study, we further investigated the effects and mechanism of KH-3, including RNA interference-mediated silencing analysis of p21. In addition, p53 and p21 have been reported as resistant factors in radiation-induced gastrointestinal (GI) syndrome in mice. The fact raises the possibility that KH-3 protects mice from GI syndrome by up-regulating p21. We then tested the possibility using the technique of abdominal subtotal-body irradiation (SBI) to avoid the hematopoietic syndrome. \n Materials /Methods: 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, and WST-8 colorimetric assay. To examine the specificity of KH-3 for p21 in the p53-mediated apoptosis, we used MOLT-4 cells and its p21-knockdown transformant. In mouse SBI model, ICR female mice, aged 8-week old, were irradiated with a gamma-ray generator with shielding lead walls at least 3.0 cm thick. KH-3 (60 mg/kg) or vehicle was ip injected 30 minutes before 18 or 24 Gy SBI, and the mice were anesthetized 5-10 minutes before SBI. The abdomen of the anesthetized mice was exposed to gamma rays at a dose rate of 0.70 Gy/min. \n Results: RNA interference-mediated silencing of p21 revealed that KH-3 was ineffective against the radiation-induced apoptosis of p21-knockdown transformant, indictating that suppression of radiation-induced apoptosis by KH-3 was specifically mediated through p53-p21 signaling pathways. For the 30-day survival study, survival rates of mice in KH-3-treated groups were 90% (18 Gy-SBI) and 40% (24-Gy SBI) respectively, whereas those of the control vehicle-injected groups were 40% (18 Gy-SBI) and 0% (24-Gy SBI) respectively. The dose-reduction factor (DRF) of KH-3 in the SBI was about 1.3. Conclusion: KH-3 is a novel kind of radioprotector that upregulates p53-p21 pathway and protects mice from GI death. KH-3 may serve as a therapeutic radioprotector for protecting normal tissues against adverse side effects of radiation/chemotherapy in abdominal cancer. |
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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 | ASTRO's 56th Annual Meeting(第56回米国放射線治療学会議) | |||||
発表年月日 | ||||||
日付 | 2014-09-14 | |||||
日付タイプ | Issued |