International Journal of Nanomedicine (Nov 2024)
Zinc-Based Nanoparticles, but Not Silicon-Based Nanoparticles, Accumulate in Mitochondria and Promote Cell Death in Liver Cancer Cells
Abstract
Joana C Pieretti,1,2 Thaissa L Horne,1 Natalia García-Villasante,1 Amedea B Seabra,2 Jordi Muntané1,3,4 1Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, Seville, Spain; 2Center for Natural and Human Sciences, Federal University of ABC, Santo André, SP, Brazil; 3Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; 4Department of Medical Physiology and Biophysics, University of Seville, Seville, SpainCorrespondence: Jordi Muntané, Instituto de Biomedicina de Sevilla (IBiS), IBiS/Hospital University “Virgen del Rocío/CSIC/University of Seville, Av. Manuel Siurot s/n, Seville, 41013, Spain, Tel +34-955923122, Fax +34-955923002, Email [email protected]: Hepatocellular carcinoma (HCC) is the main hepatic primary malignancy. Patients with advanced HCC receiving the recommended therapies have a poor outcome. In different settings, nanotechnology has gained attraction as a potential alternative strategy for improving therapeutic effectiveness. Among several nanoparticles (NPs), inorganic NPs, such as zinc and silicon oxides (ZnO and SiO2), are mainly chosen as drug nanocarriers, as both present great adsorption properties and biocompatibility.Aim: The objective is to identify the molecular mechanisms underlying the proapoptotic effects of ZnO and SiO2 NPs in differentiated hepatoblastoma cells (HepG2) and mesenchymal liver cancer cells (SNU449).Methods: Dose-dependent induction of cell cytotoxicity by ZnO and SiO2 NPs (5 to 50 μg/mL) was determined in HepG2 and SNU449 cells. NPs intracellular localization was assessed using transmission electron microscopy (TEM). Cell death was determined by trypan blue staining and caspase-3 and − 8 activities. Cell respiration was determined using MitroStress assay (Seahorse, Agilent).Results: ZnO NPs, but not SiO2 NPs, reduced cell viability in HepG2 and SNU449. Interestingly, SNU449 appeared to be more susceptible than HepG2 to ZnO NPs (IC50 of 27.4 ± 1.4 μg/mL and 41.8 ± 0.4 μg/mL, respectively). SiO2 NPs tended to be localized in lysosomes in both cell lines, while ZnO NPs demonstrated a random distribution with a high presence in mitochondria and related structures. As expected, SiO2 NPs did not reduce cell survival and cell respiration, while ZnO NPs promoted cell death and decreased oxygen consumption rate. ZnO NPs mitochondrial accumulation was associated with increased apoptosis in HepG2, while necroapoptosis was mainly involved in ZnO-induced cell death in SNU449.Conclusion: SiO2 demonstrated no cytotoxic profile against liver cancer cells. ZnO NPs demonstrated to accumulate in mitochondria impacting cell respiration and cell death in liver cancer cells. ZnO induced apoptosis and necroptosis in HepG2 and SNU449, respectively.Keywords: apoptosis, cell respiration, hepatocellular carcinoma, metastasis, mitochondrial dysfunction
