Mn-Zn ferrite nanoparticles inducing ferroptosis to reverse the resistance in CML cells.

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.