Corrigendum: Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide.

[This corrects the article DOI: 10.3389/fonc.2020.581814.].

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide.

Glioblastoma, the most common primary central nervous system tumor, is characterized by extensive vascular neoformation and an area of necrosis generated by rapid proliferation. The standard treatment for this type of tumor is surgery followed by chemotherapy based on temozolomide and radiotherapy, resulting in poor patient survival. Glioblastoma is known for strong resistance to treatment, frequent recurrence and rapid progression. The aim of this study was to evaluate whether mifepristone, an antihormonal agent, can enhance the effect of temozolomide on C6 glioma cells orthotopically implanted in Wistar rats. The levels of the vascular endothelial growth factor (VEGF), and P-glycoprotein (P-gp) were examined, the former a promoter of angiogenesis that facilitates proliferation, and the latter an efflux pump transporter linked to drug resistance. After a 3-week treatment, the mifepristone/temozolomide regimen had decreased the level of VEGF and P-gp and significantly reduced tumor proliferation (detected by PET/CT images based on 18F-fluorothymidine uptake). Additionally, mifepristone proved to increase the intracerebral concentration of temozolomide. The lower level of O6-methylguanine-DNA-methyltransferase (MGMT) (related to DNA repair in tumors) previously reported for this combined treatment was herein confirmed. After the mifepristone/temozolomide treatment ended, however, the values of VEGF, P-gp, and MGMT increased and reached control levels by 14 weeks post-treatment. There was also tumor recurrence, as occurred when administering temozolomide alone. On the other hand, temozolomide led to 100% mortality within 26 days after beginning the drug treatment, while mifepristone/temozolomide enabled 70% survival 60-70 days and 30% survived over 100 days, suggesting that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide.

Titanium dioxide nanoparticles induce the expression of early and late receptors for adhesion molecules on monocytes.

BACKGROUND: There is growing evidence that exposure to titanium dioxide nanoparticles (TiO2 NPs) could be harmful. Previously, we have shown that TiO2 NPs induces endothelial cell dysfunction and damage in glial cells. Considering that inhaled particles can induce systemic effects and the evidence that nanoparticles may translocate out of the lungs, we evaluated whether different types of TiO2 NPs can induce the expression of receptors for adhesion molecules on monocytes (U937 cell line). We evaluated the role of reactive oxygen spices (ROS) on these effects. METHODS: The expression of receptors for early (sLe(x) and PSGL-1) and late (LFA-1, VLA-4 and αVß3) adhesion molecules was evaluated in U937 cells on a time course (3-24 h) using a wide range of concentrations (0.001-100 µg/mL) of three types of TiO2 NPs (<25 nm anatase, 50 nm anatase-rutile or < 100 nm anatase). Cells exposed to TNFα were considered positive controls, and unexposed cells, negative controls. In some experiments we added 10 µmolar of N-acetylcysteine (NAC) to evaluate the role of ROS. RESULTS: All tested particles, starting at a concentration of 0.03 µg/mL, induced the expression of receptors for early and late adhesion molecules. The largest increases were induced by the different molecules after 3 h of exposure for sLe(x) and PSGL-1 (up to 3-fold of the positive controls) and after 18 h of exposure for LFA-1, VLA-4 and αVß3 (up to 2.5-fold of the positive controls). Oxidative stress was observed as early as 10 min after exposure, but the maximum peak was found after 4 h of exposure. Adhesion of exposed or unexposed monocytes to unexposed or exposed endothelial cells was tested, and we observed that monocytes cells adhere in similar amounts to endothelial cells if one of the two cell types, or both were exposed. When NAC was added, the expression of the receptors was inhibited. CONCLUSIONS: These results show that small concentrations of particles may activate monocytes that attach to endothelial cells. These results suggest that distal effects can be induced by small amounts of particles that may translocate from the lungs. ROS play a central role in the induction of the expression of these receptors.

TNFα and IL-6 Responses to Particulate Matter in Vitro: Variation According to PM Size, Season, and Polycyclic Aromatic Hydrocarbon and Soil Content.

BACKGROUND: Observed seasonal differences in particulate matter (PM) associations with human health may be due to their composition and to toxicity-related seasonal interactions. OBJECTIVES: We assessed seasonality in PM composition and in vitro PM pro-inflammatory potential using multiple PM samples. METHODS: We collected 90 weekly PM10 and PM2.5 samples during the rainy-warm and dry-cold seasons in five urban areas with different pollution sources. The elements, polycyclic aromatic hydrocarbons (PAHs), and endotoxins identified in the samples were subjected to principal component analysis (PCA). We tested the potential of the PM to induce tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6) secretion in cultured human monocytes (THP-1), and we modeled pro-inflammatory responses using the component scores. RESULTS: PM composition varied by size and by season. PCA identified two main components that varied by season. Combustion-related constituents (e.g., vanadium, benzo[a]pyrene, benzo[a]anthracene) mainly comprised component 1 (C1). Soil-related constituents (e.g., endotoxins, silicon, aluminum) mainly comprised component 2 (C2). PM from the rainy-warm season was high in C2. PM (particularly PM2.5) from the dry-cold season was rich in C1. Elevated levels of cytokine production were associated with PM10 and C2 (rainy-warm season), whereas reduced levels of cytokine production were associated with PM2.5 and C1 (dry-cold season). TNFα secretion was increased following exposure to PM with high (vs. low) C2 content, but TNFα secretion in response to PM was decreased following exposure to samples containing ≥ 0.1% of C1-related PAHs, regardless of C2 content. The results of the IL-6 assays suggested more complex interactions between PM components and particle size. CONCLUSIONS: Variations in PM soil and PAH content underlie seasonal and PM size-related patterns in TNFα secretion. These results suggest that the mixture of components in PM explains some seasonal differences in associations between health outcomes and PM in epidemiologic studies. CITATION: Manzano-León N, Serrano-Lomelin J, Sánchez BN, Quintana-Belmares R, Vega E, Vázquez-López I, Rojas-Bracho L, López-Villegas MT, Vadillo-Ortega F, De Vizcaya-Ruiz A, Rosas Perez I, O'Neill MS, Osornio-Vargas AR. 2016. TNFα and IL-6 responses to particulate matter in vitro: variation according to PM size, season, and polycyclic aromatic hydrocarbon and soil content. Environ Health Perspect 124:406-412; http://dx.doi.org/10.1289/ehp.1409287.

