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Simvastatin induced ferroptosis for triple-negative breast cancer therapy
Xianxian Yao1, Ruihong Xie1, Yongbin Cao1
1State Key Laboratory of Molecular Engineering of Polymers & Department of Macromolecular Science, Fudan University, Shanghai, 200433, China.
Abstract:
Triple-negative breast cancer (TNBC), a management of aggressive breast cancer, remains an unmet medical challenge. Although a wave of efforts had spurred to design novel therapeutic method of TNBC, unpredictable prognosis with lacking effective therapeutic targets along with the resistance to apoptosis seriously limited survival benefits. Ferroptosis is a non-apoptotic form of cell death that is induced by excessive lipid peroxidation, which provide an innovative way to combat cancer. Emerging evidence suggests that ferroptosis plays an important role in the treatment of TNBC cells. Herein, a novel ferroptosis nanomedicine was prepared by loading simvastatin (SIM), a ferroptosis drug, into zwitterionic polymer coated magnetic nanoparticles (Fe3O4@PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe3O4@PCBMA-SIM nanoparticles demonstrated more cytotoxicity against MDA-MB-231 than MCF-7 due to the higher expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which demonstrated that statins could effectively kill TNBC. Further experiments showed that SIM could inhibit the expression of HMGCR to downregulate the mevalonate (MVA) pathway and glutathione peroxidase 4 (GPX4), thereby inducing cancer cell ferroptosis. What's more, PCBMA endows Fe3O4@PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe3O4 have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe3O4@PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells.
Insights
A novel nanomedicine using simvastatin (SIM) loaded magnetic nanoparticles effectively targets triple-negative breast cancer (TNBC) by inducing ferroptosis. This approach overcomes resistance to apoptosis and shows promise for clinical application in aggressive breast cancer treatment.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to its aggressive nature, poor prognosis, and resistance to conventional therapies.
- Apoptosis resistance limits the efficacy of current treatments, necessitating novel therapeutic strategies.
- Ferroptosis, a form of regulated cell death driven by lipid peroxidation, offers a promising alternative pathway for cancer treatment.
Purpose of the Study:
- To develop and evaluate a novel ferroptosis-inducing nanomedicine for enhanced triple-negative breast cancer (TNBC) therapy.
- To investigate the efficacy of simvastatin (SIM) loaded into zwitterionic polymer-coated magnetic nanoparticles (Fe3O4@PCBMA) against TNBC cells.
- To explore the underlying mechanism of SIM-induced ferroptosis in TNBC and the role of the nanocarrier in improving therapeutic outcomes.
Main Methods:
- Preparation of simvastatin (SIM)-loaded zwitterionic polymer-coated magnetic nanoparticles (Fe3O4@PCBMA-SIM).
- Cytotoxicity assessment of Fe3O4@PCBMA-SIM nanoparticles against TNBC (MDA-MB-231) and non-TNBC (MCF-7) cell lines.
- Investigation of SIM's effect on 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), the mevalonate (MVA) pathway, and glutathione peroxidase 4 (GPX4) expression.
- Evaluation of the enhanced tumor accumulation and blood circulation of the Fe3O4@PCBMA-SIM nanoparticles.
Main Results:
- Fe3O4@PCBMA-SIM nanoparticles exhibited higher cytotoxicity against MDA-MB-231 cells compared to MCF-7 cells, correlating with HMGCR expression.
- Simvastatin effectively inhibited HMGCR, downregulated the MVA pathway and GPX4, leading to ferroptosis induction in TNBC cells.
- The zwitterionic polymer coating (PCBMA) improved the nanoparticles' blood circulation time, enhancing tumor site accumulation.
Conclusions:
- The developed Fe3O4@PCBMA-SIM nanosystem effectively induces ferroptosis in triple-negative breast cancer cells by targeting the HMGCR/MVA pathway.
- This novel nanomedicine demonstrates significant potential for overcoming drug resistance associated with apoptosis-resistant cancers.
- The FDA-approved Fe3O4 component and the ferroptosis-inducing capability of SIM suggest a promising clinical translation for TNBC treatment.
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