G-quadruplex oligonucleotide AS1411 as a cancer-targeting agent: Uses and mechanisms

Bates, Paula J.; Reyes‐Reyes, Elsa M.; Malik, Mohammad Tariq; Murphy, Emily M.; O’Toole, Martin G.; Trent, John O.

doi:10.1016/j.bbagen.2016.12.015

Cited by 248 publications

(249 citation statements)

References 209 publications

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“…Internalized AS1411 is localized only to the cytoplasm and never localizes to the nuclei of viable cells [34]. Thus, AS1411 only targets NCL extranuclear functions such as shuttling, signal transduction, or mRNA stability, which could also affect protein expression [35]. The observation that AS1411 did not affect L1-ORF1p expression suggests that nuclear functions of NCL are the ones involved in regulation of L1-ORF1p expression.…”

Section: Discussionmentioning

confidence: 99%

The Nucleolin Antagonist N6L Inhibits LINE1 Retrotransposon Activity in Non-Small Cell Lung Carcinoma Cells

Ramos¹,

Moore²,

Runge³

et al. 2020

J. Cancer

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Lung cancer is the most common cause of cancer death in the United States. The genome of nonsmall cell lung cancer (NSCLC), the most frequent lung cancer type, is strongly affected by Long Interspersed Nuclear Element (LINE1) insertions. Active LINE1s are repetitive DNA sequences that can amplify themselves in the genome utilizing a retrotransposition mechanism whereby LINE1 is copied via reverse transcription and inserted at target sites. ORF1p and ORF2p are LINE1 encoded proteins essential for LINE1 retrotransposition. LINE1s are silenced epigenetically in somatic tissues, and their reactivation has been associated with cancer pathogenesis. Here, we present evidence that nucleolin (NCL) regulates expression of LINE1-ORF1p (L1-ORF1p) in NSCLC cells. Genetic knockdown of NCL significantly inhibited expression of L1-ORF1p in various NSCLC cell lines. Treatment with the investigational NCL antagonist N6L ablated L1-ORF1p expression in all cell lines constitutively expressing L1-ORFp. N6L displayed a stronger antiproliferative activity in NSCLC tumor cell lines expressing the highest L1-ORF1p protein levels. Moreover, N6L treatment of nude mice bearing NSCLC tumor xenografts blocked L1-ORF1p expression and effectively inhibited tumor growth. These data indicate that L1-ORF1p expression is regulated by NCL and identify NCL as a novel promising target for pharmacological inhibition of LINE1.

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Section: Discussionmentioning

confidence: 99%

The Nucleolin Antagonist N6L Inhibits LINE1 Retrotransposon Activity in Non-Small Cell Lung Carcinoma Cells

Ramos¹,

Moore²,

Runge³

et al. 2020

J. Cancer

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“…Albeit, AS1411 previously has been shown the have anti-cancer activity in malignant cells, we saw no effect on proliferation and stemness (S2 Fig). This is most likely due owing to the fact that we only use 0.2 nM AS1411 (corresponding to 20 kBq/ml 57 Co-AS1411), which is far below the 1–10 uM GI50 (50% growth inhibition) found for most malignant cell lines [29]. …”

Section: Discussionmentioning

confidence: 99%

Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411

et al. 2017

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Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research. Somatostatin receptor 2 and nucleolin are known to be overexpressed by various cancer types, which have elicited comprehensive efforts to explore their therapeutic utilization. Here, we evaluated somatostatin receptor 2 targeting and nucleolin targeting for therapeutic delivery to cancer stem cells from lung cancer. Nucleolin is expressed highly but not selectively, while somatostatin receptor 2 is expressed selectively but not highly by cancer cells. The non-small cell lung cancer cell lines A549 and H1299, displayed average levels of both surface molecules as judged based on analysis of a larger cell line panel. H1299 compared to A549 cells showed significantly elevated sphere-forming capacity, indicating higher cancer stem cell content, thus qualifying as suitable test system. Nucleolin-targeting 57Co-DOTA-AS1411 aptamer showed efficient internalization by cancer cells and, remarkably, at even higher efficiency by cancer stem cells. In contrast, somatostatin receptor 2 expression levels were not sufficiently high in H1299 cells to confer efficient uptake by either non-cancer stem cells or cancer stem cells. The data provides indication that the nucleolin-targeting AS1411 aptamer might be used for therapeutic delivery to non-small cell lung cancer stem cells.

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“…Nucleolin was found to be highly expressed by cancer cells, intracellularly but also at the cell surface. A recent review described uses and mechanisms of the G-quadruplex oligonucleotide AS1411 as a targeting agent [129]. …”

Section: Protein- and Cell-based Selex Processesmentioning

confidence: 99%

Selection of Nucleic Acid Aptamers Targeting Tumor Cell-Surface Protein Biomarkers

Mercier

Dontenwill

Choulier

2017

Cancers

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Aptamers are nucleic acids referred to as chemical antibodies as they bind to their specific targets with high affinity and selectivity. They are selected via an iterative process known as ‘selective evolution of ligands by exponential enrichment’ (SELEX). Aptamers have been developed against numerous cancer targets and among them, many tumor cell-membrane protein biomarkers. The identification of aptamers targeting cell-surface proteins has mainly been performed by two different strategies: protein- and cell-based SELEX, when the targets used for selection were proteins and cells, respectively. This review aims to update the literature on aptamers targeting tumor cell surface protein biomarkers, highlighting potentials, pitfalls of protein- and cell-based selection processes and applications of such selected molecules. Aptamers as promising agents for diagnosis and therapeutic approaches in oncology are documented, as well as aptamers in clinical development.

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G-quadruplex oligonucleotide AS1411 as a cancer-targeting agent: Uses and mechanisms

Cited by 248 publications

References 209 publications

The Nucleolin Antagonist N6L Inhibits LINE1 Retrotransposon Activity in Non-Small Cell Lung Carcinoma Cells

The Nucleolin Antagonist N6L Inhibits LINE1 Retrotransposon Activity in Non-Small Cell Lung Carcinoma Cells

Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411

Selection of Nucleic Acid Aptamers Targeting Tumor Cell-Surface Protein Biomarkers

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