Cerium Dioxide Nanoparticles Induce Apoptosis and Autophagy in Human Peripheral Blood Monocytes

Abstract

Cerium dioxide nanoparticles (CeO2 NPs) have diversified industrial uses and novel therapeutic applications are actively being pursued. There is lack of mechanistic data concerning the effects of CeO2 NPs on primary human cells. We aimed at characterizing the cytotoxic effects of CeO2 NPs in human peripheral blood monocytes. CeO2 NPs and their suspensions were thoroughly characterized, including using transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential analysis. Blood from healthy human volunteers was drawn through phlebotomy and CD14+ cells were isolated. Cells were exposed to CeO2 NPs (0.5–10 μg/mL) for 20 or 40 hours and mechanisms of cell injury were studied. TEM revealed that CeO2 NPs are internalized by monocytes and are found either in vesicles or free in the cytoplasm. CeO2 NP exposure leads to decrease in cell viability and treated cells exhibit characteristic hallmarks of apoptosis (activation of Bax, loss of mitochondrial membrane potential, DNA fragmentation). CeO2 NP toxicity is caused by mitochondrial damage leading to apoptosis inducing factor (AIF) release, but not due to caspase activation or reactive oxygen species production. Moreover, CeO2 NP exposure leads to autophagy, which is further increased after pharmacological inhibition of tumour suppressor protein p53. Inhibition of autophagy partially reverses cell death by CeO2 NPs. It is concluded that CeO2 NPs are toxic to primary human monocytes at relatively low doses.

Cerium oxide nanoparticle: a remarkably versatile rare earth nanomaterial for biological applications

“…9 However, several reports suggested that the uptake of CeONP could induce oxidative stress and DNA damage, dephosphorylation of various substrates, aberrant cell signaling and alterations in the transcriptional and posttranslational levels. [109][110][111] The cell lines used in the published studies established cell lines and primary cultures from tumors or normal tissues, which has been thoroughly reviewed in the literature. Although it was recently demonstrated that localization of CeONP in acidified lysosomes induced cell death 111 and that CeONP could induce cytotoxicity through autophagy and a mitochondrial apoptosis pathway, 110 simple correlations of the cytotoxicity effect of CeONP with cell types or particle size/preparations has not been established.…”

“…[109][110][111] The cell lines used in the published studies established cell lines and primary cultures from tumors or normal tissues, which has been thoroughly reviewed in the literature. Although it was recently demonstrated that localization of CeONP in acidified lysosomes induced cell death 111 and that CeONP could induce cytotoxicity through autophagy and a mitochondrial apoptosis pathway, 110 simple correlations of the cytotoxicity effect of CeONP with cell types or particle size/preparations has not been established. 112 In vivo studies In vivo analyses of the biological effect of CeONP were carried out by peroral, intravenous or intraperitoneal administration to laboratory animals.…”

Toxicity and Protective Effects of Cerium Oxide Nanoparticles (Nanoceria) Depending on Their Preparation Method, Particle Size, Cell Type, and Exposure Route

“…Hussain et al [46] suggested many possible toxic effects of ceria on human peripheral blood monocytes. In their ex vivo study, they first observed an up-regulation in autophagy caused by an inhibition of p53 proteins, which are the proteins that regulate the cell cycle and prevent cancer formation, leading to cell death.…”

Evaluation of Apoptosis Induced by Celecoxib Loaded Liposomes in Isolated Rat Hepatocytes

“…Target molecules for NSAIDs that participate at signaling pathways, include: 15-lipoxygenase-1, peroxisome proliferator-activated receptors (PPARs), P 21 ras signaling and AKT/PKB kinase (19)(20)(21). Cerium oxide nanoparticles induced apoptosis and autophagy in human peripheral blood monocytes (22). Doxorubicin nanoparticles have the potential to serve as a beneficial healing approach to overcome the chemoresistance of adriamycin-resistant breast cancer (23).…”