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首页> 外文期刊>Neurobiology of disease >A screen for inducers of p21~(waf1/cip1) identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties
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A screen for inducers of p21~(waf1/cip1) identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties

机译：对p21〜（waf1 / cip1）诱导剂的筛选确定HIF脯氨酰羟化酶抑制剂为具有抗肿瘤特性的神经保护剂

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摘要

Preventing neuronal death is a priority for treating neurological diseases. However, therapies that inhibit pathological neuron loss could promote tumorigenesis by preventing the physiological death of cancerous cells. To avert this, we targeted the transcriptional upregulation of 21~(waf1/cip1) (p21), an endogenous tumor suppressor with neuroprotective and pro-regenerative activity. We identified potential p21 indcuers by screening a FDA-approved drug and natural product small molecule library against hippocampal HT22 cells stably expressing a luciferase reporter driven by the proximal 60 bp of the p21 promoter, and tested them for neuroprotection from glutathione depletion mediated oxidative stress, and cytotoxicity to cancer cell lines (DLD-1, Neuro-2A, SH-SY5Y, NGP, CHLA15, CHP212, and SK-N-SH) in vitro. Of the p21 inducers identified, only ciclopirox, a hypoxia-inducible factor prolyl-4-hydroxylase (HIF-PHD) inhibitor, simultaneously protected neurons from glutathione depletion and decreased cancer cell proliferation at concentrations that were not basally toxic to neurons. We found that other structurally distinct HIF-PHD inhibitors (desferrioxamine, 3,4-dihydroxybenzoate, and dimethyloxalyl glycine) also protected neurons at concentrations that killed cancer cells. HIF-PHD inhibitors stabilize HIF transcription factors, mediating genetic adaptation to hypoxia. While augmenting HIF stability is believed to promote tumorigenesis, we found that chronic HIF-PHD inhibition killed cancer cells, suggesting a protumorigenic role for these enzymes. Moreover, our findings suggest that PHD inhibitors can be used to treat neurological disease without significant concern for cell-autonomous tumor promotion.
机译：预防神经元死亡是治疗神经系统疾病的优先事项。但是，抑制病理性神经元丢失的疗法可以通过阻止癌细胞的生理性死亡来促进肿瘤发生。为了避免这种情况，我们针对21〜（waf1 / cip1）（p21）的转录上调，这是一种具有神经保护和促再生活性的内源性肿瘤抑制因子。我们通过针对稳定表达p21启动子60 bp附近驱动的荧光素酶报告基因的海马HT22细胞筛选了FDA批准的药物和天然产物小分子文库，从而鉴定了潜在的p21诱导者，并测试了它们对谷胱甘肽耗竭介导的氧化应激的神经保护作用，和对癌细胞系（DLD-1，Neuro-2A，SH-SY5Y，NGP，CHLA15，CHP212和SK-N-SH）的细胞毒性。在鉴定出的p21诱导剂中，只有环氯吡酮（一种缺氧诱导因子脯氨酰4-羟化酶（HIF-PHD）抑制剂）可以保护神经元免受谷胱甘肽耗竭，并在对神经元无基本毒性的浓度下降低癌细胞的增殖。我们发现其他结构上不同的HIF-PHD抑制剂（去铁胺，3,4-二羟基苯甲酸酯和二甲基草酰甘氨酸）也能以杀死癌细胞的浓度保护神经元。 HIF-PHD抑制剂可稳定HIF转录因子，介导对缺氧的遗传适应。虽然增强HIF稳定性被认为可以促进肿瘤发生，但我们发现慢性HIF-PHD抑制作用杀死了癌细胞，提示这些酶具有致瘤作用。此外，我们的研究结果表明，PHD抑制剂可用于治疗神经系统疾病，而对细胞自主性肿瘤的发展无明显关注。

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