ubiquinone and Glioblastoma

Most monotherapies available against glioblastoma multiforme (GBM) target individual hallmarks of this aggressive brain tumor with minimal success. In this article, we propose a therapeutic strategy using coenzyme Q. Xenografts of U251 cells in nu/nu mice were used to assay tumor growth, hypoxia, angiogenesis, and inflammation. An orthotopic model was used to explore microglial infiltration, tumor growth, and invasion into the brain parenchyma. Cell proliferation, migration, invasion, proteome remodeling, and secretome were assayed in vitro. Conditioned media were used to assay angiogenesis, monocyte chemoattraction, and differentiation into macrophages in vitro.. CoQ

Topics: Animals; Antioxidants; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Hypoxia; Inflammation; Mice; Proteome; Ubiquinone

Successful applications of photodynamic therapy (PDT) in cancer treatment require the development of effective photosensitizers with controllable singlet oxygen generation. Here we report a ubiquinone-BODIPY photosensitizer that self-assembles into nanoparticles (PS-Q-NPs) and undergoes selective activation and deaggregation within the highly reductive intracellular environment of tumor cells. PS-Q-NPs are highly stable in aqueous buffer solution, and exhibit minimal fluorescence and photosensitization due to a rapid non-radiative relaxation process. Upon endocytosis by cancer cells, reduction of the ubiquinone moiety by intracellular glutathione (GSH) triggers the conversion of the aggregated hydrophobic precursor into the active hydrophilic carboxylate derivative PS-A. The conversion results in enhanced fluorescence and therapeutic singlet oxygen generation, portending to its application as an activatable photosensitizer for fluorescence imaging-guided photodynamic cancer therapy.

Topics: Animals; Antineoplastic Agents; Boron Compounds; Cell Line, Tumor; Cell Survival; Glioblastoma; Humans; Infrared Rays; Mice; Molecular Structure; Nanoparticles; Neoplasms, Experimental; Optical Imaging; Oxidation-Reduction; Oxygen; Particle Size; Photochemotherapy; Photosensitizing Agents; Surface Properties; Tumor Microenvironment; Ubiquinone

Topics: Animals; Brain; Cell Cycle Proteins; Ferroptosis; Glioblastoma; HCT116 Cells; Humans; Lipid Metabolism; Mutation; PPAR alpha; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Rats; RNA Interference; Tumor Suppressor Protein p53; Ubiquinone

Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Drug Screening Assays, Antitumor; Glioblastoma; Humans; Neoplasm Proteins; Ubiquinone

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.

Topics: Animals; Antioxidants; Brain Neoplasms; Drug Resistance, Neoplasm; Glioblastoma; Humans; Male; Mice; Rats, Wistar; Temozolomide; Ubiquinone

Glioblastoma is the most common and malignant primary brain tumour in adults, with a dismal prognosis. This is partly due to considerable inter- and intra-tumour heterogeneity. Changes in the cellular energy-producing mitochondrial respiratory chain complex (MRC) activities are a hallmark of glioblastoma relative to the normal brain, and associate with differential survival outcomes. Targeting MRC complexes with drugs can also facilitate anti-glioblastoma activity. Whether mutations in the mitochondrial DNA (mtDNA) that encode several components of the MRC contribute to these phenomena remains underexplored. We identified a germ-line mtDNA mutation (m. 14798T > C), enriched in glioblastoma relative to healthy controls, that causes an amino acid substitution F18L within the core mtDNA-encoded cytochrome b subunit of MRC complex III. F18L is predicted to alter corresponding complex III activity, and sensitivity to complex III-targeting drugs. This could in turn alter reactive oxygen species (ROS) production, cell behaviour and, consequently, patient outcomes. Here we show that, despite a heterogeneous mitochondrial background in adult glioblastoma patient biopsy-derived cell cultures, the F18L substitution associates with alterations in individual MRC complex activities, in particular a 75% increase in MRC complex II_III activity, and a 34% reduction in CoQ10, the natural substrate for MRC complex III, levels. Downstream characterisation of an F18L-carrier revealed an 87% increase in intra-cellular ROS, an altered cellular distribution of mitochondrial-specific ROS, and a 64% increased sensitivity to clomipramine, a repurposed MRC complex III-targeting drug. In patients, F18L-carriers that received the current standard of care treatment had a poorer prognosis than non-carriers (373 days vs. 415 days, respectively). Single germ-line mitochondrial mutations could predispose individuals to differential prognoses, and sensitivity to mitochondrial targeted drugs. Thus, F18L, which is present in blood could serve as a useful non-invasive biomarker for the stratification of patients into prognostically relevant groups, one of which requires a lower dose of clomipramine to achieve clinical effect, thus minimising side-effects.

Topics: Clomipramine; DNA, Mitochondrial; Germ-Line Mutation; Glioblastoma; Humans; Kaplan-Meier Estimate; Male; Mitochondria; Mutation; Oxidation-Reduction; Reactive Oxygen Species; Ubiquinone

To investigate how the modulation of the oxidative balance affects cytotoxic therapies in glioblastoma, in vitro.. Human glioblastoma U251 and T98 cells and normal astrocytes C8D1A were loaded with coenzyme Q10 (CoQ). Mitochondrial superoxide ion (O. CoQ did not affect oxygen consumption but reduced the level of O. CoQ acts as sensitizer for cytotoxic therapies, disarming GBM cells, but not normal astrocytes, against further pro-oxidant injuries, being potentially useful in clinical practice for this fatal pathology.

Topics: Antioxidants; Apoptosis; Brain Neoplasms; Dacarbazine; DNA Damage; Glioblastoma; Humans; Hydrogen Peroxide; Mitochondria; Oxidative Stress; Oxygen Consumption; Radiation Tolerance; Reactive Oxygen Species; Temozolomide; Tumor Cells, Cultured; Ubiquinone

Case-control studies of serum antioxidants are difficult to interpret, because antioxidants may be altered by the disease under study. However, because glioblastoma multiforme (GBM) is a relatively rare disease, a cohort study would require a large sample observed for many years. In the present case-control pilot study (34 cases and 35 controls), we evaluated the association between serum levels of ascorbic acid (AA) and alpha- and gamma-tocopherol (alpha-T and gamma-T) measured before diagnostic surgery. To control for influence of GBM on serum AA, alpha-T, and gamma-T, we adjusted for oxidant stress indexes (gamma-glutamyl transpeptidase and uric acid) and an acute-phase response index (serum ferritin). When adjusted, AA is inversely related to GBM (p for trend = 0.007). In addition, AA interacts with alpha-T to further reduce GBM risk (test for interaction, p = 0.04). gamma-T is not associated with GBM (p = 0.71). However, gamma-glutamyl transpeptidase (p = 0.004), coenzyme Q (p = 0.01), and ferritin (p = 0.009) are positively and uric acid (p = 0.000) is negatively related to GBM. We conclude that 1) AA and alpha-T are jointly related to GBM after adjustment for GBM-produced oxidant stress and 2) there is a strong association between the presence of GBM and oxidant stress.

Topics: Acute-Phase Reaction; Aged; alpha-Tocopherol; Antioxidants; Ascorbic Acid; Brain Neoplasms; Case-Control Studies; Female; Ferritins; gamma-Glutamyltransferase; gamma-Tocopherol; Glioblastoma; Humans; Male; Middle Aged; Oxidative Stress; Pilot Projects; Risk Factors; Ubiquinone; Uric Acid