量研学術機関リポジトリ「QST-Repository」は、国立研究開発法人 量子科学技術研究開発機構に所属する職員等が生み出した学術成果(学会誌発表論文、学会発表、研究開発報告書、特許等)を集積しインターネット上で広く公開するサービスです。 Welcome to QST-Repository where we accumulates and discloses the academic research results(Journal Publications, Conference presentation, Research and Development Report, Patent, etc.) of the members of National Institutes for Quantum Science and Technology.
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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.
雑誌名
International Journal of Radiation Oncology Biology Physics