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

Palladium nanoparticles (PdNPs) are increasingly being used in medical and biological applications due to their unique physical and chemical properties. Recent evidence suggests that these nanoparticles can act as both a pro-oxidant and as an antioxidant. Melatonin (MLT), which also shows pro- and antioxidant properties, can enhance the efficacy of chemotherapeutic agents when combined with anticancer drugs. Nevertheless, studies regarding the molecular mechanisms underlying the anticancer effects of PdNPs and MLT in cancer cells are still lacking. Therefore, we aimed to investigate the potential toxicological and molecular mechanisms of PdNPs, MLT, and the combination of PdNPs with MLT in A549 lung epithelial adenocarcinoma cells. We evaluated cell viability, cell proliferation, cytotoxicity, oxidative stress, mitochondrial dysfunction, and apoptosis in cells treated with different concentrations of PdNPs and MLT. PdNPs and MLT induced cytotoxicity, which was confirmed by leakage of lactate dehydrogenase, increased intracellular protease, and reduced membrane integrity. Oxidative stress increased the levels of reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), protein carbonyl content (PCC), lipid hydroperoxide (LHP), and 8-isoprostane. Combining PdNPs with MLT elevated the levels of mitochondrial dysfunction by decreasing mitochondrial membrane potential (MMP), ATP content, mitochondrial number, and expression levels of the main regulators of mitochondrial biogenesis. Additionally, PdNPs and MLT induced apoptosis and oxidative DNA damage due to accumulation of 4-hydroxynonenal (HNE), 8-oxo-2′-deoxyguanosine (8-OhdG), and 8-hydroxyguanosine (8-OHG). Finally, PdNPs and MLT increased mitochondrially mediated stress and apoptosis, which was confirmed by the increased expression levels of apoptotic genes. To our knowledge, this is the first study demonstrating the effects of combining PdNPs and MLT in human lung cancer cells. These findings provide valuable insights into the molecular mechanisms involved in PdNP- and MLT-induced toxicity, and it may be that this combination therapy could be a potential effective therapeutic approach. This combination effect provides information to support the clinical evaluation of PdNPs and MLT as a suitable agents for lung cancer treatment, and the combined effect provides therapeutic value, as non-toxic concentrations of PdNPs and MLT are more effective, better tolerated, and show less adverse effects. Finally, this study suggests that MLT could be used as a supplement in nano-mediated combination therapies used to treat lung cancer.

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Toxicity of Cerium Oxide Nanoparticles in Human Lung Cancer Cells

International Journal of Toxicology ◽

10.1080/10915810600959543 ◽

2006 ◽

Vol 25 (6) ◽

pp. 451-457 ◽

Cited By ~ 319

Author(s):

Weisheng Lin ◽

Yue-wern Huang ◽

Xiao-Dong Zhou ◽

Yinfa Ma

Keyword(s):

Oxidative Stress ◽

Lung Cancer ◽

Lactate Dehydrogenase ◽

Cell Viability ◽

Cancer Cells ◽

Cerium Oxide ◽

Human Lung ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Human Lung Cancer Cells

With the fast development of nanotechnology, the nanomaterials start to cause people’s attention for potential toxic effect. In this paper, the cytotoxicity and oxidative stress caused by 20-nm cerium oxide (CeO2) nanoparticles in cultured human lung cancer cells was investigated. The sulforhodamine B method was employed to assess cell viability after exposure to 3.5, 10.5, and 23.3 μg/ml of CeO2 nanoparticles for 24, 48, and 72 h. Cell viability decreased significantly as a function of nanoparticle dose and exposure time. Indicators of oxidative stress and cytotoxicity, including total reactive oxygen species, glutathione, malondialdehyde, α-tocopherol, and lactate dehydrogenase, were quantitatively assessed. It is concluded from the results that free radicals generated by exposure to 3.5 to 23.3 μg/ml CeO2 nanoparticles produce significant oxidative stress in the cells, as reflected by reduced glutathione and α-tocopherol levels; the toxic effects of CeO2 nanoparticles are dose dependent and time dependent; elevated oxidative stress increases the production of malondialdehyde and lactate dehydrogenase, which are indicators of lipid peroxidation and cell membrane damage, respectively.

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Oxidative stress–inducing effects of various urban PM2.5 road dust on human lung epithelial cells among 10 Chinese megacities

Ecotoxicology and Environmental Safety ◽

10.1016/j.ecoenv.2021.112680 ◽

2021 ◽

Vol 224 ◽

pp. 112680

Author(s):

Jian Sun ◽

Jinjin Yu ◽

Zhenxing Shen ◽

Xinyi Niu ◽

Diwei Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Human Lung ◽

Road Dust ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Human Lung Epithelial Cells

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A model to identify novel targets involved in oxidative stress-induced apoptosis in human lung epithelial cells by RNA interference

Toxicology in Vitro ◽

10.1016/j.tiv.2009.08.008 ◽

2010 ◽

Vol 24 (1) ◽

pp. 310-318 ◽

Cited By ~ 3

Author(s):

William E. Wixted ◽

Chris Kitson ◽

Jayne C. Colebrook ◽

Emma J. Roberts ◽

Steven M. Fox ◽

...

