8-hydroxy-2--deoxyguanosine and Brain-Neoplasms

DNA modifications can be used to monitor pathological processes. We have previously shown that estimating the amount of the main DNA epigenetic mark, 5-methylcytosine (m

Topics: 5-Methylcytosine; 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Brain Neoplasms; DNA; DNA Damage; DNA Methylation; Female; Glioma; Humans; Male; Middle Aged; Oxidative Stress; Reactive Oxygen Species; Young Adult

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

To understand the interaction between oxidative stress and autophagy in gliomas of different grades.. In the present study, we analyzed levels of oxidative stress in 45 human glioma tumors, using the DNA oxidation marker 8-hydroxydeoxyguanosine (8-OHdG). In addition, we determined activation of autophagy in gliomas samples by assessing expression of microtubule-associated protein 1 light chain-3B (LC3B). To confirm our in vivo findings, in vitro studies using U87 cells were conducted.. It was determined that the grade of gliomas, that is, different malignant degrees according to WHO classification, significantly affected level of 8-OHdG. High levels of 8-OHdG were present in high-grade gliomas. This trend was significant in male patients and in young adult patients (<50 years old). Further study showed increased expression of LC3B in high-grade gliomas. In addition, levels of 8-OHdG and expression of LC3B were positively correlated. Reducing autophagic activity by 3-methyladenine resulted in significantly increased intracellular reactive oxygen species (ROS) in U87 cells.. Our study provides evidence that high levels of oxidative stress in high-grade gliomas are associated with autophagy activation that may play a protective role promoting the survival of high-grade gliomas under severe oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Autophagy; Brain Neoplasms; Cell Line, Tumor; Deoxyguanosine; Female; Glioma; Humans; Male; Middle Aged; Oxidative Stress; Young Adult

Reactive oxygen species (ROS) are mainly produced by mitochondria which can cause oxidative stress. It has been considered that mitochondrial damage induced by oxidative stress is related to Alzheimer's disease (AD). Besides, mitochondrial DNA (mtDNA) is more vulnerable to oxidative damage than other biomacromolecules, causing serious dysfunction to mitochondria. β-amyloid peptides (Aβ) is a main factor responsible for the occurrence and development of AD. Astrocytes is an important target cell for Aβ' toxicity and can be activated to neglect their normal fountain in the central nervous system. Genistein (Gen), a main active ingredient of soybean isoflavone, has been shown to have neuroprotective effects by antagonizing oxidative damage induced by Aβ. Thus, in the present study, we evaluated Aβ25-35 induced mitochondrial DNA (mtDNA) damage and the protective effect of Gen in C6 glioma cells (C6 cells). The study design was consisted of four groups: control group (vehicle), Aβ group treated with Aβ25-35, Gen + Aβ group treated with Gen + Aβ25-35 and Gen group treated with Gen only. C6 cells were pre-incubated with or without Gen (50 μM) for 2 h followed by the incubation with Aβ25-35 (25 μM) for another 24 h. Then the cells were harvested and processed to perform the analysis according to protocols. The mitochondrial ROS in C6 cells were measured by fluorescence spectrometer. Enzyme-linked immunosorbent assay (ELISA) was used to detect the mitochondrial reduced glutathione (GSH) and oxidized glutathione (GSSG) in C6 cells, then the ratio of GSH and GSSG was calculated. The levels of 8-hydroxydeoxyguanosine (8-OHdG) in C6 cells was also detected by ELISA. In addition, mtDNA deletion was detected by polymerase chain reaction (PCR). The mRNA and protein expression of 8-oxoguanine DNA glycosylase (OGG1) in both C6 cells and its mitochondria, and manganese superoxide dismutase (MnSOD) in mitochondria were detected by using reverse transcription-PCR and Western blot. The results showed that the increased mitochondrial ROS accumulation in C6 cells induced by Aβ was profoundly reversed by pre-treaded with Gen (p < 0.05). The ratio of GSH and GSSG in mitochondria was significantly increased in both Gen + Aβ group and Gen group compared with Aβ group (p < 0.05). The levels of 8-OHdG in C6 cells and mtDNA deletion were decreased after pre-treated with Gen (p < 0.05). Gen could also up-regulate the mRNA and protein expression of OGG1 in both C6 cells and its mitochond

Topics: 8-Hydroxy-2'-Deoxyguanosine; Amyloid beta-Peptides; Brain Neoplasms; Cell Line, Tumor; Deoxyguanosine; DNA Damage; DNA, Mitochondrial; Genistein; Glioma; Humans; Oxidative Stress; Peptide Fragments; Reactive Oxygen Species

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Brain Neoplasms; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA Damage; Female; Guanine; Humans; Male; Middle Aged; Oxidation-Reduction

Oxidative DNA damage generated by an attack of reactive oxygen species causes mutation or cell death that may lead to various diseases and may be related to initiation or progression of carcinogenesis. 8-Oxo-2'-deoxyguanosine (8-oxo-dG) is a major oxidative DNA damage product that can result in mutation, and hMTH1, human MutT homolog protein 1, has been identified as an enzyme that hydrolyzes 8-oxo-dGTP to the monophosphate, thus preventing accumulation of 8-oxo-dG in DNA. With immunohistochemical approaches, we investigated accumulation of 8-oxo-dG and expression of hMTH1 in brain tumor tissues obtained from surgical and autopsy cases, including 42 neuroepithelial tumors, 5 meningiomas, 2 metastatic brain tumors, and 1 schwannoma. 8-Oxo-dG accumulation and hMTH1 expression were increased in various brain tumors. Nuclei of brain tumor cells were immunoreactive for 8-oxo-dG in all cases. In most cases, both nuclei and cytoplasm of the tumor cells were immunoreactive for hMTH1. Both 8-oxo-dG accumulation and hMTH1 expression were most evident in high-grade gliomas, indicating that oxidative stress was high in these gliomas. Thus, the defense mechanism against such oxidative stress may be enhanced as well. These results suggest that oxidative stress may play a role in tumor progression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Aged; Autopsy; Brain Neoplasms; Child; Child, Preschool; Deoxyguanosine; DNA Repair Enzymes; Female; Gene Expression; Humans; Immunoblotting; Immunohistochemistry; Infant; Male; Middle Aged; Phosphoric Monoester Hydrolases; Reactive Oxygen Species