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Review

Ferroptosis Involvement in Glioblastoma Treatment

by
Andrei-Otto Mitre
1,
Alexandru Ioan Florian
2,3,*,
Andrei Buruiana
4,
Armand Boer
1,
Ioana Moldovan
1,
Olga Soritau
5,
Stefan Ioan Florian
2,3 and
Sergiu Susman
1,6
1
Department of Morphological Sciences, Iuliu Hațieganu University of Medicine and Pharmacy, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania
2
Department of Neurosurgery, Iuliu Hațieganu University of Medicine and Pharmacy, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania
3
Department, of Neurosurgery, Emergency County Hospital, 3-5 Clinicilor Street, 400006 Cluj-Napoca, Romania
4
Department of Medical Oncology, Prof. Dr. I. Chiricuta Oncology Institute, 400015 Cluj-Napoca, Romania
5
Research Department, Prof. Dr. I. Chiricuta Oncology Institute, 400015 Cluj-Napoca, Romania
6
Department of Pathology, IMOGEN Research Center, Louis Pasteur Street, 400349 Cluj-Napoca, Romania
*
Author to whom correspondence should be addressed.
Medicina 2022, 58(2), 319; https://doi.org/10.3390/medicina58020319
Submission received: 18 January 2022 / Revised: 13 February 2022 / Accepted: 16 February 2022 / Published: 20 February 2022
(This article belongs to the Special Issue The Glioblastoma Multimodal Treatment in the Molecular Era)
Browse Figures
Versions Notes

Abstract

:
Glioblastoma multiforme (GBM) is one of the deadliest brain tumors. Current standard therapy includes tumor resection surgery followed by radiotherapy and chemotherapy. Due to the tumors invasive nature, recurrences are almost a certainty, giving the patients after diagnosis only a 12–15 months average survival time. Therefore, there is a dire need of finding new therapies that could potentially improve patient outcomes. Ferroptosis is a newly described form of cell death with several implications in cancer, among which GBM. Agents that target different molecules involved in ferroptosis and that stimulate this process have been described as potentially adjuvant anti-cancer treatment options. In GBM, ferroptosis stimulation inhibits tumor growth, improves patient survival, and increases the efficacy of radiation and chemotherapy. This review provides an overview of the current knowledge regarding ferroptosis modulation in GBM.

1. Introduction

Glioblastoma multiforme (GBM) is a grade IV glioma, the most common malignant primary brain tumours in adults [1,2]. Its primarily characteristic is its high malignancy and invasion ability that renders a complete surgical resection impossible [3]. Therefore, current treatment options involve maximal surgical resection of the tumour, followed by chemotherapy and radiotherapy that are aimed at destroying the remaining cells [4,5]. However, these remaining cells can activate survival pathways and acquire resistance to both chemo and radiation therapy, most patients having tumour recurrence, that are often times more aggressive than the initial tumour [6,7,8]. This is why, even with this full treatment scheme, GBM patients have an average survival time between 12- and 15-months following diagnosis [9,10]. Current research is focusing on reducing the tumoral cells survival, either by targeting specific pathways used by the tumour for survival or by targeting pathways that offer the tumour resistance to chemo and radiation therapy [11,12].
Ferroptosis is a newly described form of regulated cell death [13]. Compared with apoptosis, necroptosis and pyroptosis, ferroptosis is iron dependent, triggered by intra-cellular alterations in iron metabolism that leads to lipid peroxidation and subsequently cellular death [14]. This mechanism has shown to be involved in a large number of pathologies, including inflammation, ischemic brain injuries and cancers, among which GBM is one [15,16,17,18,19].
This review aims to summarize the current knowledge regarding the ferroptosis process in GBM and the influence of ferroptosis pathways modulation on cancer cell activity.

2. Materials and Methods

The purpose of this review is to offer an overview of the current knowledge regarding the ferroptosis process in glioblastoma. We searched electronic databases of Medline (PubMed, PubMed Central) by using the terms ‘glioblastoma’ or ‘GBM’ and ‘ferroptosis’ or the molecules involved in the ferroptosis pathway: ‘iron’, ‘transferrin’, ‘transferrin receptor’, ‘TfR’, ‘STEAP’, ‘divalent metal transporter’, ‘DMT’, ‘PCBP’, ‘ferritin’, ‘ferroportin’, ‘system xc’, ‘SLC3A2’, ‘SLC7A11’, ‘cysteine’, ‘GSH’, ‘GPX4’, ‘glutathione’, ‘lipid peroxidation’, ‘ACSL4’, ‘ALOXE3’. Afterward, using a cross-reference search, we evaluated further articles linking ferroptosis to cancer progression and treatment. We have considered both clinical and experimental studies (both in vivo and in vitro).

3. The Ferroptosis Pathway

Cell death is a vital component of the normal animal cell development and homeostasis, it’s absence or dysregulation being involved in a series of immunological, developmental and neurological diseases, including excessive proliferative diseases such as cancers [20]. Although cysteine depletion forms of cells deaths have been observed for some time, ferroptosis was only recently described as a form of non-apoptotic cell death [13,21]. Ferroptosis is regulated by a series of very complex processes [14]. For this review, we will mainly focus on the core mechanism leading to ferroptosis: iron-related reactive oxygen species production, cysteine depletion and lipid peroxidation (Figure 1).
Iron in the cellular metabolism is presented in 2 forms: the ferrous cation (Fe2+) and ferric cation (Fe3+). Fe3+ is bound in the blood to plasma transferrin that carries it to the cells. Here, it attaches to the transferrin receptor (TfR) 1, the complex being endocytosed into the cell. Fe3+ is reduced to Fe2+ by 6-transmembrane epithelial antigen of the prostate 3 (STEAP3), which then enters the cytoplasm via divalent metal transporter 1 (DMT1) of the endosomal membrane [22,23]. Cytoplasmatic free Fe2+ is metabolic active and can be involved in a series of enzymatic processes, including DNA synthesis, cell cycle progression and angiogenesis, sequestered into ferritin by poly r(C)-binding protein (PCBP) 1 and 2 or taking place in the Fenton reaction [24]. Ferrous iron leaves the cells via ferroportin, which acts as a negative regulator of ferroptosis [25]. During the Fenton reaction, Fe2+ binds to hydrogen peroxide, which results in the generation of hydroxide and a hydroxyl radical that is a reactive oxygen species (ROS) [26]. ROS production leads to lipid peroxidation and loss of membrane permeability (Figure 1B) [27].
Another cnetral mechanism that leads to lipid peroxidation is via the cysteine/GSH depletion pathway. L-cystine enters the cells via the xc− exchanger with glutamate, which is composed of SLC7A11 and SLC3A2 carriers [28]. From here, it can be involved in a series of metabolic transformations, including the production of reduced glutathione (GSH). This happens by transforming L-cystine in γ-glutamylcysteine with the help of γ-glutamylcysteine synthase and then transforming it into GSH by glutathione synthase and glycine [29]. GSH is important in maintaining the cellular redox balance, as it is an ROS scavenger, being oxidized to glutathione disulphide (GSSG) (Figure 1A,D) [30].
Polyunsaturated fatty acids (PUFAs) are key element in ferroptosis. For PUFAs to lead to ferroptosis, first they must be esterified. Not all PUFAs act as substrate for the ferroptosis-induced lipid oxygenation, but mainly phosphatidylethanolamine (PE) PUFAs [31]. These PE-PUFAs are formed by acyl-CoA synthetase long-chain fatty member 4 (ACSL4) and lysophospatidylcholine acyltrasferase 3 [32]. By the action of 15-lipoxygenases (LOX) and Fe2+, PE-PUFAs are oxidized into lipid peroxides (Figure 1C) [33].
ROS accumulation via disruption of these pathways leads to the formation of lipid peroxides. Lipid peroxides are normally transformed in lipid alcohols by glutathione peroxidase 4 (GPX4) that uses 2 GSH molecules as substrate [34]. This step represents the main protective mechanism against ferroptosis (Figure 1D).
Besides GPX4 there are other cellular protective mechanisms against ferroptosis. In GPX4-knockdown cells, a protective mechanism was represented by the activation of ferroptosis suppressor protein 1 (FSP1), also known as apoptosis-inducing factor mitochondria-associated 2 (AIFM2) or p53-responsive gene (PRG3) [35]. FSP1 is a NADPH-dependent coenzyme Q10 (CoQ10) oxidoreductase that acts by converting ubiquinone (CoQ10) from the cellular wall into ubiquinol. Ubiquinol then acts as a ROS scavenger and can prevent ferroptosis-characteristic lipid peroxidation [36]. Further research is needed to establish the exact mechanism of FSP1 anti-ferroptosis mechanism, as 1 study showed that FSP1 can block drug-induced ferroptosis via an CoQ10 independent pathway [37]. Shi et al. showed that FSP1 levels were significantly associated with a lower overall survival and disease-free interval in several cancer types and could represent prognostic markers [38].
It is important to find and understand these alternate protective pathways because strategies aimed at promoting ferroptosis in cancer cells via up-regulating GPX4 could potentially be rendered ineffective by the compensatory activation of these other mechanisms.
Any modification of the levels and regulation of these pathways can hinder or promote ferroptosis. Increased intracellular Fe2+ and a decrease in GSH production increase the amount of ROS and lipid peroxidation; GPX4 inhibition disrupts the transformation of lipid peroxides into lipid alcohol and an increased level of lipid peroxides damages the structure of organelles and cell membranes, causing a loss of permeability and leading to cell death via ferroptosis.