Keyword(s):

Oxidative Stress ◽

Rna Interference ◽

Epithelial Cells ◽

Human Lung ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Novel Targets ◽

Induced Apoptosis ◽

Human Lung Epithelial Cells

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BA6 Induces Apoptosis via Stimulation of Reactive Oxygen Species and Inhibition of Oxidative Phosphorylation in Human Lung Cancer Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6342104 ◽

2019 ◽

Vol 2019 ◽

pp. 1-21 ◽

Cited By ~ 6

Author(s):

Meng-Hsuan Cheng ◽

Hung-Ling Huang ◽

Yen-You Lin ◽

Kuan-Hao Tsui ◽

Pei-Chin Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Lung Cancer ◽

Reactive Oxygen Species ◽

Cancer Cells ◽

Human Lung ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Oxygen Species ◽

Apoptotic Pathway ◽

Induced Apoptosis

Lung cancer is the leading cause of cancer deaths in the world, with a five-year survival rate of less than 30%. Clinically effective chemotherapeutic treatments at the initial stage may eventually face the dilemma of no drug being effective due to drug resistance; therefore, finding new effective drugs for lung cancer treatment is a necessary and important issue. Compounds capable of further increasing the oxidative stress of cancer cells are considered to have anticancer potential because they possessed the ability to induce apoptosis. This study mainly investigated the effects of BA6 (heteronemin), the marine sponge sesterterpene, on lung cancer cell apoptosis, via modulation of mitochondrial reactive oxygen species (mtROS) and oxidative phosphorylation (OXPHOS). BA6 has cellular cytotoxic activities against a variety of cancer cell lines, but it has no effect on nontumor cells. The BA6-treated lung cancer cells show a significant increase in both cellular ROS and mtROS, which in turn caused the loss of mitochondrial membrane potential (MMP). The increase of oxidative stress in lung cancer cells treated with BA6 was accompanied by a decrease in the expression of antioxidant enzymes Cu/Zn SOD, MnSOD, and catalase. In addition, OXPHOS performed in the mitochondria and glycolysis in the cytoplasm were inhibited, which subsequently reduced downstream ATP production. Pretreatment with mitochondria-targeted antioxidant MitoTEMPO reduced BA6-induced apoptosis through the mitochondria-dependent apoptotic pathway, which was accompanied by increased cell viability, decreased mtROS, enhanced MMP, and suppressed expression of cleaved caspase-3 and caspase-9 proteins. In conclusion, the results of this study clarify the mechanism of BA6-induced apoptosis in lung cancer cells via the mitochondrial apoptotic pathway, suggesting that it is a potentially innovative alternative to the treatment of human lung cancer.

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Oxidative stress modulates the expression of toll‑like receptor 3 during respiratory syncytial virus infection in human lung epithelial A549 cells

Molecular Medicine Reports ◽

10.3892/mmr.2018.9089 ◽

2018 ◽

Cited By ~ 2

Author(s):

Min‑Min Wang ◽

Min Lu ◽

Chuan‑Long Zhang ◽

Xuan Wu ◽

Jing‑Xian Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Respiratory Syncytial Virus ◽

Virus Infection ◽

Respiratory Syncytial Virus Infection ◽

Human Lung ◽

A549 Cells ◽

Toll Like Receptor ◽

Lung Epithelial ◽

Syncytial Virus

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Regulation of apoptosis by Bcl-2 cysteine oxidation in human lung epithelial cells

Molecular Biology of the Cell ◽

10.1091/mbc.e12-10-0747 ◽

2013 ◽

Vol 24 (6) ◽

pp. 858-869 ◽

Cited By ~ 43

Author(s):

Sudjit Luanpitpong ◽

Pithi Chanvorachote ◽

Christian Stehlik ◽

William Tse ◽

Patrick S. Callery ◽

...

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Human Lung ◽

Critical Role ◽

B Cell Lymphoma ◽

Lung Epithelial Cells ◽

Mitogen Activated Protein Kinase ◽

Cysteine Oxidation ◽

Lung Epithelial ◽

Human Lung Epithelial Cells

Hydrogen peroxide is a key mediator of oxidative stress known to be important in various cellular processes, including apoptosis. B-cell lymphoma-2 (Bcl-2) is an oxidative stress–responsive protein and a key regulator of apoptosis; however, the underlying mechanisms of oxidative regulation of Bcl-2 are not well understood. The present study investigates the direct effect of H2O2on Bcl-2 cysteine oxidation as a potential mechanism of apoptosis regulation. Exposure of human lung epithelial cells to H2O2induces apoptosis concomitant with cysteine oxidation and down-regulation of Bcl-2. Inhibition of Bcl-2 oxidation by antioxidants or by site-directed mutagenesis of Bcl-2 at Cys-158 and Cys-229 abrogates the effects of H2O2on Bcl-2 and apoptosis. Immunoprecipitation and confocal microscopic studies show that Bcl-2 interacts with mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2 [ERK1/2]) to suppress apoptosis and that this interaction is modulated by cysteine oxidation of Bcl-2. The H2O2-induced Bcl-2 cysteine oxidation interferes with Bcl-2 and ERK1/2 interaction. Mutation of the cysteine residues inhibits the disruption of Bcl-2–ERK complex, as well as the induction of apoptosis by H2O2. Taken together, these results demonstrate the critical role of Bcl-2 cysteine oxidation in the regulation of apoptosis through ERK signaling. This new finding reveals crucial redox regulatory mechanisms that control the antiapoptotic function of Bcl-2.

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