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

Abstract

The surface modification of magnetite nanoparticles (Fe 3 O 4 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 Fe 3 O 4 NP-associated reductive stress against cancer cells, especially against chemotherapy-induced drug-resistant senescent cancer cells. In the present study, Fe 3 O 4 NPs in situ coated by dextran (Fe 3 O 4 @Dex) and glucosamine-based amorphous carbon coating (Fe 3 O 4 @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). Fe 3 O 4 @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. Fe 3 O 4 @aC also promoted reductive stress-mediated cytotoxicity in nonsenescent breast cancer cells. We postulate that Fe 3 O 4 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.

A Nanorobotics-Based Approach of Breast Cancer in the Nanotechnology Era

“…designed to counteract the main neoplastic hallmark features of BC by sustaining proliferative pathways [31,32], evading growth suppressors/evasion of anti-growth signaling [12], resisting programmed cell death [33][34][35][36][37][38][39][40][41][42], inducing angiogenesis (neovascularization) [43][44][45][46], activating invasion and metastasis [47][48][49], preventing genomic instability, mutation, mitosis/cell cycle deregulation [50], evading/avoiding immune destruction [51] and deregulating autophagy [52,53].…”

“…Tang et al (2017) reviewed many common nanomaterials that can induce autophagy: gold NPs, quantum dots (QD), titanium dioxide NPs, zinc oxide NPs, nano rare earth oxides, fullerene, fullerenol and carbon nanotubes [3]. Recently, Lewinska et al (2024) emphasized the role of surface-modified magnetic nanoparticles, such as iron-oxide/magnetite (Fe 3 O 4 NPs), against chemotherapy-induced drug-resistant senescent BC cells, i.e., Hs 57 8T, BT-20, MDA-MB-468, and MDA-MB-175-VII lines, demonstrating their hyperthermia and OS-mediated anticancer effects [53]. Thus, in etoposide-stimulated non-senescent and senescent BC cells, glucosamine-based amorphous carbon coated NPs with reductive activity (Fe 3 O 4 @aC) caused an increase in the levels of autophagic (BECN1, LC3B), proinflammatory (NF-κB, IL-6, and IL-8), antioxidant (FOXO3a, SOD1, and GPX4) and cell-cycle-inhibitory (p21, p27, and p57) proteins, nucleolar stress and apoptotic cell death, in parallel with a decrease in ROS production [53].…”

“…Recently, Lewinska et al (2024) emphasized the role of surface-modified magnetic nanoparticles, such as iron-oxide/magnetite (Fe 3 O 4 NPs), against chemotherapy-induced drug-resistant senescent BC cells, i.e., Hs 57 8T, BT-20, MDA-MB-468, and MDA-MB-175-VII lines, demonstrating their hyperthermia and OS-mediated anticancer effects [53]. Thus, in etoposide-stimulated non-senescent and senescent BC cells, glucosamine-based amorphous carbon coated NPs with reductive activity (Fe 3 O 4 @aC) caused an increase in the levels of autophagic (BECN1, LC3B), proinflammatory (NF-κB, IL-6, and IL-8), antioxidant (FOXO3a, SOD1, and GPX4) and cell-cycle-inhibitory (p21, p27, and p57) proteins, nucleolar stress and apoptotic cell death, in parallel with a decrease in ROS production [53]. The roles of other types of metal oxide NPs have been also demonstrated, such as copper oxide NPs (CuO NPs) that induces autophagy as a survival mechanism against CuO NP-mediated toxicity in an MCF7 BC cell line, while the inhibition of autophagy induces apoptosis [160].…”

“…Hyperthermia and OS-mediated anticancer effects: decreased ROS production, increased level of antioxidant proteins, cell cycle inhibitors, proinflammatory and autophagic biomarkers, nucleolar stress, apototic cell death in drug-induced senescent BC cells (Hs 57 8T, BT-20, MDA-MB-468, MDA-MB-175-VII) and promoted reductive stress-mediated cytotoxicity in non-senescent BC cells. [53] DNA-based nanorobot (HApt-tFNA): anti-HER2 AP on a tetrahedral framework nucleic acid.…”

“…In this review, readers will be able to deepen their knowledge of the structure, behavior and role of nanorobots, among other nanomaterials, in BC theranostic. We have summarized here the characteristics of several functionalized nanodevices that have been designed to counteract the main neoplastic hallmark features of BC by sustaining proliferative path-ways [31,32], evading growth suppressors/evasion of anti-growth signaling [12], resisting programmed cell death [33][34][35][36][37][38][39][40][41][42], inducing angiogenesis (neovascularization) [43][44][45][46], activating invasion and metastasis [47][48][49], preventing genomic instability, mutation, mitosis/cell cycle deregulation [50], evading/avoiding immune destruction [51] and deregulating autophagy [52,53].…”