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Silica nanoparticle-induced oxidative stress and mitochondrial damage is followed by activation of intrinsic apoptosis pathway in glioblastoma cells

Authors Kusaczuk M, Krętowski R, Naumowicz M, Stypułkowska A, Cechowska-Pasko M

Received 29 November 2017

Accepted for publication 1 February 2018

Published 12 April 2018 Volume 2018:13 Pages 2279—2294

DOI https://doi.org/10.2147/IJN.S158393

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Govarthanan Muthusamy

Peer reviewer comments 2

Editor who approved publication: Dr Thomas J Webster


Magdalena Kusaczuk,1 Rafał Krętowski,1 Monika Naumowicz,2 Anna Stypułkowska,1 Marzanna Cechowska-Pasko1

1Department of Pharmaceutical Biochemistry, Medical University of Białystok, 2Institute of Chemistry, University of Białystok, Białystok, Poland

Introduction: Recently, the focus of oncological research has been on the optimization of therapeutic strategies targeted at malignant diseases. Nanomedicine utilizing silicon dioxide nanoparticles (SiNPs) is one such strategy and is rapidly developing as a promising tool for cancer diagnosis, imaging, and treatment. Nevertheless, little is known about the mechanisms of action of SiNPs in brain tumors.
Materials and methods: Here, we explored the effects of 5–15 nm SiNPs in the human glioblastoma cell line LN229. In this respect, MTT assays, microscopic observations, flow cytometry analyses, and luminescent assays were performed. Moreover, RT-qPCR and Western blot analyses were done to determine gene and protein expressions.
Results: We demonstrated that SiNPs triggered evident cytotoxicity, with microscopic observations of the nuclei, annexin V–fluorescein isothiocyanate/propidium iodide staining, and elevated caspase 3/7 activity, suggesting that SiNPs predominantly induced apoptotic death in LN229 cells. We further showed the occurrence of oxidative stress induced by enhanced reactive oxygen-species generation. This effect was followed by deregulated expression of genes encoding the antioxidant enzymes SOD1, SOD2, and CAT, and impaired mitochondria function. SiNP-induced mitochondrial dysfunction was characterized by membrane-potential collapse, ATP depletion, elevated expression of BAX, PUMA, and NOXA with simultaneous downregulation of BCL2/BCL2L1, and activation of caspase 9. Moreover, RT-qPCR and Western blot analyses demonstrated increased levels of the endoplasmic reticulum stress markers GRP78, GRP94, and DDIT3, as well as strongly increased expressions of the IL1B and COX2 genes, suggesting activation of endoplasmic reticulum stress and a proinflammatory response.
Conclusions: Altogether, our data indicate that in LN229 cells, SiNPs evoke cell death via activation of the intrinsic apoptosis pathway and suggest that other aspects of cellular function may also be affected. As such, SiNPs represent a potentially promising agent for facilitating further progress in brain cancer therapy. However, further exploration of SiNP long-term toxicity and molecular effects is necessary prior to their widespread application.

Keywords: mitochondrial membrane potential, nanomedicine, ER stress, nanotoxicity, silica nanoparticles

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