4. Ferroptosis in Cancer Treatment

Current anti-cancer therapies aim to reduce or completely eradicate the tumour cells. This is conventionally conducted by surgical removal of the tumour, followed by radiation therapy and chemotherapy, as well as other forms of targeted therapies (Shah, Viral, 2018). The common denominator of these strategies is generally the aim of targeting a gene or protein that can trigger the apoptosis process. This involves the permeabilization of the mitochondrial outer membrane, which triggers the release of cytochrome c, the formation of the apoptosome the activation of caspase-9, concluding caspase-3 activation [39]. Caspase-3 triggers the execution pathway that involves poly (ADP-ribose) polymerases cleavage with DNA degradation, cytoskeletal reorganization, nuclear fragmentation and ultimately, the formation of apoptotic bodies and cell death [40,41,42]. Therefore, tumour development inhibition by caspase-3 activation is 1 of the main therapeutic targets of current anti-cancer therapies [43,44].
However, one of the main concerns regarding this strategy is represented by the cancer cells developing resistance to apoptosis [45]. The most common anti-apoptotic mechanisms developed by cancer cells are the expression of BCR-ABL or the silencing of tumour suppressor p53 [46,47,48]. In this regard ferroptosis presents as a valuable alternative, as it is a non-apoptotic form of cell death and could aid current anti-cancer treatments [49].
Cancer cells have a higher iron metabolic demand, making them more susceptible than normal cells to ferroptosis [49]. Recent studies have highlighted the involvement of ferroptosis in several cancer types, including breast cancer, pancreatic cancer, hepatocellular carcinoma, renal cell carcinoma and glioblastoma [50,51,52,53,54]. Ferroptosis sensitivity of cancer cells could be related to Ras-mitogen-activated protein kinase (MEK) activation. This contributes to the up-regulation of transferrin receptor 1 and the increase in intra cellular iron levels, and also to the additional formation of ROS by cystine inhibition [55,56]. There are many other molecules that are discovered to be involved in ferroptosis in different cancer cells, many of which could pose as a therapeutic target for future studies, including nuclear factor erythroid 2-related factor 2, heat shock-factor-1 and Beclin 1 [18]. Several studies have shown that in glioblastoma cell lines increasing ferroptosis activity resulted in decreased tumour growth and aggressiveness [57,58,59,60,61,62]. This could pose as a potential therapeutic strategy in GBM, aiding the current post-operative treatments [63,64,65,66].
However, it is important to note that most of these results are in vitro. Ferroptosis activation, by destroying the cellular membranes, determines the outburst of intra-cellular elements and ROS, which trigger a local inflammatory response that could damage the surrounding healthy tissue [67]. In non-alcoholic fatty liver disease and in ischemia-reperfusion injury ferroptosis played a pro-inflammatory role, aiding disease progression. In these cases, ferroptosis inhibition resulted in a better outcome [68,69]. Moreover, ferroptosis contributes to cyclooxygenase 2 activation that leads to the formation of prostaglandins and inflammation [70]. In the brain, several neurodegenerative diseases were linked to ferroptosis, including multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease [71]. In all of these pathologies, ferroptosis was involved in a part of the neuroinflammatory process. These results should caution future research into evaluating the possible neurological damage possibly associated with ferroptosis modulation in GBM subjects.
In the following section, we will describe the influence of modulating the ferroptosis pathway in GBM.

5. Ferroptosis in Glioblastoma

5.1. Iron Metabolism

GBM cells appear to have high free iron levels, even higher than GBM cancer stem-cells, which are probably able to store more as ferritin [72]. So far, the exact mechanisms and relationship that iron metabolism dysregulation has to cancer progression is unclear, but amending it could represent a promising strategy in improving the outcome of anti-cancer treatments [73]. Iron-related gene expression (hepcidin, TfR1 and TfR2) is different between normal human brain tissue and brain tumours, either down- or up-regulated [74,75]. In GBM sample tissues, TfR levels were higher compared to meningiomas and other brain tumours, with the exception of one tissue sample from a patient that underwent radiation therapy [76]. TfR2 is highly expressed in glioblastoma cell lines, which contributes to cell proliferation. Additionally, high TfR2 levels are associated with a better sensitivity for temozolomide and thus a more favourable prognosis [77].
STEAP3 is involved in iron homeostasis by reducing Fe3+ to Fe2+ that can be used by the cell [78]. However, the STEAP3 protein is also involved in other processes, including the inflammatory response, being vital for the Toll-Like Receptor 4-mediated macrophage production of chemoattractant protein-5, interferon-beta and interferon induced protein-10 [79,80]. In GBM cells, STEAP3 is highly expressed compared with normal brain tissues. This makes STEAP3 expression as a potential prognosis marker, poorer overall survival being associated with an increased STEAP3 level [81,82]. Furthermore, STEAP3 promotes TfR expression and induces mesenchymal transition. Its expression was directly correlated with increased cell proliferation, invasion, and sphere formation in vitro and with increased tumour growth in vivo [83].
DMT1 is associated with increased intracellular iron levels and iron accumulation in the brain and is currently studied as a molecule involved in neurodegenerative diseases [84]. In an experimental C6 glioma cells rat model, propofol administration reduced DMT1 expression in the glioma cells. The reduction was further associated with a significant decrease in GSH/GSSG ratio and of ROS. Additionally, tumour cells in the propofol groups had a lower tumoral cell count [85]. These results could link the expression of DMT1 and iron levels to ROS production and tumour proliferation, presenting DMT1 as a potential therapeutical target. During temozolomide (TMZ) treatment of GBM, DMT1 levels were elevated, associated with an increase in ROS via the ferroptosis pathway. Therefore, TMZ can suppress cell growth via the ferroptosis pathway by targeting DMT1 expression [86].
PCBP2 is an important element in iron homeostasis, as well as in posttranscriptional and translational regulation. It is upregulated in glioma tissues and cell lines and its knockdown inhibits glioma growth [87]. PCBP2 inhibitor microRNA-214 reduced glioma growth and proliferation [88].
In cancer patients, ferritin is detected in higher levels in the serum, correlating with a poorer prognosis and outcome. This illustrates the importance of iron and iron metabolism in cancer progression and possible resistance to therapy [89]. In GBM patients, ferritin levels in the serum and cerebrospinal fluid were higher than in patients without tumours. This excess ferritin appeared to be produced by the GBM cells [90].

5.2. The xCT System

Cysteine deprivation is an important inducer of ferroptosis and greatly contributes to the ferroptosis in GBM [91]. The cystine/glutamate xc- system antiporter is a heterodimer composed of the subunit SLC3A2, with the role of anchoring and stabilizing the SLC7A11 subunit, and SLC7A11, which is mediating the antiporting activity. Throughout the literature, this system is also referred to as simply SLC7A11 or xCT. For this reason, we will refer from now on to the antiporter as xCT. As mentioned before, this system is important in ferroptosis because its ability to regulate intracellular cystine intake and subsequently cysteine availability [92]. In GBM, xCT plays an important role in tumour survival and progression [93]. In the study of Takeuchi et al., including 40 GBM patients, xCT expression was correlated with the clinical outcome. Stronger xCT expression was significantly associated with a shorter progression-free survival and a shorter overall survival [94].
The tumour suppressor and transcription factor p53 is usually deregulated in GBM, increasing the tumours invasiveness, angiogenesis and regulating cellular metabolism. As this factor is downregulated, p53 reactivators could pose as a possible therapeutic strategy [95]. One study showed that there is a negative correlation between the expression of p53 and SLC7A11 in GBM. p53 can directly suppress SLC7A11 gene expression. Treatment with p53 reactivator decreased xCT activity and tumour growth; therefore, these treatments were able to influence both the p53 and the xCT systems [96].
In glucose deprivation environments, high cell density and epidermal growth factor treatment upregulated xCT in GBM cell lines, causing tumour death [97,98]. The effect is explained by an increase in cysteine levels, NADPH depletion and subsequent ROS accumulation [99,100]. However, these in vitro results are contrary to the previously presented in vivo study of Takeuchi et al. [94]. Further studies are needed to completely elucidate the influence of the xCT system in GBM progression and treatment.
Cancer cells have an increased metabolic activity and an increased production of ROS that often requires the overexpression of antioxidant pathways. Therefore, the xCT system is important in cancers and presents as a valuable target in anti-cancer therapy, including GBM [101]. Overexpression of the xCT system is involved in GBM cell growth and survival to therapy by increasing the mitochondrial biogenesis and ATP generation, by reducing ROS formation [102]. Via xCT involvement, ferroptosis takes an important part in regulating the GBM response to radiation, TMZ and immuno-therapy. All of these therapies suppress xCT and potentate tumoral cell death, guiding towards a possible better outcome for GBM patients [103,104,105].
In GBM cells, Gao et al. found that ibuprofen could inhibit the cells viability via increasing lipid peroxidation and ferroptosis. The treatment also downregulated xCT and GPX4 expression [19]. Using another drug repurposing approach, Sleire et al. found that sulfasalazine inhibited xCT activity in glioblastoma human xenografts in mice. This potentiated the effects of radiation therapy by increasing ROS and depleting GSH, improving the overall survival of the animals [106]. Similar results were found by other authors. Associating sulfasalazine treatment with valproic acid increased intracellular ROS and induced cell death, and sulfasalazine also increased TMZ cytotoxicity in vitro [107,108]. TMZ induces xCT expression in GBM treated cells, probably as a compensatory mechanism for the increase in ROS. Erastin xCT inhibition, together with TMZ proved to be more efficient than erastin or sulfasalazine alone [109]. In human subjects, Takeuchi et al. showed that the usage of sulfasalazine is associated with a high degree of hematologic toxic effects, while not providing a significant increase in survival [110]. Although sulfasalazine might not be efficient in GBM patients, xCT inhibition appears as to be potential target for future therapies associated with current radio- and chemo-therapeutic protocols, and could thus improve patient outcome [111].
Similar results have also been studied in GBM cancer stem cells. xCT overexpression might contribute to tumour progression and survival, while its inhibition decreases cancer stem cells invasion, survival and self-renewal abilities [112,113,114].

