The multifunctional APE1 DNA repair–redox signaling protein as a drug target in human disease

Caston, Rachel A.; Gampala, Silpa; Armstrong, Lee; Messmann, Richard A.; Fishel, Melissa L.; Kelley, Mark R.

doi:10.1016/j.drudis.2020.10.015

Cited by 75 publications

(106 citation statements)

References 97 publications

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“…The compound APX3330 was originally developed by Eisai Co., Ltd. and Apexian Pharmaceuticals, Inc., as a selective Ref-1 inhibitor designed to treat chronic hepatitis C and B and cancer, as well as other disease indications [8]. APX3330 has been extensively characterized as a direct, highly selective inhibitor of Ref-1 redox activity that does not affect the protein's other DNA repair endonuclease activity, not discussed here [1,8,[11][12][13][14][15]. APX3330 is able to block Ref-1's ability to convert various TFs from their oxidized, inactive state to an active, reduced state [16].…”

Section: Inhibiting Ref-1 Redox Signaling Activitymentioning

confidence: 99%

“…In addition to DR, APX3330 is being explored for treatment of DME and nvAMD. Furthermore, there is a robust pipeline of APX3330 analogues such as APX2009 and APX2014 [ 1 , 22 ] that can also be explored for multiple delivery routes for multiple ocular indications, and potentially used in combination with currently approved drugs, such as the anti-VEGF agents aflibercept or bevacizumab [ 22 ]. Given the important role of Ref-1 in pathways involved in retinal disease, there is great potential in targeting it as a novel therapeutic option.…”

Section: Future Directionsmentioning

confidence: 99%

“…Furthermore, it selectively binds to both recombinant Ref-1 and Ref-1 from cell extracts, and displays additional specific, on-target properties [ 8 , 13 , 15 , 17 , 18 ]. Therefore, APX3330 is a specific inhibitor of Ref-1’s redox function [ 1 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…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 [ 1 ]. 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.…”

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confidence: 99%

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APE1/Ref-1 as a Novel Target for Retinal Diseases

2021

Journal of Cellular Signaling

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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 [1]. 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 agerelated 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. [1].

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Section: Inhibiting Ref-1 Redox Signaling Activitymentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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APE1/Ref-1 as a Novel Target for Retinal Diseases

2021

Journal of Cellular Signaling

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“…28 Multiple cancers including PDAC exhibit increased Ref-1 expression levels that concomitantly associate with their resistance to radiation and chemotherapy and potentially to a metabolic shift, leading to poorer patient prognosis. 29,30 Due to Ref-1's role in regulating multiple TFs associated with cancer-related pathways, Ref-1 has become a novel target for anti-cancer therapy in PDAC. 25,31,32 Although the redox signaling functions of have been studied in a number of biological contexts, its interacting TF partner(s) critical for regulation of metabolic pathways in PDAC is still not well understood.…”

Section: Introductionmentioning

confidence: 99%

Ref-1 Redox Activity Alters Cancer Cell Metabolism in Pancreatic Cancer: Exploiting This Novel Finding as a Potential Target  

