Abstract
Although some effective therapies have been available for cancer, it still poses a great threat to human health and life due to its drug resistance and low response in patients. Here, we develop a ferroptosis-based therapy by combining iron nanoparticles and cancer-specific gene interference. The expression of two iron metabolic genes (FPN and LCN2) was selectively knocked down in cancer cells by Cas13a or microRNA controlled by a NF-κB-specific promoter. Cells were simultaneously treated by iron nanoparticles. As a result, a significant ferroptosis was induced in a wide variety of cancer cells. However, the same treatment had little effect on normal cells. By transferring genes with adeno-associated virus and iron nanoparticles, the significant tumor growth inhibition and durable cure were obtained in mice with the therapy. In this work, we thus show a cancer therapy based on gene interference-enhanced ferroptosis.
© 2021. The Author(s).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CRISPR-Associated Proteins / genetics
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CRISPR-Associated Proteins / metabolism
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Cation Transport Proteins / antagonists & inhibitors*
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Cation Transport Proteins / genetics
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Cation Transport Proteins / metabolism
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Cell Line, Tumor
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Dependovirus / genetics
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Dependovirus / metabolism
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Ferroptosis / genetics*
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Gene Expression Regulation, Neoplastic
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Humans
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Iron / metabolism*
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Lipocalin-2 / antagonists & inhibitors*
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Lipocalin-2 / genetics
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Lipocalin-2 / metabolism
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Liver / metabolism
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Liver / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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MicroRNAs / genetics
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MicroRNAs / metabolism
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Nanoparticles / administration & dosage
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Nanoparticles / chemistry
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Neoplasms / genetics
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Neoplasms / mortality
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Neoplasms / pathology
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Neoplasms / therapy*
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Promoter Regions, Genetic
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RNA Interference*
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Reactive Oxygen Species / agonists*
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Reactive Oxygen Species / metabolism
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Signal Transduction
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Spleen / metabolism
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Spleen / pathology
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Survival Analysis
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Tumor Burden
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Xenograft Model Antitumor Assays
Substances
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CRISPR-Associated Proteins
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Cation Transport Proteins
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LCN2 protein, human
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Lipocalin-2
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MicroRNAs
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NF-kappa B
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Reactive Oxygen Species
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metal transporting protein 1
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Iron