5.3. Lipid Peroxidation

PE-PUFAs are vital for ferroptosis, as they are the main substrate for lipid peroxidation [31]. ACSL4 is an acyl-CoA synthetase involved in the process of PE-PUFA synthesis and therefore is a key component in ferroptosis [115]. One of the main characteristics of GBM is represented by the tumour necrosis [116]. In this process, one mechanism is represented by neutrophils-induced ferroptosis. ACSL4 inhibition is associated with diminished necrosis areas and a less aggressive tumour behaviour. Thus, ferroptosis has a pro-tumorigenic role in early tumour progression by participating in the necrosis process, further enhancing the process by neutrophils recruitment that further increase ferroptosis and necrosis [117]. Suppressing the ACSL4 pathway reduces tumour progression and, furthermore, it increases the tumour sensibility to TMZ treatment [118].
Lipoxygenase (LOX) activity catalyse the oxygenation of PE-PUFAs into lipid peroxides that further activate signalling pathways or are used as substrates for further lipid mediators [119]. Additionally, iron plays the role of an enzyme effector for LOXs activity, especially 15-LOX isoforms, which plays a significant part in generating lipid peroxides [120]. In cancer therapy 15-LOX-1 stimulation seems to have a beneficial effect in reducing cancer growth and progression in vitro [121,122,123,124]. In GBM, 15-LOX upregulation by silencing IL-13Rα2 reduces tumour growth and promotes apoptosis [125].
MicroRNA (miRNA) 17-92-cluster up-regulation is involved in the pathogenesis of GBM [126]. A member of this cluster, miR-18a, is highly expressed in human GBM cell lines and regulates tumour cells progression, migration and invasion abilities [127]. MiR-18a also down-regulates ALOXE3 activity, reducing ferroptosis and thus providing a survival advantage in GBM. Inhibition of the miR-18a/ALOXE3 axis could provide a beneficial therapeutic approach [128].
The previously discussed molecules and pathways have a pivotal role in ferroptosis; however, its main regulatory enzyme is represented by GPX4. GPX4 is directly involved in transforming lipid peroxides into lipid alcohols by using GSH as a substrate. In its absence or reduced activity, lipid peroxides accumulate and induce lipid membrane damage that leads to cell death [129]. In cancer treatment, GPX4 modulation via influencing ferroptosis plays a crucial role in cancer cell death [130,131]. Absence or reduced expression of this molecule is also increasing 15-LOX activity, that not only increases the ROS availability, but also increases the tumour angiogenesis by a VEGF independent pathway [132,133].
Dihydroartemisinin (DHA) was studied as a potential GBM inhibitor by inducing apoptosis, autophagy and by suppressing the invasion ability of GBM cells [134,135]. Recently, the DHA inhibitory effect in GBM has been associated with ferroptosis. DHA significantly reduces GPX4, while maintaining ACSL4 and xCT system activity, increases ferroptosis and causes cancer cell death [54]. Treatment with a curcumin analogue reduced GPX4 activity, reducing GBM cells growth and TMZ resistance in vitro and improving survival in vivo in experimental rodents [136].

6. Conclusions

GBM remains one of the deadliest tumours, with a poor prognostic even considering current therapeutic efforts. By being a non-caspase dependent form of cell death, ferroptosis presents as a promising process that could be involved in cancer treatment. By inducing it in GBM, cancer cells growth and differentiation is inhibited and also, the response to radiation and to TMZ treatment is marginally improved. Inhibiting the xCT system, reducing cysteine levels and thus GSH levels, as well as reducing GPX4 activity and increasing iron availability and ROS formation, each stimulate lipid peroxidation and thus, promote ferroptosis that in turn limits the cells’ ability to survive and to develop mechanisms of resistance to treatments (Figure 2). Future studies should test whether ferroptosis inducers have a real clinical impact on cancer patients, as adjuvant therapy to current standard therapies.

