Carbon-Coated Iron Oxide Nanoparticles Promote Reductive Stress-Mediated Cytotoxic Autophagy in Drug-Induced Senescent Breast Cancer Cells

The surface modification of magnetite nanoparticles (Fe3O4 NPs) is a promising approach to obtaining biocompatible
and multifunctional nanoplatforms with numerous applications in biomedicine,
for example, to fight cancer. However, little is known about the effects
of Fe3O4 NP-associated reductive stress against
cancer cells, especially against chemotherapy-induced drug-resistant
senescent cancer cells. In the present study, Fe3O4 NPs in situ coated by dextran (Fe3O4@Dex) and glucosamine-based amorphous carbon coating
(Fe3O4@aC) with potent reductive activity were
characterized and tested against drug-induced senescent breast cancer
cells (Hs 578T, BT-20, MDA-MB-468, and MDA-MB-175-VII cells). Fe3O4@aC caused a decrease in reactive oxygen species
(ROS) production and an increase in the levels of antioxidant proteins
FOXO3a, SOD1, and GPX4 that was accompanied by elevated levels of
cell cycle inhibitors (p21, p27, and p57), proinflammatory (NFκB,
IL-6, and IL-8) and autophagic (BECN1, LC3B) markers, nucleolar stress,
and subsequent apoptotic cell death in etoposide-stimulated senescent
breast cancer cells. Fe3O4@aC also promoted
reductive stress-mediated cytotoxicity in nonsenescent breast cancer
cells. We postulate that Fe3O4 NPs, in addition
to their well-established hyperthermia and oxidative stress-mediated
anticancer effects, can also be considered, if modified using amorphous
carbon coating with reductive activity, as stimulators of reductive
stress and cytotoxic effects in both senescent and nonsenescent breast
cancer cells with different gene mutation statuses.