APE1/Ref-1 as a Novel Target for Retinal Diseases.
APE1/Ref-1 as a Novel Target for Retinal Diseases.
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APE1/REF-1是视网膜疾病的新靶标。
DOI：
10.33696/signaling.2.044
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Kelley MR
中科院分区：
文献类型：
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作者：
Heisel C;Yousif J;Mijiti M;Charizanis K;Brigell M;Corson TW;Kelley MR
APE1/Ref-1（也称为Ref-1）因其在DNA修复和还原氧化（氧化还原）信号传导中的作用而被广泛研究。Caston等人发表的题为“The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease”的综述总结了Ref-1的分子功能及其在多种疾病中的作用，并特别关注了各种类型的癌症。先前的研究表明，Ref-1在调节涉及多种途径的特异性转录因子（tf）中起着关键作用，不仅在癌症中，而且在其他疾病适应症中也是如此。特殊治疗兴趣的疾病指征包括视网膜血管疾病，如糖尿病视网膜病变（DR）、糖尿病黄斑水肿（DME）和新生血管性年龄相关性黄斑变性（nvAMD）。虽然Ref-1控制着许多受氧化还原调节的tf，但已经发现有三种将癌症研究与视网膜疾病直接联系起来；HIF-1α， NF-κB和STAT3。HIF-1α控制血管生成中VEGF的表达，而NF-κB和STAT3调节许多已知的与炎症有关的细胞因子和因子。这些通路在DR、DME和AMD中高度相关并被证实为主要参与者。因此，癌症研究中关于Ref-1及其抑制作用的发现可能也适用于这些眼部疾病。本报告讨论了从癌症到视网膜疾病的潜在治疗途径，Ref-1氧化还原信号功能作为可能的靶点，以及目前已确定的阻断该活性的小分子。其中一种分子APX3330正在进行临床试验，而其他分子则处于临床前开发阶段。抑制Ref-1及其对炎症和血管生成的影响使其成为治疗视网膜血管疾病的潜在新靶点。这篇评论总结了与视网膜相关的研究，这些研究建立在Caston等人综述的结果之上。
APE1/Ref-1 (also called Ref-1) has been extensively studied for its role in DNA repair and reduction-oxidation (redox) signaling. The review titled: “The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease” by Caston et. al. summarizes the molecular functions of Ref-1 and the role it plays in a number of diseases, with a specific focus on various types of cancer. Previous studies have demonstrated that Ref-1 plays a critical role in regulating specific transcription factors (TFs) involved in a number of pathways, not only in cancer, but other disease indications as well. Disease indications of particular therapeutic interest include retinal vascular diseases such as diabetic retinopathy (DR), diabetic macular edema (DME), and neovascular age-related macular degeneration (nvAMD). While Ref-1 controls a number of TFs that are under redox regulation, three have been found to directly link cancer studies to retinal diseases; HIF-1α, NF-κB and STAT3. HIF-1α controls the expression of VEGF for angiogenesis while NF-κB and STAT3 regulate a number of known cytokines and factors involved in inflammation. These pathways are highly implicated and validated as major players in DR, DME and AMD. Therefore, findings in cancer studies for Ref-1 and its inhibition may be translated to these ocular diseases. This report discusses the path from cancer to the potential treatment of retinal disease, the Ref-1 redox signaling function as a possible target, and the current small molecules which have been identified to block this activity. One molecule, APX3330, is in clinical trials, while the others are in preclinical development. Inhibition of Ref-1 and its effects on inflammation and angiogenesis makes it a potential new therapeutic target for the treatment of retinal vascular diseases. This commentary summarizes the retinal-relevant research that built on the results summarized in the review by Caston et. al..