Author Contributions

Conceptualization, A.-O.M., A.I.F. and S.S.; methodology, A.B. (Andrei Buruiana), A.B. (Armand Boer), O.S. and A.-O.M.; data curation, A.-O.M., A.I.F., S.S. and A.B. (Andrei Buruiana); writing—original draft preparation, A.-O.M., I.M., O.S. and A.I.F.; writing—review and editing, A.B. (Andrei Buruiana), A.B. (Armand Boer), I.M., O.S., S.I.F. and S.S.; visualization, A.B. (Andrei Buruiana), S.I.F. and I.M.; supervision, O.S., S.I.F. and S.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Batash, R.; Asna, N.; Schaffer, P.; Francis, N.; Schaffer, M. Glioblastoma Multiforme, Diagnosis and Treatment; Recent Literature Review. Curr. Med. Chem. 2017, 24, 3002–3009. [Google Scholar] [CrossRef] [PubMed]
  2. Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary. Acta Neuropathol. 2016, 131, 803–820. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Alifieris, C.; Trafalis, D.T. Glioblastoma Multiforme: Pathogenesis and Treatment. Pharmacol. Ther. 2015, 152, 63–82. [Google Scholar] [CrossRef] [PubMed]
  4. Stupp, R.; Hegi, M.E.; van den Bent, M.J.; Mason, W.P.; Weller, M.; Mirimanoff, R.O.; Cairncross, J.G.; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Changing Paradigms—An Update on the Multidisciplinary Management of Malignant Glioma. Oncologist 2006, 11, 165–180. [Google Scholar] [CrossRef] [PubMed]
  5. Barani, I.J.; Larson, D.A. Radiation Therapy of Glioblastoma. Cancer Treat. Res. 2015, 163, 49–73. [Google Scholar] [CrossRef]
  6. Birzu, C.; French, P.; Caccese, M.; Cerretti, G.; Idbaih, A.; Zagonel, V.; Lombardi, G. Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives. Cancers 2021, 13, 47. [Google Scholar] [CrossRef]
  7. Ventero, M.P.; Fuentes-Baile, M.; Quereda, C.; Perez-Valeciano, E.; Alenda, C.; Garcia-Morales, P.; Esposito, D.; Dorado, P.; Manuel Barbera, V.; Saceda, M. Radiotherapy Resistance Acquisition in Glioblastoma. Role of SOCS1 and SOCS3. PLoS ONE 2019, 14, e0212581. [Google Scholar] [CrossRef] [Green Version]
  8. Safari, M.; Khoshnevisan, A. Cancer Stem Cells and Chemoresistance in Glioblastoma Multiform: A Review Article. J. Stem Cells 2015, 10, 271–285. [Google Scholar]
  9. Witthayanuwat, S.; Pesee, M.; Supaadirek, C.; Supakalin, N.; Thamronganantasakul, K.; Krusun, S. Survival Analysis of Glioblastoma Multiforme. Asian Pac. J. Cancer Prev. 2018, 19, 2613–2617. [Google Scholar] [CrossRef]
  10. Stupp, R.; Hegi, M.E.; Mason, W.P.; van den Bent, M.J.; Taphoorn, M.J.B.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; et al. Effects of Radiotherapy with Concomitant and Adjuvant Temozolomide versus Radiotherapy Alone on Survival in Glioblastoma in a Randomised Phase III Study: 5-Year Analysis of the EORTC-NCIC Trial. Lancet Oncol. 2009, 10, 459–466. [Google Scholar] [CrossRef]
  11. Jhanwar-Uniyal, M.; Labagnara, M.; Friedman, M.; Kwasnicki, A.; Murali, R. Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets. Cancers 2015, 7, 538. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Susman, S.; Pîrlog, R.; Leucuța, D.; Mitre, A.O.; Padurean, V.A.; Melincovici, C.; Moldovan, I.; Crișan, D.; Florian, S.I. The Role of P-Stat3 Y705 Immunohistochemistry in Glioblastoma Prognosis. Diagn. Pathol. 2019, 14, 124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; et al. Ferroptosis: An Iron-Dependent Form of Non-Apoptotic Cell Death. Cell 2012, 149, 1060. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Tang, D.; Chen, X.; Kang, R.; Kroemer, G. Ferroptosis: Molecular Mechanisms and Health Implications. Cell Res. 2021, 31, 107. [Google Scholar] [CrossRef] [PubMed]
  15. Cui, Y.; Zhang, Y.; Zhao, X.; Shao, L.; Liu, G.; Sun, C.; Xu, R.; Zhang, Z. ACSL4 Exacerbates Ischemic Stroke by Promoting Ferroptosis-Induced Brain Injury and Neuroinflammation. Brain Behav. Immun. 2021, 93, 312–321. [Google Scholar] [CrossRef]
  16. Magtanong, L.; Dixon, S.J. Ferroptosis and Brain Injury. Dev. Neurosci. 2018, 40, 382–395. [Google Scholar] [CrossRef]
  17. Qiu, Y.; Cao, Y.; Cao, W.; Jia, Y.; Lu, N. The Application of Ferroptosis in Diseases. Pharmacol. Res. 2020, 159, 104919. [Google Scholar] [CrossRef]
  18. Mou, Y.; Wang, J.; Wu, J.; He, D.; Zhang, C.; Duan, C.; Li, B. Ferroptosis, a New Form of Cell Death: Opportunities and Challenges in Cancer. J. Hematol. Oncol. 2019, 12, 34. [Google Scholar] [CrossRef] [Green Version]
  19. Gao, X.; Guo, N.; Xu, H.; Pan, T.; Lei, H.; Yan, A.; Mi, Y.; Xu, L. Ibuprofen Induces Ferroptosis of Glioblastoma Cells via Downregulation of Nuclear Factor Erythroid 2-Related Factor 2 Signaling Pathway. Anticancer Drugs 2020, 31, 27–34. [Google Scholar] [CrossRef]
  20. Fuchs, Y.; Steller, H. Programmed Cell Death in Animal Development and Disease. Cell 2011, 147, 742. [Google Scholar] [CrossRef] [Green Version]
  21. De Brabander, M.; Van Belle, H.; Aerts, F.; Van De Veire, R.; Geuens, G. Protective Effect of Levamisole and Its Sulfhydryl Metabolite OMPI against Cell Death Induced by Glutathione Depletion. Int. J. Immunopharmacol. 1979, 1, 93–100. [Google Scholar] [CrossRef]
  22. Bogdan, A.R.; Miyazawa, M.; Hashimoto, K.; Tsuji, Y. Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease. Trends Biochem. Sci. 2016, 41, 274–286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Gao, G.; Li, J.; Zhang, Y.; Chang, Y.-Z. Cellular Iron Metabolism and Regulation. Adv. Exp. Med. Biol. 2019, 1173, 21–32. [Google Scholar] [CrossRef] [PubMed]
  24. Leidgens, S.; Bullough, K.Z.; Shi, H.; Li, F.; Shakoury-Elizeh, M.; Yabe, T.; Subramanian, P.; Hsu, E.; Natarajan, N.; Nandal, A.; et al. Each Member of the Poly-r(C)-Binding Protein 1 (PCBP) Family Exhibits Iron Chaperone Activity toward Ferritin. J. Biol. Chem. 2013, 288, 17791–17802. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Geng, N.; Shi, B.-J.; Li, S.-L.; Zhong, Z.-Y.; Li, Y.-C.; Xua, W.-L.; Zhou, H.; Cai, J.-H. Knockdown of Ferroportin Accelerates Erastin-Induced Ferroptosis in Neuroblastoma Cells. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 3826–3836. [Google Scholar] [CrossRef]
  26. Winterbourn, C.C. Toxicity of Iron and Hydrogen Peroxide: The Fenton Reaction. Toxicol. Lett. 1995, 82–83, 969–974. [Google Scholar] [CrossRef]
  27. Shah, R.; Shchepinov, M.S.; Pratt, D.A. Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis. ACS Cent. Sci. 2018, 4, 387. [Google Scholar] [CrossRef] [PubMed]
  28. Liu, M.; Zhu, W.; Pei, D. System Xc−: A Key Regulatory Target of Ferroptosis in Cancer. Invest. New Drugs 2021, 39, 1123–1131. [Google Scholar] [CrossRef]
  29. Conrad, M.; Sato, H. The Oxidative Stress-Inducible Cystine/Glutamate Antiporter, System x (c) (-): Cystine Supplier and Beyond. Amino Acids 2012, 42, 231–246. [Google Scholar] [CrossRef]
  30. Flohé, L. The Fairytale of the GSSG/GSH Redox Potential. Biochim. Biophys. Acta 2013, 1830, 3139–3142. [Google Scholar] [CrossRef]
  31. Kagan, V.E.; Mao, G.; Qu, F.; Angeli, J.P.F.; Doll, S.; Croix, C.S.; Dar, H.H.; Liu, B.; Tyurin, V.A.; Ritov, V.B.; et al. Oxidized Arachidonic/Adrenic Phosphatidylethanolamines Navigate Cells to Ferroptosis. Nat. Chem. Biol. 2017, 13, 81. [Google Scholar] [CrossRef] [PubMed]
  32. Doll, S.; Proneth, B.; Tyurina, Y.Y.; Panzilius, E.; Kobayashi, S.; Ingold, I.; Irmler, M.; Beckers, J.; Aichler, M.; Walch, A.; et al. Acsl4 Dictates Ferroptosis Sensitivity by Shaping Cellular Lipid Composition. Nat. Chem. Biol. 2017, 13, 91. [Google Scholar] [CrossRef]
