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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
KH-3, a Transcriptional Modulator of p53, Protects Mice from Radiation-Induced Gastrointestinal Syndrome
