8-hydroxy-2--deoxyguanosine and Glioblastoma

2021 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification includes molecular diagnostic parameters such as isocitrate dehydrogenase (IDH) mutation or 1p19q codeletion status, in addition to the classical histological classification. Several studies have revealed that patients with IDH1 mutation have a longer survival rate compared to wildtype individuals. In glioma cells, increased oxidative stress has been identified. However, till now, the relation between oxidative stress levels and IDH1 mutation status in those patients was not examined. Therefore, the aim of this study was to investigate the urinary levels of oxidatively induced DNA damage products, 8-hydroxy-2'- deoxyguanosine (8-OH-dG), (5'R) and (5'S)-8,5'-cyclo-2'-deoxyadenosines (R-cdA and S-cdA) as reliable oxidative stress markers in patients with IDH1-wildtype (n = 20) and IDH1-mutant (n = 22) glioma. Absolute quantification of 8-OH-dG, R-cdA and S-cdA was achieved by liquid chromatography-tandem mass spectrometry with isotope dilution. The levels of 8-OH-dG were significantly greater in IDH1-wildtype glioma patients than those in IDH1-mutant ones (p = 0.017). No statistically significant difference was observed for R-cdA and S-cdA levels. 8-OH-dG levels were positively correlated with patients' tumor recurrence in all patients (r = 0.382, p = 0.014). The mutation status of glioma is well correlated with oxidative stress. Examination of noninvasively measured oxidative DNA damage products along with IDH1 mutation status in glioma patients, might be particularly important in terms of evaluating and monitoring the effectiveness of treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; DNA Damage; Glioblastoma; Humans; Isocitrate Dehydrogenase; Mutation; Neoplasm Recurrence, Local; Oxidative Stress

Glioblastoma is one of the most frequent primary brain tumours of the central nervous system, with a poor survival time. With inefficient chemotherapy, it is urgent to develop new strategies for tumour therapy. The present approach is based on the inhibition of cell proliferation using platinum nanoparticles (NP-Pt). The aim of the study was to evaluate and compare the antiproliferative properties of NP-Pt and cisplatin against U87 and U118 glioma cell lines and U87 tumour tissue. NP-Pt and cisplatin were incubated with U87 and U118 glioma cells or administered directly into glioma tumour tissue. Cell morphology, the level of DNA synthesis, the migration of cells, protein expression levels of proliferating cell nuclear antigen (PCNA) and the level of DNA oxidation in glioma tumours were investigated. The results showed that NP-Pt treatment of U87 and U118 glioma cells decreased the level of DNA synthesis and the migration of cancer cells but also downregulated the level of PCNA protein expression in tumour tissue. Furthermore, NP-Pt caused oxidative DNA damage in tumour tissue to a higher degree than cisplatin. Consequently, NP-Pt can be considered as an effective inhibitor of glioblastoma tumour cell proliferation. However, the mechanism of action and potential side effects need to be elucidated further.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cisplatin; Deoxyguanosine; DNA Replication; Glioblastoma; Humans; Nanoparticles; Proliferating Cell Nuclear Antigen

Glioblastoma is one of the most aggressive malignant primary brain cancer in adults. To date, surgery, radiotherapy and current pharmacological treatments are not sufficient to manage this pathology that has a high mortality rate (median survival 12-15months). Recently, anticancer multi-targeted compounds have attracted much attention with the aim to obtain new drugs able to hit different biological targets that are involved in the onset and progression of the disease. Here, we report the synthesis of novel memantine-derived drugs (MP1-10) and their potential antitumor activities in human U87MG glioblastoma cell line. MP1-10 were synthetized joining memantine, which is a NMDA antagonist, to different histone deacetylase inhibitors to obtain one molecule with improved therapeutic efficacy. Biological results indicated that MP1 and MP2 possessed more potent anti-proliferative effects on U87MG cells than MP3-10 in a dose-dependent manner. MP1 and MP2 induced significant cell death by apoptosis characterized by apoptotic morphological changes in Hoechst staining. Both drugs also exhibited non-genotoxic and only mild cytotoxic effects in human whole blood cells. However, only MP1, showing good chemico-physical properties (solubility, LogP) and enzymatic stabilities in gastric and intestinal fluids, can be considered a suitable candidate for in vivo pharmacokinetic studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Antineoplastic Agents; Blood Cells; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Deoxyguanosine; Excitatory Amino Acid Antagonists; Gastric Juice; Glioblastoma; Histone Deacetylase Inhibitors; Humans; Intestinal Mucosa; Intestinal Secretions; Male; Memantine; Solubility; Young Adult