  33. Li, J.; Cao, F.; Yin, H.; Huang, Z.; Lin, Z.; Mao, N.; Sun, B.; Wang, G. Ferroptosis: Past, Present and Future. Cell Death Dis. 2020, 11. [Google Scholar] [CrossRef] [PubMed]
  34. Imai, H.; Matsuoka, M.; Kumagai, T.; Sakamoto, T.; Koumura, T. Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and Ferroptosis. Curr. Top. Microbiol. Immunol. 2017, 403, 143–170. [Google Scholar] [CrossRef] [PubMed]
  35. Doll, S.; Freitas, F.P.; Shah, R.; Aldrovandi, M.; da Silva, M.C.; Ingold, I.; Goya Grocin, A.; Xavier da Silva, T.N.; Panzilius, E.; Scheel, C.H.; et al. FSP1 Is a Glutathione-Independent Ferroptosis Suppressor. Nature 2019, 575, 693–698. [Google Scholar] [CrossRef] [PubMed]
  36. Bersuker, K.; Hendricks, J.M.; Li, Z.; Magtanong, L.; Ford, B.; Tang, P.H.; Roberts, M.A.; Tong, B.; Maimone, T.J.; Zoncu, R.; et al. The CoQ Oxidoreductase FSP1 Acts Parallel to GPX4 to Inhibit Ferroptosis. Nature 2019, 575, 688–692. [Google Scholar] [CrossRef]
  37. Dai, E.; Zhang, W.; Cong, D.; Kang, R.; Wang, J.; Tang, D. AIFM2 Blocks Ferroptosis Independent of Ubiquinol Metabolism. Biochem. Biophys. Res. Commun. 2020, 523, 966–971. [Google Scholar] [CrossRef]
  38. Shi, Z.-Z.; Tao, H.; Fan, Z.-W.; Song, S.-J.; Bai, J. Prognostic and Immunological Role of Key Genes of Ferroptosis in Pan-Cancer. Front. Cell Dev. Biol. 2021, 9, 748925. [Google Scholar] [CrossRef]
  39. Jin, Z.; El-Deiry, W.S. Overview of Cell Death Signaling Pathways. Cancer Biol. Ther. 2005, 4, 139–163. [Google Scholar] [CrossRef] [Green Version]
  40. Elmore, S. Apoptosis: A Review of Programmed Cell Death. Toxicol. Pathol. 2007, 35, 495. [Google Scholar] [CrossRef]
  41. Herceg, Z.; Wang, Z.-Q. Functions of Poly(ADP-Ribose) Polymerase (PARP) in DNA Repair, Genomic Integrity and Cell Death. Mutat. Res. Fundam. Mol. Mech. Mutagenesis 2001, 477, 97–110. [Google Scholar] [CrossRef]
  42. Wu, X.Y.; Zhang, Y.L.; Xia, H.L.; Guan, Z.M.; Liu, Z.Y.; Wang, W.X.; Liu, Y. LIMK1 Attenuates Sevoflurane-Induced Neurodevelopmental Toxicity through Caspase-3/ Cofilin/PARP-1 Pathway. J. Biol. Regul. Homeost. Agents 2020, 34, 1923–1928. [Google Scholar] [CrossRef] [PubMed]
  43. Zhou, M.; Liu, X.; Li, Z.; Huang, Q.; Li, F.; Li, C.-Y. Caspase-3 Regulates the Migration, Invasion and Metastasis of Colon Cancer Cells. Int. J. Cancer 2018, 143, 921–930. [Google Scholar] [CrossRef] [PubMed]
  44. Carneiro, B.A.; El-Deiry, W.S. Targeting Apoptosis in Cancer Therapy. Nat. Rev. Clin. Oncol. 2020, 17, 395–417. [Google Scholar] [CrossRef] [PubMed]
  45. Li, Y.-J.; Lei, Y.-H.; Yao, N.; Wang, C.-R.; Hu, N.; Ye, W.-C.; Zhang, D.-M.; Chen, Z.-S. Autophagy and Multidrug Resistance in Cancer. Chin. J. Cancer 2017, 36, 52. [Google Scholar] [CrossRef]
  46. Wang, X.; Simpson, E.R.; Brown, K.A. P53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis. Cancer Res. 2015, 75, 5001–5007. [Google Scholar] [CrossRef] [Green Version]
  47. Bedi, A.; Barber, J.P.; Bedi, G.C.; el-Deiry, W.S.; Sidransky, D.; Vala, M.S.; Akhtar, A.J.; Hilton, J.; Jones, R.J. BCR-ABL-Mediated Inhibition of Apoptosis with Delay of G2/M Transition after DNA Damage: A Mechanism of Resistance to Multiple Anticancer Agents. Blood 1995, 86, 1148–1158. [Google Scholar] [CrossRef] [Green Version]
  48. Mohammad, R.M.; Muqbil, I.; Lowe, L.; Yedjou, C.; Hsu, H.-Y.; Lin, L.-T.; Siegelin, M.D.; Fimognari, C.; Kumar, N.B.; Dou, Q.P.; et al. Broad Targeting of Resistance to Apoptosis in Cancer. Semin. Cancer Biol. 2015, 35, S78. [Google Scholar] [CrossRef]
  49. Hassannia, B.; Vandenabeele, P.; Vanden Berghe, T. Targeting Ferroptosis to Iron Out Cancer. Cancer Cell 2019, 35, 830–849. [Google Scholar] [CrossRef]
  50. Ma, S.; Henson, E.S.; Chen, Y.; Gibson, S.B. Ferroptosis Is Induced Following Siramesine and Lapatinib Treatment of Breast Cancer Cells. Cell Death Dis. 2016, 7, e2307. [Google Scholar] [CrossRef] [Green Version]
  51. Woo, S.M.; Seo, S.U.; Min, K.; Im, S.-S.; Nam, J.-O.; Chang, J.-S.; Kim, S.; Park, J.-W.; Kwon, T.K. Corosolic Acid Induces Non-Apoptotic Cell Death through Generation of Lipid Reactive Oxygen Species Production in Human Renal Carcinoma Caki Cells. Int. J. Mol. Sci. 2018, 19, 1309. [Google Scholar] [CrossRef] [Green Version]
  52. Eling, N.; Reuter, L.; Hazin, J.; Hamacher-Brady, A.; Brady, N.R. Identification of Artesunate as a Specific Activator of Ferroptosis in Pancreatic Cancer Cells. Oncoscience 2015, 2, 517–532. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Nie, J.; Lin, B.; Zhou, M.; Wu, L.; Zheng, T. Role of Ferroptosis in Hepatocellular Carcinoma. J. Cancer Res. Clin. Oncol. 2018, 144, 2329–2337. [Google Scholar] [CrossRef] [PubMed]
  54. Yi, R.; Wang, H.; Deng, C.; Wang, X.; Yao, L.; Niu, W.; Fei, M.; Zhaba, W. Dihydroartemisinin Initiates Ferroptosis in Glioblastoma through GPX4 Inhibition. Biosci. Rep. 2020, 40, BSR20193314. [Google Scholar] [CrossRef] [PubMed]
  55. Yang, W.S.; Stockwell, B.R. Synthetic Lethal Screening Identifies Compounds Activating Iron-Dependent, Nonapoptotic Cell Death in Oncogenic-RAS-Harboring Cancer Cells. Chem. Biol. 2008, 15, 234. [Google Scholar] [CrossRef] [Green Version]
  56. Yagoda, N.; von Rechenberg, M.; Zaganjor, E.; Bauer, A.J.; Yang, W.S.; Fridman, D.J.; Wolpaw, A.J.; Smukste, I.; Peltier, J.M.; Boniface, J.J.; et al. RAS–RAF–MEK-Dependent Oxidative Cell Death Involving Voltage-Dependent Anion Channels. Nature 2007, 447, 864. [Google Scholar] [CrossRef] [Green Version]
  57. Zhang, Y.; Kong, Y.; Ma, Y.; Ni, S.; Wikerholmen, T.; Xi, K.; Zhao, F.; Zhao, Z.; Wang, J.; Huang, B.; et al. Loss of COPZ1 Induces NCOA4 Mediated Autophagy and Ferroptosis in Glioblastoma Cell Lines. Oncogene 2021, 40, 1425–1439. [Google Scholar] [CrossRef]
  58. Fan, Z.; Wirth, A.-K.; Chen, D.; Wruck, C.J.; Rauh, M.; Buchfelder, M.; Savaskan, N. Nrf2-Keap1 Pathway Promotes Cell Proliferation and Diminishes Ferroptosis. Oncogenesis 2017, 6, e371. [Google Scholar] [CrossRef] [Green Version]
  59. Yuan, F.; Sun, Q.; Zhang, S.; Ye, L.; Xu, Y.; Xu, Z.; Liu, B.; Zhang, S.; Chen, Q. HSP27 Protects against Ferroptosis of Glioblastoma Cells. Hum. Cell 2021, 35, 238–249. [Google Scholar] [CrossRef]
  60. Qiu, C.; Zhang, X.; Huang, B.; Wang, S.; Zhou, W.; Li, C.; Li, X.; Wang, J.; Yang, N. Disulfiram, a Ferroptosis Inducer, Triggers Lysosomal Membrane Permeabilization by Up-Regulating ROS in Glioblastoma. Onco. Targets Ther. 2020, 13, 10631–10640. [Google Scholar] [CrossRef]
  61. Wen, J.; Chen, H.; Ren, Z.; Zhang, P.; Chen, J.; Jiang, S. Ultrasmall Iron Oxide Nanoparticles Induced Ferroptosis via Beclin1/ATG5-Dependent Autophagy Pathway. Nano. Converg. 2021, 8, 10. [Google Scholar] [CrossRef]
  62. Chen, Q.; Wang, W.; Wu, Z.; Chen, S.; Chen, X.; Zhuang, S.; Song, G.; Lv, Y.; Lin, Y. Over-Expression of LncRNA TMEM161B-AS1 Promotes the Malignant Biological Behavior of Glioma Cells and the Resistance to Temozolomide via up-Regulating the Expression of Multiple Ferroptosis-Related Genes by Sponging Hsa-MiR-27a-3p. Cell Death Discov. 2021, 7, 311. [Google Scholar] [CrossRef] [PubMed]
  63. Zhang, Y.; Fu, X.; Jia, J.; Wikerholmen, T.; Xi, K.; Kong, Y.; Wang, J.; Chen, H.; Ma, Y.; Li, Z.; et al. Glioblastoma Therapy Using Codelivery of Cisplatin and Glutathione Peroxidase Targeting SiRNA from Iron Oxide Nanoparticles. ACS Appl. Mater. Interfaces 2020, 12, 43408–43421. [Google Scholar] [CrossRef] [PubMed]
