Detoxification of oxidative stress in glioma stem cells: Mechanism, clinical relevance, and therapeutic development

Kim, Sung-Hak; Kwon, Chang‐Hyuk; Nakano, ﻿Ichiro

doi:10.1002/jnr.23431

Cited by 46 publications

(39 citation statements)

References 57 publications

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“…GBM CSCs seem to reside within a specific microenvironment, or niche, characterized by the presence of lower oxygen tensions (i.e., hypoxia) [2,30], oxidative stress [31], inflammation [32] and a peritumoral acidic pH [33]. Soluble factors and extracellular matrix components generally get secreted by cancer cells, and determine extracellular matrix remodelling and consequently cancer progression [34].…”

Section: Glioma Csc Microenvironment (Or Niche)mentioning

confidence: 99%

Targeting Glioblastoma with the Use of Phytocompounds and Nanoparticles

et al. 2015

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Glioblastoma multiforme (GBM) are extremely lethal and still poorly treated primary brain tumors, characterized by the presence of highly tumorigenic cancer stem cell (CSC) subpopulations, considered responsible for tumor relapse. In order to successfully eradicate GBM growth and recurrence, new anti-cancer strategies selectively targeting CSCs should be designed. CSCs might be eradicated by targeting some of their cell surface markers and transporters, inducing their differentiation, impacting their hyper-glycolytic metabolism, inhibiting CSC-related signaling pathways and/or by targeting their microenvironmental niche. In this regard, phytocompounds such as curcumin, isothiocyanates, resveratrol and epigallocatechin-3-gallate have been shown to prevent or reverse cancer-related epigenetic dysfunctions, reducing tumorigenesis, preventing metastasis and/or increasing chemotherapy and radiotherapy efficacy. However, the actual bioavailability and metabolic processing of phytocompounds is generally unknown, and the presence of the blood brain barrier often represents a limitation to glioma treatments. Nowadays, nanoparticles (NPs) can be loaded with therapeutic compounds such as phytochemicals, improving their bioavailability and their targeted delivery within the GBM tumor bulk. Moreover, NPs can be designed to increase their tropism and specificity toward CSCs by conjugating their surface with antibodies specific for CSC antigens, with ligands or with glucose analogues. Here we discuss the use of phytochemicals as anti-glioma agents and the applicability of phytochemical-loaded NPs as drug delivery systems to target GBM. Additionally, we provide some examples on how NPs can be specifically formulated to improve CSC targeting.

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Section: Glioma Csc Microenvironment (Or Niche)mentioning

confidence: 99%

Targeting Glioblastoma with the Use of Phytocompounds and Nanoparticles

et al. 2015

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“…At mM concentrations, it also inhibits catalase and cytochrome P-450 enzymes (55). NO is released during the synthesis of L-citrulline, which is catalyzed by NOS enzymes (12). This gaseous molecule will form two metabolites: Nitrite and nitrate (13).…”

Section: Discussionmentioning

confidence: 99%

“…The excessive levels of reactive oxygen species (ROS) may result in cell damage and apoptosis (10). However, ROS production, which includes nitric oxide (NO), may improve the survival, growth and neoplastic phenotype of various cancer cells, including astrocytic brain tumors (11,12).…”

Section: Introductionmentioning

confidence: 99%

Function of neuronal nitric oxide synthase enzyme in temozolomide-induced damage of astrocytic tumor cells

Resende

Titze‐de‐Almeida

2018

Oncol Lett

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Abstract. Astrocytic tumors, including astrocytomas and glioblastomas, are the most common type of primary brain tumors. Treatment for glioblastomas includes radiotherapy, chemotherapy with temozolomide (TMZ) and surgical ablation. Despite certain therapeutic advances, the survival time of patients is no longer than 12-14 months. Cancer cells overexpress the neuronal isoform of nitric oxide synthase (nNOS). In the present study, it was examined whether the nNOS enzyme serves a role in the damage of astrocytoma (U251MG and U138MG) and glioblastoma (U87MG) cells caused by TMZ. First, TMZ (250 µM) triggered an increase in oxidative stress at 2, 48 and 72 h in the U87MG, U251MG and U138MG cell lines, as revealed by 2',7'-dichlorofluorescin-diacetate assay. The drug also reduced cell viability, as measured by MTT assay. U87MG cells presented a more linear decline in cell viability at time-points 2, 48 and 72 h, compared with the U251MG and U138MG cell lines. The peak of oxidative stress occurred at 48 h. To examine the role of NOS enzymes in the cell damage caused by TMZ, N(ω)-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) were used. L-NAME increased the cell damage caused by TMZ while reducing the oxidative stress at 48 h. The preferential nNOS inhibitor 7-NI also improved the TMZ effects. It caused a 12.8% decrease in the viability of TMZ-injured cells. Indeed, 7-NI was more effective than L-NAME in restraining the increase in oxidative stress triggered by TMZ. Silencing nNOS with a synthetic small interfering (si)RNA (siRNAnNOShum_4400) increased by 20% the effects of 250 µM of TMZ on cell viability (P<0.05). Hoechst 33342 nuclear staining confirmed that nNOS knock-down enhanced TMZ injury. In conclusion, our data reveal that nNOS enzymes serve a role in the damage produced by TMZ on astrocytoma and glioblastoma cells. RNA interference with nNOS merits further studies in animal models to disclose its potential use in brain tumor anticancer therapy.

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“…Moreover, elevated tissue levels of PRDX4 have been found in cancer cells including glioma [74][75][76], lung cancer [77], leukemia [78], prostate cancer [79], colorectal cancer [80], and multiple myeloma [81]. A defect in the PRDX4 gene has been identified in rare cases of the malignancy [82,83].…”

Section: Extracellular Prdx4mentioning

confidence: 98%