Context Since methods utilised in the treatment of glioblastoma multiforme (GBM) are inadequate and have too many side effects, usage of herbal products in the treatment process comes into prominence. Lichens are symbiotic organisms used for medicinal purposes for many years. There are various anticancer treatments about components of two lichen species used in the present study. Objective Antitumor potential of three lichen secondary metabolites including olivetoric acid (OLA) and physodic acid (PHA) isolated from Pseudevernia furfuracea (L.) Zopf (Parmeliaceae) and psoromic acid (PSA) isolated from Rhizoplaca melanophthalma (DC.) Leuckert (Lecanoraceae) were investigated on human U87MG-GBM cell lines and primary rat cerebral cortex (PRCC) cells for the first time. Materials and methods PRCC cells used as healthy brain cells were obtained from Sprague-Dawley rats. The treatments were carried out on the cells cultured for 48 h. Cytotoxic effects of different concentrations (2.5, 5, 10, 20 and 40 mg/L) of metabolites on the cells were determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) analyses. Total antioxidant capacity (TAC) and total oxidant status (TOS) parameters were used for assessing oxidative alterations. Oxidative DNA damage potentials of metabolites were investigated via evaluating 8-hydroxy-2'-deoxyguanosine (8-OH-dG) levels. Results Median inhibitory concentration (IC50) values of OLA, PHA and PSA were 125.71, 698.19 and 79.40 mg/L for PRCC cells and 17.55, 410.72 and 56.22 mg/L for U87MG cells, respectively. It was revealed that cytotoxic effects of these metabolites showed positive correlation with concentration, LDH activity and oxidative DNA damage. Discussion and conclusion The present findings obtained in this study revealed that primarily OLA and then PSA had high potential for use in the treatment of GBM.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antineoplastic Agents, Phytogenic; Benzoxepins; Biomarkers; Brain Neoplasms; Carboxylic Acids; Cell Line, Tumor; Cell Proliferation; Cerebral Cortex; Deoxyguanosine; Dibenzoxepins; DNA Damage; Dose-Response Relationship, Drug; Glioblastoma; Humans; L-Lactate Dehydrogenase; Lichens; Neurons; Oxidative Stress; Plant Extracts; Rats, Sprague-Dawley; Salicylates; Time Factors

Recently, the number of new psychoactive substances has significantly increased. Despite the systematic introduction of prohibition in trade of medicinal products which mimic the effects of illegal drugs, the problem concerning this group of drugs is still important although knowledge about the mechanism of action of those types of substances is scarce. This study aimed to follow the neurotoxic effect of N-benzylpiperazine (BZP), the central nervous system psychostimulant, using the human cancer LN-18 cell model. The statistically significant elevation of LDH levels, increased mitochondrial membrane potential, decreased ATP and increased ROS production, increased levels of DNA damage marker (8-OHdG) and activation of caspases: -3 and -9 confirmed by Real-Time PCR imply the activation of mitochondrial proapoptotic pathways induced by BZP after 24 h incubation. This study is a novel, preliminary attempt to explain the toxicity of one of the most popular designer drug of abuse at the cellular level.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenosine Triphosphate; bcl-2-Associated X Protein; Caspases; Cell Line, Tumor; Deoxyguanosine; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; L-Lactate Dehydrogenase; Membrane Potential, Mitochondrial; Neurotoxins; Piperazines; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; RNA, Messenger; Transcription Factor RelA

To assess oxidative DNA damage and total antioxidant capacity (TAC) in glioblastoma multiforme (GBM) and to compare the results with normal brain tissues.. Oxidative DNA damage and TAC were evaluated in GBM tissues extracted from 26 patients and in normal brain tissues of 15 subjects who underwent autopsy within the first 4h of death. Oxidative DNA damage was assessed by measuring 8-hydroxy-2-deoxyguanosine (8-OH-dG) using the 8-OH-dG enzyme immunoassay kit, a quantitative assay for 8-OH-dG, and TAC was analysed using the ImAnOx colorimetric test system for the determination of antioxidative capacity. The results were compared between two groups and any correlation between 8-OH-dG and TAC was sought.. The median level of TAC in GBM (121.5 nmol/g wet tissue) was remarkably lower than that in normal brain tissue (298 nmol/g wet tissue). The difference was statistically significant (P=0.00001). In contrast, oxidative DNA damage was significantly higher in patients with GBM (74.9 ng/g wet tissue) than in controls (34.71 ng/g wet tissue). Again, the difference was statistically significant (P=0.00001). We also found a negative correlation between oxidative DNA damage and TAC (P<0.001).. These findings indicate that the degree of oxidative DNA damage is increased and TAC is decreased in GBM. Oxidative DNA damage is correlated with the levels of TAC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Cerebral Cortex; Deoxyguanosine; DNA Damage; Female; Glioblastoma; Glutathione Peroxidase; Glutathione Reductase; Humans; Male; Middle Aged; Oxidative Stress; Prospective Studies