  64. Buccarelli, M.; Marconi, M.; Pacioni, S.; De Pascalis, I.; D’Alessandris, Q.G.; Martini, M.; Ascione, B.; Malorni, W.; Larocca, L.M.; Pallini, R.; et al. Inhibition of Autophagy Increases Susceptibility of Glioblastoma Stem Cells to Temozolomide by Igniting Ferroptosis. Cell Death Dis. 2018, 9, 841. [Google Scholar] [CrossRef] [PubMed]
  65. Zhang, X.; Guo, Y.; Li, H.; Han, L. FIN56, a Novel Ferroptosis Inducer, Triggers Lysosomal Membrane Permeabilization in a TFEB-Dependent Manner in Glioblastoma. J. Cancer 2021, 12, 6610–6619. [Google Scholar] [CrossRef]
  66. Deng, S.; Zheng, Y.; Mo, Y.; Xu, X.; Li, Y.; Zhang, Y.; Liu, J.; Chen, J.; Tian, Y.; Ke, Y. Ferroptosis Suppressive Genes Correlate with Immunosuppression in Glioblastoma. World Neurosurg. 2021, 152, e436–e448. [Google Scholar] [CrossRef]
  67. Sun, Y.; Chen, P.; Zhai, B.; Zhang, M.; Xiang, Y.; Fang, J.; Xu, S.; Gao, Y.; Chen, X.; Sui, X.; et al. The Emerging Role of Ferroptosis in Inflammation. Biomed. Pharmacother. 2020, 127, 110108. [Google Scholar] [CrossRef]
  68. Wu, J.; Wang, Y.; Jiang, R.; Xue, R.; Yin, X.; Wu, M.; Meng, Q. Ferroptosis in Liver Disease: New Insights into Disease Mechanisms. Cell Death Discov. 2021, 7, 276. [Google Scholar] [CrossRef]
  69. Li, Y.; Feng, D.; Wang, Z.; Zhao, Y.; Sun, R.; Tian, D.; Liu, D.; Zhang, F.; Ning, S.; Yao, J.; et al. Ischemia-Induced ACSL4 Activation Contributes to Ferroptosis-Mediated Tissue Injury in Intestinal Ischemia/Reperfusion. Cell Death Differ. 2019, 26, 2284–2299. [Google Scholar] [CrossRef] [Green Version]
  70. Proneth, B.; Conrad, M. Ferroptosis and Necroinflammation, a yet Poorly Explored Link. Cell Death Differ. 2019, 26, 14–24. [Google Scholar] [CrossRef] [Green Version]
  71. Reichert, C.O.; de Freitas, F.A.; Sampaio-Silva, J.; Rokita-Rosa, L.; Barros, P.d.L.; Levy, D.; Bydlowski, S.P. Ferroptosis Mechanisms Involved in Neurodegenerative Diseases. Int. J. Mol. Sci. 2020, 21, 8765. [Google Scholar] [CrossRef]
  72. Park, K.-J.J.; Kim, J.; Testoff, T.; Adams, J.; Poklar, M.; Zborowski, M.; Venere, M.; Chalmers, J.J. Quantitative Characterization of the Regulation of Iron Metabolism in Glioblastoma Stem-like Cells Using Magnetophoresis. Biotechnol. Bioeng. 2019, 116, 1644–1655. [Google Scholar] [CrossRef]
  73. Legendre, C.; Garcion, E. Iron Metabolism: A Double-Edged Sword in the Resistance of Glioblastoma to Therapies. Trends Endocrinol. Metab. 2015, 26, 322–331. [Google Scholar] [CrossRef] [PubMed]
  74. Hänninen, M.M.; Haapasalo, J.; Haapasalo, H.; Fleming, R.E.; Britton, R.S.; Bacon, B.R.; Parkkila, S. Expression of Iron-Related Genes in Human Brain and Brain Tumors. BMC Neurosci. 2009, 10, 36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Voth, B.; Nagasawa, D.T.; Pelargos, P.E.; Chung, L.K.; Ung, N.; Gopen, Q.; Tenn, S.; Kamei, D.T.; Yang, I. Transferrin Receptors and Glioblastoma Multiforme: Current Findings and Potential for Treatment. J. Clin. Neurosci. 2015, 22, 1071–1076. [Google Scholar] [CrossRef] [PubMed]
  76. Recht, L.; Torres, C.O.; Smith, T.W.; Raso, V.; Griffin, T.W. Transferrin Receptor in Normal and Neoplastic Brain Tissue: Implications for Brain-Tumor Immunotherapy. J. Neurosurg. 1990, 72, 941–945. [Google Scholar] [CrossRef]
  77. Calzolari, A.; Larocca, L.M.; Deaglio, S.; Finisguerra, V.; Boe, A.; Raggi, C.; Ricci-Vitani, L.; Pierconti, F.; Malavasi, F.; Maria, R.D.; et al. Transferrin Receptor 2 Is Frequently and Highly Expressed in Glioblastomas. Transl. Oncol. 2010, 3, 123. [Google Scholar] [CrossRef] [Green Version]
  78. Ohgami, R.S.; Campagna, D.R.; McDonald, A.; Fleming, M.D. The Steap Proteins Are Metalloreductases. Blood 2006, 108, 1388. [Google Scholar] [CrossRef]
  79. Zhang, F.; Tao, Y.; Zhang, Z.; Guo, X.; An, P.; Shen, Y.; Wu, Q.; Yu, Y.; Wang, F. Metalloreductase Steap3 Coordinates the Regulation of Iron Homeostasis and Inflammatory Responses. Haematologica 2012, 97, 1826. [Google Scholar] [CrossRef]
  80. Li, P.-L.; Liu, H.; Chen, G.-P.; Li, L.; Shi, H.-J.; Nie, H.-Y.; Liu, Z.; Hu, Y.-F.; Yang, J.; Zhang, P.; et al. STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) Inhibits Pathological Cardiac Hypertrophy. Hypertension 2020, 76, 1219–1230. [Google Scholar] [CrossRef]
  81. Chen, H.; Xu, C.; Yu, Q.; Zhong, C.; Peng, Y.; Chen, J.; Chen, G. Comprehensive Landscape of STEAP Family Functions and Prognostic Prediction Value in Glioblastoma. J. Cell Physiol. 2021, 236, 2988–3000. [Google Scholar] [CrossRef] [PubMed]
  82. Xiao, D.; Zhou, Y.; Wang, X.; Zhao, H.; Nie, C.; Jiang, X. A Ferroptosis-Related Prognostic Risk Score Model to Predict Clinical Significance and Immunogenic Characteristics in Glioblastoma Multiforme. Oxid. Med. Cell Longev. 2021, 2021, 9107857. [Google Scholar] [CrossRef] [PubMed]
  83. Han, M.; Xu, R.; Wang, S.; Yang, N.; Ni, S.; Zhang, Q.; Xu, Y.; Zhang, X.; Zhang, C.; Wei, Y.; et al. Six-Transmembrane Epithelial Antigen of Prostate 3 Predicts Poor Prognosis and Promotes Glioblastoma Growth and Invasion. Neoplasia 2018, 20, 543–554. [Google Scholar] [CrossRef] [PubMed]
  84. Ingrassia, R.; Garavaglia, B.; Memo, M. DMT1 Expression and Iron Levels at the Crossroads Between Aging and Neurodegeneration. Front. Neurosci. 2019, 13, 575. [Google Scholar] [CrossRef] [Green Version]
  85. Yang, C.; Xia, Z.; Li, T.; Chen, Y.; Zhao, M.; Sun, Y.; Ma, J.; Wu, Y.; Wang, X.; Wang, P.; et al. Antioxidant Effect of Propofol in Gliomas and Its Association With Divalent Metal Transporter 1. Front. Oncol. 2020, 10, 590931. [Google Scholar] [CrossRef] [PubMed]
  86. Song, Q.; Peng, S.; Sun, Z.; Heng, X.; Zhu, X. Temozolomide Drives Ferroptosis via a DMT1-Dependent Pathway in Glioblastoma Cells. Yonsei Med. J. 2021, 62, 843–849. [Google Scholar] [CrossRef]
  87. Han, W.; Xin, Z.; Zhao, Z.; Bao, W.; Lin, X.; Yin, B.; Zhao, J.; Yuan, J.; Qiang, B.; Peng, X. RNA-Binding Protein PCBP2 Modulates Glioma Growth by Regulating FHL3. J. Clin. Invest. 2013, 123, 2103–2118. [Google Scholar] [CrossRef]
  88. Tang, S.-L.; Gao, Y.-L.; Chen, X.-B. MicroRNA-214 Targets PCBP2 to Suppress the Proliferation and Growth of Glioma Cells. Int. J. Clin. Exp. Pathol. 2015, 8, 12571. [Google Scholar]
  89. Alkhateeb, A.A.; Connor, J.R. The Significance of Ferritin in Cancer: Anti-Oxidation, Inflammation and Tumorigenesis. Biochim. Biophys. Acta Rev. Cancer 2013, 1836, 245–254. [Google Scholar] [CrossRef]
  90. Sato, Y.; Sato, Y.; Hayashi, T.; Shojima, K.; Kaji, M. Cerebrospinal Fluid Ferritin in Patients with Central Nervous System Tumors. Kurume Med. J. 1985, 32, 229–235. [Google Scholar] [CrossRef] [Green Version]
  91. Hayashima, K.; Kimura, I.; Katoh, H. Role of Ferritinophagy in Cystine Deprivation-Induced Cell Death in Glioblastoma Cells. Biochem. Biophys. Res. Commun. 2021, 539, 56–63. [Google Scholar] [CrossRef] [PubMed]
  92. Koppula, P.; Zhuang, L.; Gan, B. Cystine Transporter SLC7A11/XCT in Cancer: Ferroptosis, Nutrient Dependency, and Cancer Therapy. Protein Cell 2021, 12, 599–620. [Google Scholar] [CrossRef] [PubMed]
  93. Hu, N.; Hu, W.-H.; Zhou, S.-L.; Yang, Z.; Liang, W.-L.; Yang, R.-Y.; Li, M.-H.; Jing, Z.; Li, Z.-A.; Fu, X.-D.; et al. SLC7A11 Negatively Associates with Mismatch Repair Gene Expression and Endows Glioblastoma Cells Sensitive to Radiation under Low Glucose Conditions. Neoplasma 2021, 68, 1147–1156. [Google Scholar] [CrossRef] [PubMed]