Variation in the composition and in vitro proinflammatory effect of urban particulate matter from different sites.

Spatial variation in particulate matter-related health and toxicological outcomes is partly due to its composition. We studied spatial variability in particle composition and induced cellular responses in Mexico City to complement an ongoing epidemiologic study. We measured elements, endotoxins, and polycyclic aromatic hydrocarbons in two particle size fractions collected in five sites. We compared the in vitro proinflammatory response of J774A.1 and THP-1 cells after exposure to particles, measuring subsequent TNFα and IL-6 secretion. Particle composition varied by site and size. Particle constituents were subjected to principal component analysis, identifying three components: C(1) (Si, Sr, Mg, Ca, Al, Fe, Mn, endotoxin), C(2) (polycyclic aromatic hydrocarbons), and C(3) (Zn, S, Sb, Ni, Cu, Pb). Induced TNFα levels were higher and more heterogeneous than IL-6 levels. Cytokines produced by both cell lines only correlated with C(1) , suggesting that constituents associated with soil induced the inflammatory response and explain observed spatial differences.

Particulate matter promotes in vitro receptor-recognizable low-density lipoprotein oxidation and dysfunction of lipid receptors.

Particulate matter may promote cardiovascular disease, possibly as a consequence of its oxidative potential. Studies using susceptible animals indicate that particulate matter aggravates atherosclerosis by increasing lipid/macrophage content in plaques. Macrophage lipid uptake requires oxidized low-density lipoprotein and scavenger receptors; same receptors are involved in particulate matter uptake. We studied in vitro particulate matter potential to oxidize low-density lipoproteins and subsequent cell uptake through scavenger receptors. Particulate matter-induced low-density lipoproteins oxidation was evaluated by the thiobarbituric acid assay. Binding/internalization was tested in wild type and scavenger receptor-transfected Chinese hamster ovary cells, and in RAW264.7 cells using fluorescently labeled low-density lipoproteins. Dose-dependent binding/internalization only occurred in scavenger receptor-transfected Chinese hamster ovary cells and RAW264.7 cells. Competition binding/internalization using particles showed that particulate matter induced decreased binding (∼50%) and internalization (∼70%) of particle-oxidized low-density lipoproteins and native low-density lipoproteins. Results indicate that particulate matter was capable of oxidizing low-density lipoproteins, favoring macrophage internalization, and also altered scavenger and low-density lipoproteins receptor function.

The oxidative potential and biological effects induced by PM10 obtained in Mexico City and at a receptor site during the MILAGRO Campaign.

As part of a field campaign that studied the impact of Mexico City pollution plume at the local, sub-regional and regional levels, we studied transport-related changes in PM(10) composition, oxidative potential and in vitro toxicological patterns (hemolysis, DNA degradation). We collected PM(10) in Mexico City (T(0)) and at a suburban-receptor site (T(1)), pooled according to two observed ventilation patterns (T(0) → T(1) influence and non-influence). T(0) samples contained more Cu, Zn, and carbon whereas; T(1) samples contained more of Al, Si, P, S, and K (p < 0.05). Only SO(4)(-2) increased in T(1) during the influence periods. Oxidative potential correlated with Cu/Zn content (r = 0.74; p < 0.05) but not with biological effects. T(1) PM(10) induced greater hemolysis and T(0) PM(10) induced greater DNA degradation. Influence/non-influence did not affect oxidative potential nor biological effects. Results indicate that ventilation patterns had little effect on intrinsic PM(10) composition and toxicological potential, which suggests a significant involvement of local sources.

DNA damage response of A549 cells treated with particulate matter (PM10) of urban air pollutants.

We describe the events triggered by a sub-lethal concentration of airborne particulate matter (PM(10)) in A549 cells, which include the formation DNA double-strand breaks, gammaH2A.X generation, and 53BP1 recruitment. To protect the genome, cells activated ATM/ATR/Chk1/Chk2/p53 pathway but, after 48 h, cells turned into a senescence-like state. Trolox, an antioxidant, was able to prevent most of the alterations observed after particulate matter exposure, demonstrating the important role of ROS as mediator of PM(10)-induced genotoxicity and suggesting that DNA damage could be the mechanisms by which particulate matter augment the risk of lung cancer.