Abstract
The main reasons for the inefficiency of standard glioblastoma (GBM) therapy are the occurrence of chemoresistance and the invasion of GBM cells into surrounding brain tissues. New therapeutic approaches obstructing these processes may provide substantial survival improvements. The purpose of this study was to assess the potential of lipophilic antioxidant coenzyme Q10 (CoQ10) as a scavenger of reactive oxygen species (ROS) to increase sensitivity to temozolomide (TMZ) and suppress glioma cell invasion. To that end, we used a previously established TMZ-resistant RC6 rat glioma cell line, characterized by increased production of ROS, altered antioxidative capacity, and high invasion potential. CoQ10 in combination with TMZ exerted a synergistic antiproliferative effect. These results were confirmed in a 3D model of microfluidic devices showing that the CoQ10 and TMZ combination is more cytotoxic to RC6 cells than TMZ monotherapy. In addition, cotreatment with TMZ increased expression of mitochondrial antioxidant enzymes in RC6 cells. The anti-invasive potential of the combined treatment was shown by gelatin degradation, Matrigel invasion, and 3D spheroid invasion assays as well as in animal models. Inhibition of MMP9 gene expression as well as decreased N-cadherin and vimentin protein expression implied that CoQ10 can suppress invasiveness and the epithelial to mesenchymal transition in RC6 cells. Therefore, our data provide evidences in favor of CoQ10 supplementation to standard GBM treatment due to its potential to inhibit GBM invasion through modulation of the antioxidant capacity.
Highlights
Glioblastoma (GBM) is the most common primary malignant tumor with an astrocytic lineage [1]
We assessed the inhibitory effect of combined coenzyme Q10 (CoQ10) and TMZ treatments on RC6 cell growth after 72 h using the Sulforhodamine B (SRB) assay
We found that CoQ10, TMZ, and their combination induced a similar reduction in N-cadherin expression 2-fold (p ≤ 0 01), 1.9-fold (p ≤ 0 05), and 2.3-fold (p ≤ 0 01), respectively (Figure 8(b)), while CoQ10 and the combination led to a significant decrease of vimentin expression in RC6 cells by 1.6-fold (p ≤ 0 001) and 1.4-fold (p ≤ 0 01), respectively (Figure 8(c))
Summary
Glioblastoma (GBM) is the most common primary malignant tumor with an astrocytic lineage [1]. Invasion of glioma cells into brain parenchyma is a complex process that includes changes in cell-cell adhesion, remodeling of the extracellular matrix (ECM), and cell migration [4]. Different types of proteases are involved in ECM degradation and remodeling, including members of the matrix metalloproteinase (MMP) family, their inhibitors (tissue inhibitors of metalloproteinases (TIMP)), urokinasetype plasminogen activator (uPA) and its receptor, and cathepsin B. Increased expression of these proteases positively correlates with invasion potential and glioma grade [7, 8]. Glioma cells resistant to bis-chloroethyl nitrosourea (BCNU), known as carmustine, showed a significant decrease in E-cadherin expression, increase in vimentin expression and phenotypic changes consistent with EMT, spindle-shaped morphology, and enhanced pseudopodia formation [12]
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