  94. Takeuchi, S.; Wada, K.; Toyooka, T.; Shinomiya, N.; Shimazaki, H.; Nakanishi, K.; Nagatani, K.; Otani, N.; Osada, H.; Uozumi, Y.; et al. Increased XCT Expression Correlates with Tumor Invasion and Outcome in Patients with Glioblastomas. Neurosurgery 2013, 72, 33–41. [Google Scholar] [CrossRef] [PubMed]
  95. Zhang, Y.; Dube, C.; Gibert, M., Jr.; Cruickshanks, N.; Wang, B.; Coughlan, M.; Yang, Y.; Setiady, I.; Deveau, C.; Saoud, K.; et al. The P53 Pathway in Glioblastoma. Cancers 2018, 10, 297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Umans, R.A.; Martin, J.; Harrigan, M.E.; Patel, D.C.; Chaunsali, L.; Roshandel, A.; Iyer, K.; Powell, M.D.; Oestreich, K.; Sontheimer, H. Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme. Cancers 2021, 13, 6169. [Google Scholar] [CrossRef] [PubMed]
  97. Yamaguchi, I.; Yoshimura, S.H.; Katoh, H. High Cell Density Increases Glioblastoma Cell Viability under Glucose Deprivation via Degradation of the Cystine/Glutamate Transporter XCT (SLC7A11). J. Biol. Chem. 2020, 295, 6936–6945. [Google Scholar] [CrossRef] [Green Version]
  98. Yamamoto, M.; Teramoto, K.; Katoh, H. Epidermal Growth Factor Promotes Glioblastoma Cell Death under Glucose Deprivation via Upregulation of XCT (SLC7A11). Cell. Signal. 2021, 78, 109874. [Google Scholar] [CrossRef]
  99. Goji, T.; Takahara, K.; Negishi, M.; Katoh, H. Cystine Uptake through the Cystine/Glutamate Antiporter XCT Triggers Glioblastoma Cell Death under Glucose Deprivation. J. Biol. Chem. 2017, 292, 19721–19732. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Teramoto, K.; Katoh, H. The Cystine/Glutamate Antiporter XCT Is a Key Regulator of EphA2 S897 Phosphorylation under Glucose-Limited Conditions. Cell Signal 2019, 62, 109329. [Google Scholar] [CrossRef]
  101. Koppula, P.; Zhang, Y.; Zhuang, L.; Gan, B. Amino Acid Transporter SLC7A11/XCT at the Crossroads of Regulating Redox Homeostasis and Nutrient Dependency of Cancer. Cancer Commun. 2018, 38, 12–13. [Google Scholar] [CrossRef] [Green Version]
  102. Polewski, M.D.; Reveron-Thornton, R.F.; Cherryholmes, G.A.; Marinov, G.K.; Cassady, K.; Aboody, K.S. Increased Expression of System Xc- in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance. Mol. Cancer Res. 2016, 14, 1229–1242. [Google Scholar] [CrossRef] [Green Version]
  103. Lang, X.; Green, M.D.; Wang, W.; Yu, J.; Choi, J.E.; Jiang, L.; Liao, P.; Zhou, J.; Zhang, Q.; Dow, A.; et al. Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11. Cancer Discov. 2019, 9, 1673–1685. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Lei, G.; Zhang, Y.; Koppula, P.; Liu, X.; Zhang, J.; Lin, S.H.; Ajani, J.A.; Xiao, Q.; Liao, Z.; Wang, H.; et al. The Role of Ferroptosis in Ionizing Radiation-Induced Cell Death and Tumor Suppression. Cell Res. 2020, 30, 146. [Google Scholar] [CrossRef] [PubMed]
  105. Wang, W.; Green, M.; Choi, J.E.; Gijón, M.; Kennedy, P.D.; Johnson, J.K.; Liao, P.; Lang, X.; Kryczek, I.; Sell, A.; et al. CD8+ T Cells Regulate Tumor Ferroptosis during Cancer Immunotherapy. Nature 2019, 569, 270. [Google Scholar] [CrossRef] [PubMed]
  106. Sleire, L.; Skeie, B.S.; Netland, I.A.; Førde, H.E.; Dodoo, E.; Selheim, F.; Leiss, L.; Heggdal, J.I.; Pedersen, P.-H.; Wang, J.; et al. Drug Repurposing: Sulfasalazine Sensitizes Gliomas to Gamma Knife Radiosurgery by Blocking Cystine Uptake through System Xc-, Leading to Glutathione Depletion. Oncogene 2015, 34, 5951–5959. [Google Scholar] [CrossRef]
  107. Garcia, C.G.; Kahn, S.A.; Geraldo, L.H.M.; Romano, I.; Domith, I.; Silva, D.C.L.E.; Dos Santos Assunção, F.; Ferreira, M.J.; Portugal, C.C.; de Souza, J.M.; et al. Combination Therapy with Sulfasalazine and Valproic Acid Promotes Human Glioblastoma Cell Death Through Imbalance of the Intracellular Oxidative Response. Mol. Neurobiol. 2018, 55, 6816–6833. [Google Scholar] [CrossRef]
  108. Ignarro, R.S.; Facchini, G.; Vieira, A.S.; De Melo, D.R.; Lopes-Cendes, I.; Castilho, R.F.; Rogerio, F. Sulfasalazine Intensifies Temozolomide Cytotoxicity in Human Glioblastoma Cells. Mol. Cell Biochem. 2016, 418, 167–178. [Google Scholar] [CrossRef]
  109. Chen, L.; Li, X.; Liu, L.; Yu, B.; Xue, Y.; Liu, Y. Erastin Sensitizes Glioblastoma Cells to Temozolomide by Restraining XCT and Cystathionine-γ-Lyase Function. Oncol. Rep. 2015, 33, 1465–1474. [Google Scholar] [CrossRef] [Green Version]
  110. Takeuchi, S.; Wada, K.; Nagatani, K.; Otani, N.; Osada, H.; Nawashiro, H. Sulfasalazine and Temozolomide with Radiation Therapy for Newly Diagnosed Glioblastoma. Neurol. India 2014, 62, 42–47. [Google Scholar] [CrossRef]
  111. Nehser, M.; Dark, J.; Schweitzer, D.; Campbell, M.; Zwicker, J.; Hitt, D.M.; Little, H.; Diaz-Correa, A.; Holley, D.C.; Patel, S.A.; et al. System Xc- Antiporter Inhibitors: Azo-Linked Amino-Naphthyl-Sulfonate Analogues of Sulfasalazine. Neurochem. Res. 2020, 45, 1375–1386. [Google Scholar] [CrossRef] [PubMed]
  112. Polewski, M.D.; Reveron-Thornton, R.F.; Cherryholmes, G.A.; Marinov, G.K.; Aboody, K.S. SLC7A11 Overexpression in Glioblastoma Is Associated with Increased Cancer Stem Cell-Like Properties. Stem Cells Dev. 2017, 26, 1236–1246. [Google Scholar] [CrossRef] [PubMed]
  113. Koch, K.; Hartmann, R.; Suwala, A.K.; Rios, D.H.; Kamp, M.A.; Sabel, M.; Steiger, H.-J.; Willbold, D.; Sharma, A.; Kahlert, U.D.; et al. Overexpression of Cystine/Glutamate Antiporter XCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs). Cancers 2021, 13, 6001. [Google Scholar] [CrossRef] [PubMed]
  114. Singer, E.; Judkins, J.; Salomonis, N.; Matlaf, L.; Soteropoulos, P.; McAllister, S.; Soroceanu, L. Reactive Oxygen Species-Mediated Therapeutic Response and Resistance in Glioblastoma. Cell Death Dis. 2015, 6, e1601. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Küch, E.-M.; Vellaramkalayil, R.; Zhang, I.; Lehnen, D.; Brügger, B.; Stremmel, W.; Ehehalt, R.; Poppelreuther, M.; Füllekrug, J. Differentially Localized Acyl-CoA Synthetase 4 Isoenzymes Mediate the Metabolic Channeling of Fatty Acids towards Phosphatidylinositol. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2014, 1841, 227–239. [Google Scholar] [CrossRef] [PubMed]
  116. Aldape, K.; Zadeh, G.; Mansouri, S.; Reifenberger, G.; von Deimling, A. Glioblastoma: Pathology, Molecular Mechanisms and Markers. Acta Neuropathol. 2015, 129, 829–848. [Google Scholar] [CrossRef]
  117. Yee, P.P.; Wei, Y.; Kim, S.-Y.; Lu, T.; Chih, S.Y.; Lawson, C.; Tang, M.; Liu, Z.; Anderson, B.; Thamburaj, K.; et al. Neutrophil-Induced Ferroptosis Promotes Tumor Necrosis in Glioblastoma Progression. Nat. Commun. 2020, 11, 5424. [Google Scholar] [CrossRef]
  118. Bao, C.; Zhang, J.; Xian, S.-Y.; Chen, F. MicroRNA-670-3p Suppresses Ferroptosis of Human Glioblastoma Cells through Targeting ACSL4. Free Radic. Res. 2021, 55, 853–864. [Google Scholar] [CrossRef]
  119. Mashima, R.; Okuyama, T. The Role of Lipoxygenases in Pathophysiology; New Insights and Future Perspectives. Redox Biol. 2015, 6, 297. [Google Scholar] [CrossRef] [Green Version]
  120. Yang, W.S.; Kim, K.J.; Gaschler, M.M.; Patel, M.; Shchepinov, M.S.; Stockwell, B.R. Peroxidation of Polyunsaturated Fatty Acids by Lipoxygenases Drives Ferroptosis. Proc. Natl. Acad. Sci. USA 2016, 113, E4966. [Google Scholar] [CrossRef] [Green Version]
