Oxidative stress induced by DMSA-IONPs impairs breast cancer cell migration and paracrine cell communication

The migration of tumor cells requires a complex interplay of these cells with their microenvironment. Significantly, these migrating (metastatic) cells undergo metabolic and oxidative changes that render them more sensitive to shifts in their redox homeostasis. Nanoparticle (NP)-based pro-oxidant therapies are strategies that can potentially influence cell viability and migration. Among these, iron oxide NPs (IONPs) stand out due to their biocompatibility and the fact they induce ROS production through the Fenton Reaction. Here we investigate the possibility of using dimercaptosuccinic acid (DMSA)-coated IONPs as therapeutic tools to combat breast cancer (BC) cell migration and metastasis, influencing the paracrine communication between tumor and endothelial cells.

DMSA-IONPs affected the migration and invasion of a BC cell line by modulating the actin cytoskeleton. ROS production induced by DMSA-IONPs provoked actin carbonylation, which drives actin cytoskeletal rearrangements that reduces the cell area and the number of invadosomes per cell. Moreover, the presence of DMSA-IONPs in endo-lysosomal compartments affected unconventional pathways for protein secretion (UCPS), stimulating the release of late endosomes or multivesicular bodies, and blocking the release of lysosomes and autophagosomes. These effects alter secretory autophagy and lysosomal secretory pathways, which together influence the migration and chemotaxis of endothelial cells, modulating paracrine communication.

DMSA-IONPs can potentially inhibit the metastasis of a model BC cell line by directly affecting BC cell migration and indirectly altering the migration of endothelial cells.