Anisotropic Platinum Nanoparticle-Induced Cytotoxicity, Apoptosis, Inflammatory Response, and Transcriptomic and Molecular Pathways in Human Acute Monocytic Leukemia Cells

Abstract

The thermoplasmonic properties of platinum nanoparticles (PtNPs) render them desirable for use in diagnosis, detection, therapy, and surgery. However, their toxicological effects and impact at the molecular level remain obscure. Nanotoxicology is mainly focused on the interactions of nanostructures with biological systems, particularly with an emphasis on elucidating the relationship between the physical and chemical properties such as size and shape. Therefore, we hypothesized whether these unique anisotropic nanoparticles could induce cytotoxicity similar to that of spherical nanoparticles and the mechanism involved. Thus, we synthesized unique and distinct anisotropic PtNPs using lycopene as a biological template and investigated their biological activities in model human acute monocytic leukemia (THP-1) macrophages. Exposure to PtNPs for 24 h dose-dependently decreased cell viability and proliferation. Levels of the cytotoxic markers lactate dehydrogenase and intracellular protease significantly and dose-dependently increased with PtNP concentration. Furthermore, cells incubated with PtNPs dose-dependently produced oxidative stress markers including reactive oxygen species (ROS), malondialdehyde, nitric oxide, and carbonylated protein. An imbalance in pro-oxidants and antioxidants was confirmed by significant decreases in reduced glutathione, thioredoxin, superoxide dismutase, and catalase levels against oxidative stress. The cell death mechanism was confirmed by mitochondrial dysfunction and decreased ATP levels, mitochondrial copy numbers, and PGC-1α expression. To further substantiate the mechanism of cell death mediated by endoplasmic reticulum stress (ERS), we determined the expression of the inositol-requiring enzyme (IRE1), (PKR-like ER kinase) PERK, activating transcription factor 6 (ATF6), and activating transcription factor 4 ATF4, the apoptotic markers p53, Bax, and caspase 3, and the anti-apoptotic marker Bcl-2. PtNPs could activate ERS and apoptosis mediated by mitochondria. A proinflammatory response to PtNPs was confirmed by significant upregulation of interleukin-1-beta (IL-1β), interferon γ (IFNγ), tumor necrosis factor alpha (TNFα), and interleukin (IL-6). Transcriptomic and molecular pathway analyses of THP-1 cells incubated with the half maximal inhibitory concentration (IC50) of PtNPs revealed the altered expression of genes involved in protein misfolding, mitochondrial function, protein synthesis, inflammatory responses, and transcription regulation. We applied transcriptomic analyses to investigate anisotropic PtNP-induced toxicity for further mechanistic studies. Isotropic nanoparticles are specifically used to inhibit non-specific cellular uptake, leading to enhanced in vivo bio-distribution and increased targeting capabilities due to the higher radius of curvature. These characteristics of anisotropic nanoparticles could enable the technology as an attractive platform for nanomedicine in biomedical applications.

Palladium Nanoparticle-Induced Oxidative Stress, Endoplasmic Reticulum Stress, Apoptosis, and Immunomodulation Enhance the Biogenesis and Release of Exosome in Human Leukemia Monocytic Cells (THP-1)

“…We have previously shown that different shapes and sizes of platinum nanoparticles decrease CAT activity in THP-1 cells. 40 , 82 Similarly, the level of SOD was significantly lower in cells treated with PdNPs (10 μmol) and CSP (8 μmol) than in control cells, whereas GW4869-treated cells showed no significant effect (18 μmol) on CAT activity compared to the control (20 μmol) ( Figure 6D ). The concentrations of CAT and SOD were reportedly significantly compromised in PdNP-exposed human ovarian cancer cells, 37 human cervical cancer cells, 59 human breast cancer cells, 60 and human lung epithelial adenocarcinoma cells.…”

“…Similarly, metal nanoparticles such as silver induce oxidative stress in male somatic and spermatogonial stem cells, 75 F9 teratocarcinoma stem cells, 76 mouse embryonic fibroblast cells, 77 and various types of human cancer cells including human breast 78 , 79 and human lung cancer cells 80 , 81 via the generation of ROS. Similarly, platinum nanoparticles cause oxidative stress in THP-1 cells, 82 and PdNPs induce oxidative stress and eventual cell death in human ovarian cancer cell lines A2780 37 and SKOV3. 61

Figure 5 Effect of PdNPs on oxidative stress markers.

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“… 88 Ultra-small- and medium-sized platinum nanoparticles decreased the levels of TRX in THP-1 cells. 40 , 82 TRX and GSH are major thiol-dependent antioxidants involved in maintaining cell homeostasis and DNA synthesis and repair. 98 …”

“… 105 We have previously shown that platinum nanoparticles induce the expression of ER stress-related genes in THP-1 cells. 82 Additionally, the combination of platinum nanoparticles and retinoic acid induces the expression of ER stress-related genes in human neuroblastoma cells. 89 Two different sizes of silver nanoparticles reportedly induced ER stress breast cancer cells by the accumulation and aggregation of misfolded proteins and activation of the unfolded protein response UPR.…”

Platinum Nanoparticles Enhance Exosome Release in Human Lung Epithelial Adenocarcinoma Cancer Cells (A549): Oxidative Stress and the Ceramide Pathway are Key Players

“…Interestingly, cells pre-treated with NAC showed that caspase-3 levels were equal to those in the control, indicating that NAC inhibits the PtNPs- or C6-cer-or CSP induced apoptosis. Previous studies have demonstrated that PtNPs or platinum nanocomposites induce apoptosis through the activation of caspase-3 in various types of cancer cells, including prostate cancer cells, 39 human acute monocytic leukemia cells 94 human hepatic cancer cells, 95 and human neuroblastoma cancer cells. 41 Ceramide triggers caspase-3 activation and induces apoptosis in A549 lung cancer cells.…”