Inhibiting p53-dependent apoptosis by inhibitors of p53 is an effective strategy for preventing radiation-induced damage in hematopoietic lineages, while p53 and p21 also play radioprotective roles in the gastrointestinal epithelium. We previously identified some zinc(II) chelators, including 8-quinolinol derivatives, that suppress apoptosis in attempts to discover compounds that target the zinc-binding site in p53. We found that 5-chloro-8-quinolinol (5CHQ) has a unique p53-modulating activity that shifts its transactivation from proapoptotic to protective responses, including enhancing p21 induction and suppressing PUMA induction. This p53-modulating activity also influenced p53 and p53-target gene expression in unirradiated cells without inducing DNA damage. The specificity of 5CHQ for p53 and p21 was demonstrated by silencing the expression of each protein. These effects seem to be attributable to the sequence-specific alteration of p53 DNA-binding, as evaluated by chromatin immunoprecipitation and electrophoretic mobility shift assays. In addition, 5-chloro-8-methoxyquinoline itself had no antiapoptotic activity, indicating that the hydroxyl group at the 8-position is required for its antiapoptotic activity. We applied this remarkable agonistic activity to protecting the hematopoietic and gastrointestinal system in mouse irradiation models. The dose reduction factors of 5CHQ in total-body and abdominally irradiated mice were about 1.2 and 1.3, respectively. 5CHQ effectively protected mouse epithelial stem cells from a lethal dose of abdominal irradiation. Furthermore, the specificity of 5CHQ for p53 in reducing the lethality induced by abdominal irradiation was revealed in Trp53-KO mice. These results indicate that the pharmacologic upregulation of radioprotective p53 target genes is an effective strategy for addressing the gastrointestinal syndrome. Mol Cancer Ther; 17(2); 432–42. ©2017 AACR. See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”

中文翻译：

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作为辐射防护激动剂的 p53 反式激活的化学调节剂

通过 p53 抑制剂抑制 p53 依赖性细胞凋亡是预防造血谱系辐射诱导损伤的有效策略，而 p53 和 p21 在胃肠道上皮中也发挥辐射保护作用。我们之前确定了一些锌 (II) 螯合剂，包括 8-羟基喹啉衍生物，它们抑制细胞凋亡，试图发现靶向 p53 中锌结合位点的化合物。我们发现 5-chloro-8-quinolinol (5CHQ) 具有独特的 p53 调节活性，可将其反式激活从促凋亡转变为保护性反应，包括增强 p21 诱导和抑制 PUMA 诱导。这种 p53 调节活性还影响未照射细胞中 p53 和 p53 靶基因的表达，而不会引起 DNA 损伤。5CHQ 对 p53 和 p21 的特异性通过沉默每种蛋白质的表达来证明。这些影响似乎可归因于 p53 DNA 结合的序列特异性改变，正如染色质免疫沉淀和电泳迁移率变化测定所评估的那样。此外，5-氯-8-甲氧基喹啉本身没有抗凋亡活性，表明其抗凋亡活性需要8位羟基。我们将这种显着的激动活性应用于保护小鼠辐射模型中的造血和胃肠系统。5CHQ在全身和腹部照射小鼠中的剂量减少因子分别约为1.2和1.3。5CHQ 有效保护小鼠上皮干细胞免受致命剂量的腹部照射。此外，在 Trp53-KO 小鼠中揭示了 5CHQ 对 p53 在降低腹部照射诱导的致死率方面的特异性。这些结果表明，放射防护 p53 靶基因的药理学上调是解决胃肠道综合征的有效策略。摩尔癌症治疗; 17(2); 432-42。©2017 AACR。请参阅此 MCT 焦点部分中的所有文章，“放射肿瘤学中的发育疗法”。