1. Ferroptosis-enhanced chemotherapy for triple-negative breast cancer with magnetic composite nanoparticles.
- Author
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Zhang J, Zhou K, Lin J, Yao X, Ju D, Zeng X, Pang Z, and Yang W
- Subjects
- Humans, Mice, Animals, Cell Line, Tumor, Lipid Peroxides therapeutic use, Phosphatidylinositol 3-Kinases, Magnetic Phenomena, Ferroptosis, Triple Negative Breast Neoplasms pathology, Nanoparticles
- Abstract
Triple-negative breast cancer (TNBC) causes great suffering to patients because of its heterogeneity, poor prognosis, and chemotherapy resistance. Ferroptosis is characterized by iron-dependent oxidative damage by accumulating intracellular lipid peroxides to lethal levels, and plays a vital role in the treatment of TNBC based on its intrinsic characteristics. To identify the relationship between chemotherapy resistance and ferroptosis in TNBC, we analyzed the single cell RNA-sequencing public dataset of GSE205551. It was found that the expression of Gpx4 in DOX-resistant TNBC cells was significantly higher than that in DOX-sensitive TNBC cells. Based on this finding, we hypothesize that inducing ferroptosis by inhibiting the expression of Gpx4 can reduce the resistance of TNBC to DOX and enhance the therapeutic effect of chemotherapy on TNBC. Herein, dihydroartemisinin (DHA)-loaded polyglutamic acid-stabilized Fe
3 O4 magnetic nanoparticles (Fe3 O4 -PGA-DHA) was combined with DOX-loaded polyaspartic acid-stabilized Fe3 O4 magnetic nanoparticles (Fe3 O4 -PASP-DOX) for ferroptosis-enhanced chemotherapy of TNBC. Compared with Fe3 O4 -PASP-DOX, Fe3 O4 -PGA-DHA + Fe3 O4 -PASP-DOX demonstrated significantly stronger cytotoxicity against different TNBC cell lines and achieved significantly more intracellular accumulation of reactive oxygen species and lipid peroxides. Furthermore, transcriptomic analyses demonstrated that Fe3 O4 -PASP-DOX-induced apoptosis could be enhanced by Fe3 O4 -PGA-DHA-induced ferroptosis and Fe3 O4 -PGA-DHA + Fe3 O4 -PASP-DOX might trigger ferroptosis in MDA-MB-231 cells by inhibiting the PI3K/AKT/mTOR/GPX4 pathway. Fe3 O4 -PGA-DHA + Fe3 O4 -PASP-DOX showed superior anti-tumor efficacy on MDA-MB-231 tumor-bearing mice, providing great potential for improving the therapeutic effect of TNBC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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