A Potential Mechanism of Temozolomide Resistance in Glioma–Ferroptosis

Hu, Zhifang; Mi, Yajing; Qian, Huiming; Guo, Na; Yan, Aibin; Zhang, Yuelin; Gao, Xingchun

doi:10.3389/fonc.2020.00897

Cited by 65 publications

(48 citation statements)

References 97 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results indicate that KR might be a potential inducer of ferroptosis and acts similar to erastin by inducing apoptotic cell death through ROS accumulation [94]. In contrast, Hu et al [93] demonstrated that ferroptosis might play an important role in the resistance of gliomas to temozolomide, which might be confirmed on the basis of the results obtained after 7-deazaKR treatment. Ferroptosis is a very complex process with multiple factors, and it remains to be clarified whether it is involved in physiology and development of cancer cells or whether it occurs after pharmacological interventions (anticancer therapy) [93,95].…”

Section: Discussionsupporting

confidence: 77%

“…Cellular lipid peroxidation is usually accompanied with ferroptosis, a newly discovered type of programmed cell death, which is activated when iron homeostasis in the cells is disrupted [93]. The induction of ferroptosis is mainly based on the Fenton reaction, wherein the accumulated iron (II) is oxidized into iron (III) by hydrogen peroxide, and lipid peroxides are in turn converted into ROS hydroxyl radical) [92].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

et al. 2021

View full text Add to dashboard Cite

Recently, small compound-based therapies have provided new insights into the treatment of glioblastoma multiforme (GBM) by inducing oxidative impairment. Kinetin riboside (KR) and newly designed derivatives (8-azaKR, 7-deazaKR) selectively affect the molecular pathways crucial for cell growth by interfering with the redox status of cancer cells. Thus, these compounds might serve as potential alternatives in the oxidative therapy of GBM. The increased basal levels of reactive oxygen species (ROS) in GBM support the survival of cancer cells and cause drug resistance. The simplest approach to induce cell death is to achieve the redox threshold and circumvent the antioxidant defense mechanisms. Consequently, cells become more sensitive to oxidative stress (OS) caused by exogenous agents. Here, we investigated the effect of KR and its derivatives on the redox status of T98G cells in 2D and 3D cell culture. The use of spheroids of T98G cells enabled the selection of one derivative—7-deazaKR—with comparable antitumor activity to KR. Both compounds induced ROS generation and genotoxic OS, resulting in lipid peroxidation and leading to apoptosis. Taken together, these results demonstrated that KR and 7-deazaKR modulate the cellular redox environment of T98G cells, and vulnerability of these cells is dependent on their antioxidant capacity.

show abstract

Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In addition, autophagy suppression in GBMs can enhance the sensitivity of GBM stem cells by inducing ferroptosis (11). Thus, combined therapy of TMZ and erastin may be an effective treatment for GBM, and targeted ferroptosis can be one of the potential therapies to reverse TMZ resistance (23).…”

Section: Discussionmentioning

confidence: 99%

Clinical and Biological Significances of a Ferroptosis-Related Gene Signature in Glioma

et al. 2020

View full text Add to dashboard Cite

Ferroptosis is a form of cell death characterized by non-apoptosis induced by small molecules in tumors. Studies have demonstrated that ferroptosis regulates the biological behaviors of tumors. Therefore, genes that control ferroptosis can be a promising candidate bioindicator in tumor therapy. Herein, functions of ferroptosis-related genes in glioma were investigated. We systematically assessed the relationship between ferroptosis-related genes expression profiles and prognosis in glioma patients based on The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) RNA sequencing datasets. Using the non-negative matrix factorization (NMF) clustering method, 84 ferroptosis-related genes in the RNA sequencing data were distinctly classified into two subgroups (named cluster 1 and cluster 2) in glioma. The least absolute shrinkage and selection operator (LASSO) was used to develop a 25 gene risk signature. The relationship between the gene risk signature and clinical features in glioma was characterized. Results show that the gene risk signature associated with clinical features can be as an independent prognostic indicator in glioma patients. Collectively, the ferroptosis-related risk signature presented in this study can potentially predict the outcome of glioma patients.

show abstract

“…To improve the effect of TMZ, many studies have combined it with radiation, other chemotherapeutic drugs, and phytochemicals, but many patients still develop drug resistance [ 1 , 4 ]. Moreover, the distinctive tumor microenvironment of GBM stimulates an intrastromal and intratumoral hypoxia cycle, which impairs drug delivery to tumor cells [ 5 , 6 ] and involves aberrant dysregulation of cellular signal transduction pathways [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Upon oxidative stress, cells protect themselves via a sophisticated intracellular antioxidant system that involves the regulation of glutathione (GSH)/glutathione peroxidase4 (GPX4) [ 6 , 8 ]. Cancer cells exhibit increased levels of intracellular reactive oxygen species (ROS) due to their hypermetabolism [ 9 , 10 ], leading to high expression of aquaporins, NADPH oxidases (NOX) and GPX4 compared to normal cells [ 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Cold Atmospheric Plasma Increases Temozolomide Sensitivity of Three-Dimensional Glioblastoma Spheroids via Oxidative Stress-Mediated DNA Damage

Shaw

Kumar

Privat-Maldonado

et al. 2021

Cancers

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is the most frequent and aggressive primary malignant brain tumor in adults. Current standard radiotherapy and adjuvant chemotherapy with the alkylating agent temozolomide (TMZ) yield poor clinical outcome. This is due to the stem-like properties of tumor cells and genetic abnormalities in GBM, which contribute to resistance to TMZ and progression. In this study, we used cold atmospheric plasma (CAP) to enhance the sensitivity to TMZ through inhibition of antioxidant signaling (linked to TMZ resistance). We demonstrate that CAP indeed enhances the cytotoxicity of TMZ by targeting the antioxidant specific glutathione (GSH)/glutathione peroxidase 4 (GPX4) signaling. We optimized the threshold concentration of TMZ on five different GBM cell lines (U251, LN18, LN229, U87-MG and T98G). We combined TMZ with CAP and tested it on both TMZ-sensitive (U251, LN18 and LN229) and TMZ-resistant (U87-MG and T98G) cell lines using two-dimensional cell cultures. Subsequently, we used a three-dimensional spheroid model for the U251 (TMZ-sensitive) and U87-MG and T98G (TMZ-resistant) cells. The sensitivity of TMZ was enhanced, i.e., higher cytotoxicity and spheroid shrinkage was obtained when TMZ and CAP were administered together. We attribute the anticancer properties to the release of intracellular reactive oxygen species, through inhibiting the GSH/GPX4 antioxidant machinery, which can lead to DNA damage. Overall, our findings suggest that the combination of CAP with TMZ is a promising combination therapy to enhance the efficacy of TMZ towards the treatment of GBM spheroids.

show abstract

A Potential Mechanism of Temozolomide Resistance in Glioma–Ferroptosis

Cited by 65 publications

References 97 publications

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

Clinical and Biological Significances of a Ferroptosis-Related Gene Signature in Glioma

Cold Atmospheric Plasma Increases Temozolomide Sensitivity of Three-Dimensional Glioblastoma Spheroids via Oxidative Stress-Mediated DNA Damage

Contact Info

Product

Resources

About