  121. Zuo, X.; Morris, J.S.; Broaddus, R.; Shureiqi, I. 15-LOX-1 Transcription Suppression via the NuRD Complex in Colon Cancer Cells. Oncogene 2009, 28, 1496. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Wolff, C.; Zoschke, C.; Kalangi, S.K.; Reddanna, P.; Schäfer-Korting, M. Tumor Microenvironment Determines Drug Efficacy in Vitro—Apoptotic and Anti-Inflammatory Effects of 15-Lipoxygenase Metabolite, 13-HpOTrE. Eur. J. Pharm. Biopharm. 2019, 142, 1–7. [Google Scholar] [CrossRef] [PubMed]
  123. Clemente, S.M.; Martínez-Costa, O.H.; Monsalve, M.; Samhan-Arias, A.K. Targeting Lipid Peroxidation for Cancer Treatment. Molecules 2020, 25, 5144. [Google Scholar] [CrossRef] [PubMed]
  124. Orafaie, A.; Matin, M.M.; Sadeghian, H. The Importance of 15-Lipoxygenase Inhibitors in Cancer Treatment. Cancer Metastasis Rev. 2018, 37, 397–408. [Google Scholar] [CrossRef] [PubMed]
  125. Hsi, L.C.; Kundu, S.; Palomo, J.; Xu, B.; Ficco, R.; Vogelbaum, M.A.; Cathcart, M.K. Silencing IL-13Rα2 Promotes Glioblastoma Cell Death via Endogenous Signaling. Mol. Cancer Ther. 2011, 10, 1149–1160. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Rezaei, O.; Honarmand, K.; Nateghinia, S.; Taheri, M.; Ghafouri-Fard, S. MiRNA Signature in Glioblastoma: Potential Biomarkers and Therapeutic Targets. Exp. Mol. Pathol. 2020, 117, 104550. [Google Scholar] [CrossRef] [PubMed]
  127. Song, Y.; Wang, P.; Zhao, W.; Yao, Y.; Liu, X.; Ma, J.; Xue, Y.; Liu, Y. MiR-18a Regulates the Proliferation, Migration and Invasion of Human Glioblastoma Cell by Targeting Neogenin. Exp. Cell Res. 2014, 324, 54–64. [Google Scholar] [CrossRef]
  128. Yang, X.; Liu, J.; Wang, C.; Cheng, K.K.-Y.; Xu, H.; Li, Q.; Hua, T.; Jiang, X.; Sheng, L.; Mao, J.; et al. MiR-18a Promotes Glioblastoma Development by down-Regulating ALOXE3-Mediated Ferroptotic and Anti-Migration Activities. Oncogenesis 2021, 10, 15. [Google Scholar] [CrossRef]
  129. Forcina, G.C.; Dixon, S.J. GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis. Proteomics 2019, 19, e1800311. [Google Scholar] [CrossRef]
  130. Yang, W.S.; SriRamaratnam, R.; Welsch, M.E.; Shimada, K.; Skouta, R.; Viswanathan, V.S.; Cheah, J.H.; Clemons, P.A.; Shamji, A.F.; Clish, C.B.; et al. Regulation of Ferroptotic Cancer Cell Death by GPX4. Cell 2014, 156, 317–331. [Google Scholar] [CrossRef] [Green Version]
  131. Li, S.; He, Y.; Chen, K.; Sun, J.; Zhang, L.; He, Y.; Yu, H.; Li, Q. RSL3 Drives Ferroptosis through NF-ΚB Pathway Activation and GPX4 Depletion in Glioblastoma. Oxid Med. Cell Longev. 2021, 2021, 2915019. [Google Scholar] [CrossRef]
  132. Seiler, A.; Schneider, M.; Förster, H.; Roth, S.; Wirth, E.K.; Culmsee, C.; Plesnila, N.; Kremmer, E.; Rådmark, O.; Wurst, W.; et al. Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12/15-Lipoxygenase Dependent- and AIF-Mediated Cell Death. Cell Metab. 2008, 8, 237–248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Schneider, M.; Wortmann, M.; Mandal, P.K.; Arpornchayanon, W.; Jannasch, K.; Alves, F.; Strieth, S.; Conrad, M.; Beck, H. Absence of Glutathione Peroxidase 4 Affects Tumor Angiogenesis through Increased 12/15-Lipoxygenase Activity. Neoplasia 2010, 12, 254. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Chen, J.; Chen, X.; Wang, F.; Gao, H.; Hu, W. Dihydroartemisinin Suppresses Glioma Proliferation and Invasion via Inhibition of the ADAM17 Pathway. Neurol. Sci. 2015, 36, 435–440. [Google Scholar] [CrossRef] [PubMed]
  135. Zhang, Z.-S.; Wang, J.; Shen, Y.-B.; Guo, C.-C.; Sai, K.; Chen, F.-R.; Mei, X.; Han, F.; Chen, Z.-P. Dihydroartemisinin Increases Temozolomide Efficacy in Glioma Cells by Inducing Autophagy. Oncol. Lett. 2015, 10, 379. [Google Scholar] [CrossRef] [PubMed]
  136. Chen, T.-C.; Chuang, J.-Y.; Ko, C.-Y.; Kao, T.-J.; Yang, P.-Y.; Yu, C.-H.; Liu, M.-S.; Hu, S.-L.; Tsai, Y.-T.; Chan, H.; et al. AR Ubiquitination Induced by the Curcumin Analog Suppresses Growth of Temozolomide-Resistant Glioblastoma through Disrupting GPX4-Mediated Redox Homeostasis. Redox Biol. 2020, 30, 101413. [Google Scholar] [CrossRef]
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Figure 1. The ferroptosis pathway. (A): the xCT-cysteine pathway; (B): the iron pathway; (C): the PUFA and lipid peroxidation pathway; (D): the GPX4 involvement. Abbreviations: ACSL4, long-chain-fatty-acid-CoA ligase 4; Cys, cysteine; DMT1, divalent metal transporter 1; Fe, iron; γ-GCS, γ-glutamylcysteine synthetase; γ-glutamylcys, γ-glutamylcysteine; Glu, glutamate; GPX4, glutathione peroxidase 4; GS, glutathione synthetase; GSH, glutathione; GSSG, glutathione disulphide; LOH, lipid alcohol; LOOH, lipid peroxide; LOX, lipoxygenase; LPCAT3, lysophosphatidylcholine acyltransferase 3; PE, phosphatidylethanolamine; PUFA, polyunsaturated fatty acids; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; STEAP3, six-transmembrane epithelial antigen of the prostate 3; TFR1, transferrin receptor 1; xCT, cystine/glutamate antiporter.
Figure 1. The ferroptosis pathway. (A): the xCT-cysteine pathway; (B): the iron pathway; (C): the PUFA and lipid peroxidation pathway; (D): the GPX4 involvement. Abbreviations: ACSL4, long-chain-fatty-acid-CoA ligase 4; Cys, cysteine; DMT1, divalent metal transporter 1; Fe, iron; γ-GCS, γ-glutamylcysteine synthetase; γ-glutamylcys, γ-glutamylcysteine; Glu, glutamate; GPX4, glutathione peroxidase 4; GS, glutathione synthetase; GSH, glutathione; GSSG, glutathione disulphide; LOH, lipid alcohol; LOOH, lipid peroxide; LOX, lipoxygenase; LPCAT3, lysophosphatidylcholine acyltransferase 3; PE, phosphatidylethanolamine; PUFA, polyunsaturated fatty acids; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; STEAP3, six-transmembrane epithelial antigen of the prostate 3; TFR1, transferrin receptor 1; xCT, cystine/glutamate antiporter.
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Figure 2. Ferroptosis modulation in glioblastoma. Abbreviations: DMT1, divalent metal transporter 1; GPX4, glutathione peroxidase 4; PCBP2, poly(rC)-binding protein 2; STEAP3, six-transmembrane epithelial antigen of the prostate 3; TFR, transferrin receptor; TMZ, temozolomide; xCT, cystine/glutamate antiporter.
Figure 2. Ferroptosis modulation in glioblastoma. Abbreviations: DMT1, divalent metal transporter 1; GPX4, glutathione peroxidase 4; PCBP2, poly(rC)-binding protein 2; STEAP3, six-transmembrane epithelial antigen of the prostate 3; TFR, transferrin receptor; TMZ, temozolomide; xCT, cystine/glutamate antiporter.
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Mitre, A.-O.; Florian, A.I.; Buruiana, A.; Boer, A.; Moldovan, I.; Soritau, O.; Florian, S.I.; Susman, S. Ferroptosis Involvement in Glioblastoma Treatment. Medicina 2022, 58, 319. https://doi.org/10.3390/medicina58020319

AMA Style

Mitre A-O, Florian AI, Buruiana A, Boer A, Moldovan I, Soritau O, Florian SI, Susman S. Ferroptosis Involvement in Glioblastoma Treatment. Medicina. 2022; 58(2):319. https://doi.org/10.3390/medicina58020319

Chicago/Turabian Style

Mitre, Andrei-Otto, Alexandru Ioan Florian, Andrei Buruiana, Armand Boer, Ioana Moldovan, Olga Soritau, Stefan Ioan Florian, and Sergiu Susman. 2022. "Ferroptosis Involvement in Glioblastoma Treatment" Medicina 58, no. 2: 319. https://doi.org/10.3390/medicina58020319

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