Gene interfered-ferroptosis therapy for cancers

• Published in: Nature communications Vol. 12; no. 1; pp. 5311 - 16
• Main Authors: Gao, Jinliang, Luo, Tao, Wang, Jinke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-09-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 42/41; 42/44; 42/89; 631/67/1059/153; 631/67/1059/602; Animals; Cancer; Cation Transport Proteins - antagonists & inhibitors; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell Line, Tumor; CRISPR-Associated Proteins - genetics; CRISPR-Associated Proteins - metabolism; Dependovirus - genetics; Dependovirus - metabolism; Drug resistance; Ferroptosis; Ferroptosis - genetics; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Growth inhibition; Health risks; Humanities and Social Sciences; Humans; Interference; Iron; Iron - metabolism; Lipocalin-2 - antagonists & inhibitors; Lipocalin-2 - genetics; Lipocalin-2 - metabolism; Liver - metabolism; Liver - pathology; Metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; multidisciplinary; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Neoplasms - genetics; Neoplasms - mortality; Neoplasms - pathology; Neoplasms - therapy; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Promoter Regions, Genetic; Reactive Oxygen Species - agonists; Reactive Oxygen Species - metabolism; Ribonucleic acid; RNA; RNA Interference; Science; Science (multidisciplinary); Signal Transduction; Spleen - metabolism; Spleen - pathology; Survival Analysis; Therapy; Tumor Burden; Viruses; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25632-1

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.
Improved therapeutic strategies are needed as drug resistance limits the therapeutic efficacy of several clinically approved cancer therapeutics. Here, the authors report a ferroptosis-based therapy using a combination of iron nanoparticles with gene interference to knockdown iron metabolic genes, FPN and LCN2.