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.

Phenylbutyrate (PBA) is an aromatic short-chain fatty acid which is a chemical derivative of butyric acid naturally produced by colonic bacteria fermentation. At the intestinal level butyrate exerts a multitude of activities including amelioration of mucosal inflammation, regulation of transepithelial fluid transport, improvement in oxidative status and colon cancer prevention. Moreover, increasing number of studies report the beneficial role of butyric acid in prevention or inhibition of other types of malignancies, leading to cancer cell growth arrest and apoptosis. Similarly, phenylbutyrate displays potentially favorable effects on many pathologies including cancer, genetic metabolic syndromes, neuropathies, diabetes, hemoglobinopathies, and urea cycle disorders. The mechanisms by which PBA exerts these effects are different. Some of them are connected with the regulation of gene expression, playing the role of a histone deacetylase inhibitor, while others contribute to the ability of rescuing conformational abnormalities of proteins, serving as chemical chaperone, and some are dedicated to its metabolic characteristic enabling excretion of toxic ammonia, thus acting as ammonia scavenger. Phenylbutyrate may exert variable effects depending on the cell type, thus the term “butyrate paradox” has been proposed. These data indicate a broad spectrum of beneficial effects evoked by PBA with a high potential in therapy. In this review, we focus on cellular and systemic effects of PBA treatment with special attention to the three main branches of its molecular activity: ammonia scavenging, chaperoning and histone deacetylase inhibiting, and describe its particular role in various human diseases.

Phenylbutyrate (PBA) is a histone deacetylase inhibitor known for inducing differentiation, cell cycle arrest, and apoptosis in various cancer cells. However, the effects of PBA seem to be very cell-type-specific and sometimes limited exclusively to a particular cell line. Here, we provided novel information concerning cellular effects of PBA in LN-229 and LN-18 glioblastoma cell lines which have not been previously evaluated in context of PBA exposure. We found that LN-18 cells were PBA-insensitive even at high concentrations of PBA. In contrary, in LN-229 cells, 5 and 15 mmol/L PBA inhibited cell growth and proliferation mainly by causing prominent changes in cell morphology and promoting S- and G2/M-dependent cell cycle arrest. Moreover, we observed nearly a 3-fold increase in apoptosis of LN-229 cells treated with 15 mmol/L PBA, in comparison to control. Furthermore, PBA was found to up-regulate the expression of p21 whereas p53 expression level remained unchanged. We also showed that PBA down-regulated the expression of the anti-apoptotic genes Bcl-2/Bcl-X _L , however without affecting the expression of pro-apoptotic Bax and Bim. Taken together, our results suggest that PBA might potentially be considered as an agent slowing-down the progress of glioblastoma; however, further analyses are still needed to comprehensively resolve the nature of its activity in this type of cancer.

Silica nanoparticles (SiNPs) are one of the most commonly used nanomaterials in various medical applications. However, possible mechanisms of the toxicity caused by SiNPs remain unclear. The study presented here provides novel information on molecular and cellular effects of SiNPs in glioblastoma LBC3 and LN-18 cells. It has been demonstrated that SiNPs of 7 nm, 5–15 nm and 10–20 nm induce time- and dose-dependent cytotoxicity in LBC3 and LN-18 cell lines. In contrast to glioblastoma cells, we observed only weak reduction in viability of normal skin fibroblasts treated with SiNPs. Furthermore, in LBC3 cells treated with 5–15 nm SiNPs we noticed induction of apoptosis and necrosis, while in LN-18 cells only necrosis. The 5–15 nm SiNPs were also found to cause oxidative stress, a loss in mitochondrial membrane potential, and changes in the ultrastructure of the mitochondria in LBC3 cells. Quantitative real-time PCR results showed that in LBC3 cells the mRNA levels of pro-apoptotic genes Bim, Bax, Puma, and Noxa were significantly upregulated. An increase in activity of caspase-9 in these cells was also observed. Moreover, the activation of SiNP-induced autophagy was demonstrated in LBC3 cells as shown by an increase in LC3-II/LC3-I ratio, the upregulation of Atg5 gene and an increase in AVOs-positive cells. In conclusion, this research provides novel information concerning molecular mechanisms of apoptosis and autophagy in LBC3 cells.