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Mn-Zn ferrite nanoparticles inducing ferroptosis to reverse the resistance in CML cells
Miao Zhu1,2, Yanqian Zhao3, Li Xu4,5,6
1Department of Hematology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou University, Jiangsu, People's Republic of China.
Background:
Chronic myeloid leukemia (CML) is a malignant clonal disease of hematopoietic stem cells driven by the BCR-ABL fusion gene. Although tyrosine kinase inhibitors (TKIs) serve as targeted therapies, drug resistance remains one of the key challenges affecting the long-term survival of CML patients. A novel iron-based nano-reagent of Mn-Zn Ferrite was constructed to explore its role in regulating the redox homeostasis of CML cells and to clarify its therapeutic potential in reversing drug resistance in CML.
Methods:
CCK8 experiments were used to evaluate the effect of Mn-Zn Ferrite nanoparticles (Nano-Iron) on the drug sensitivity of adriamycin in K562 cells and adriamycin-resistant K562 cells (K562/ADR). Apoptosis, reactive oxygen species (ROS) levels, superoxide dismutase (SOD) levels in K562 cells and K562/ADR cells were measured after treatment of Nano-Iron and adriamycin. Further detection was conducted on the levels of glutathione (GSH), oxidized glutathione (GSSG) and GSH/GSSG ratio in K562 cells and K562/ADR cells after combined intervention. Meanwhile, the expression of glutathione peroxidase 4 (GPX4) and malondialdehyde (MDA) levels after combined intervention were determined. In vivo experiments involved in constructing systemic metastasis tumor models of K562 and K562/ADR in mice, which were treated with Nano-Iron and adriamycin. On the 10th, 15th and 20th day after tumor formation, in vivo imaging and medial canthal vein blood collection were performed to evaluate the proportion of tumor cells in peripheral blood. All mice were weighed regularly and euthanized when showing mental depression, at the same time, another batch of mice were used to calculate their survival period. Spleens and femurs were collected for hematoxylin-eosin (HE) and GPX4 staining.
Results:
Mn Zn ferrite (Nano-Iron) enhances the sensitivity of K562/ADR cells to adriamycin. After co-treatment with Nano-Iron and adriamycin, more apoptosis of K562/ADR cells was induced and accompanied with an increase of ROS and MDA levels, as well as a decrease of GSH/GSSG ratio and GPX4 expression. In vivo experiments have shown that the combination therapy of Nano-Iron and adriamycin prolongs the survival period of mice, significantly inhibits the infiltration of tumor cells in the bone marrow and suppresses the expression of GPX4 in the femur of mice.
Conclusion:
Mn-Zn Ferrite (Nano-Iron) enhances the therapeutic sensitivity of K562/ADR cells to adriamycin by inducing ferroptosis, demonstrating the therapeutic potential in reversing drug resistance.
Insights
Novel iron nanoparticles (Mn-Zn Ferrite) resensitize drug-resistant chronic myeloid leukemia (CML) cells to chemotherapy. This nano-reagent reverses adriamycin resistance by inducing ferroptosis, offering new therapeutic potential for CML patients.
Area of Science:
- Biomedical Engineering
- Nanotechnology in Cancer Therapy
- Hematologic Malignancies
Background:
- Chronic myeloid leukemia (CML) is driven by the BCR-ABL gene, and drug resistance to tyrosine kinase inhibitors (TKIs) limits long-term patient survival.
- Developing novel strategies to overcome TKI resistance is crucial for improving CML treatment outcomes.
Purpose of the Study:
- To investigate the therapeutic potential of a novel iron-based nano-reagent, Mn-Zn Ferrite (Nano-Iron), in overcoming adriamycin resistance in CML.
- To explore the role of Nano-Iron in regulating redox homeostasis and inducing ferroptosis in drug-resistant CML cells.
Main Methods:
- CCK8 assays evaluated the effect of Nano-Iron on adriamycin sensitivity in K562 and adriamycin-resistant K562 (K562/ADR) cells.
- Assessed apoptosis, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH/GSSG ratio), and glutathione peroxidase 4 (GPX4) levels.
- In vivo studies utilized systemic metastasis mouse models of CML treated with Nano-Iron and adriamycin, monitoring tumor cell infiltration and survival.
Main Results:
- Nano-Iron significantly enhanced adriamycin sensitivity in K562/ADR cells.
- Co-treatment induced K562/ADR cell apoptosis, increased ROS and MDA, and decreased GSH/GSSG ratio and GPX4 expression.
- In vivo, combination therapy prolonged survival, inhibited bone marrow tumor cell infiltration, and suppressed GPX4 expression.
Conclusions:
- Mn-Zn Ferrite (Nano-Iron) effectively reverses adriamycin resistance in CML by inducing ferroptosis.
- This nano-reagent demonstrates significant therapeutic potential for overcoming drug resistance in CML treatment.