Gampala

Shah

et al. 2020

Preprint

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Background: Pancreatic cancer is a complex disease with a desmoplastic stroma, extreme hypoxia, and inherent resistance to therapy. Understanding the signaling and adaptive response of such an aggressive cancer is key to making advances in therapeutic efficacy. Redox factor-1 (Ref-1), a redox signaling protein, regulates the DNA binding activity of several transcription factors (TFs), including HIF-1α, STAT3 and NFκB . The conversion of these TFs from an oxidized to reduced state lead to enhancement of their DNA binding. In our previously published work, knockdown of Ref-1 under normoxia resulted in altered gene expression patterns on pathways including EIF2, protein kinase A, and mTOR. In this study, single cell RNA sequencing (scRNA-seq) and proteomics were used to explore the effects of Ref-1 on metabolic pathways under hypoxia.Methods: scRNA-seq comparing pancreatic cancer cells expressing less than 20% of the Ref-1 protein was analyzed using left truncated mixture Gaussian model and validated using proteomics and qRT-PCR. The impact of knocking down Ref-1 under hypoxia was dramatic on the mitochondria and metabolic pathways. Ref-1’s role in mitochondrial function was confirmed using mitochondrial function assays and qRT-PCR. Further, the effect of Ref-1 redox function inhibition against pancreatic cancer metabolism was assayed using 3D co-culture in vitro and xenograft studies in vivo and compared to Devimistat, a drug that disrupts mitochondrial metabolism.Results: Distinct transcriptional variation in central metabolism, cell cycle, apoptosis, immune response, and genes downstream of a series of signaling pathways and transcriptional regulatory factors were identified in Ref-1 knockdown vs Scrambled control from the scRNA-seq data. Mitochondrial DEG subsets downregulated with Ref-1 knockdown were significantly reduced following Ref-1 redox inhibition and more dramatically in combination with Devimistat in vitro. Mitochondrial function assays demonstrated that Ref-1 knockdown and Ref-1 redox signaling inhibition decreased utilization of TCA cycle substrates and slowed the growth of pancreatic cancer co-culture spheroids. In vivo xenograft studies demonstrated that tumor reduction was potent with Ref-1 redox inhibitor similar to Devimistat.Conclusion: Ref-1 redox signaling inhibition conclusively alters cancer cell metabolism by causing TCA cycle dysfunction while also reducing the pancreatic tumor growth in vitro as well as in vivo.

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Construction of Multiply Guaranteed DNA Sensors for Biological Sensing and Bioimaging Applications

Wang,

Zou,

Wang

2024

ChemBioChem

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Nucleic acids exhibit exceptional functionalities for both molecular recognition and catalysis, along with the capability of predictable assembly through strand displacement reactions. The inherent programmability and addressability of DNA probes enable their precise, on‐demand assembly and accurate execution of hybridization, significantly enhancing target detection capabilities. Decades of research in DNA nanotechnology have led to advances in the structural design of functional DNA probes, resulting in increasingly sensitive and robust DNA sensors. Moreover, increasing attention has been devoted to enhancing the accuracy and sensitivity of DNA‐based biosensors by integrating multiple sensing procedures. In this review, we summarize various strategies aimed at enhancing the accuracy of DNA sensors. These strategies involve multiple guarantee procedures, utilizing dual signal output mechanisms, and implementing sequential regulation methods. Our goal is to provide new insights into the development of more accurate DNA sensors, ultimately facilitating their widespread application in clinical diagnostics and assessment.

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The multifunctional APE1 DNA repair–redox signaling protein as a drug target in human disease

Cited by 75 publications

References 97 publications

APE1/Ref-1 as a Novel Target for Retinal Diseases

APE1/Ref-1 as a Novel Target for Retinal Diseases

Ref-1 Redox Activity Alters Cancer Cell Metabolism in Pancreatic Cancer: Exploiting This Novel Finding as a Potential Target

Construction of Multiply Guaranteed DNA Sensors for Biological Sensing and Bioimaging Applications

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The multifunctional APE1 DNA repair–redox signaling protein as a drug target in human disease

Cited by 75 publications

References 97 publications

APE1/Ref-1 as a Novel Target for Retinal Diseases

APE1/Ref-1 as a Novel Target for Retinal Diseases

Ref-1 Redox Activity Alters Cancer Cell Metabolism in Pancreatic Cancer: Exploiting This Novel Finding as a Potential Target&nbsp;&nbsp;

Construction of Multiply Guaranteed DNA Sensors for Biological Sensing and Bioimaging Applications

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Ref-1 Redox Activity Alters Cancer Cell Metabolism in Pancreatic Cancer: Exploiting This Novel Finding as a Potential Target