Ferroptosis and Its Potential Role in Glioma: From Molecular Mechanisms to Therapeutic Opportunities
Abstract
:1. Introduction
2. Molecular Mechanisms of Ferroptosis
2.1. Iron Metabolism
2.2. Lipid Metabolism
2.3. The xCT and GPX4
2.4. FSP1 and DHODH
3. Targeting Ferroptosis to Treat Glioma
3.1. Metabolic Pathway
3.2. The xCT Pathway
3.3. GPX4 Expression
3.4. Tumor Immune Microenvironment
4. Challenges of Ferroptosis in Glioma
5. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
•OH | Hydroxyl radicals |
15-LOX | 15-lipoxygenase |
15-LOX-1 | 15-lipoxygenase-1 |
AA | Arachidonic acid |
ACSL4 | Acyl–coenzyme A synthetase long-chain family 4 |
acyl-CoA | Acyl-coenzyme A |
AGEs | Advanced glycation end products |
ALOXE3 | Arachidonate lipoxygenase 3 |
AR | Androgen receptor |
ART | Artesunate |
ASAH2 | N-acylsphingosine aminohydrolase 2 |
ATG5 | Autophagy related 5 |
ATG7 | Autophagy related 7 |
ATP | Adenosine triphosphate |
BBB | Blood-brain barrier |
CDDO | 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid |
CMA | Chaperone-mediated autophagy |
CNS | Central nervous system |
CP | Ceruloplasmin |
Cys | Cysteine |
DHA | Dihydroartemisinin |
DHI | Dihydrotanshinone I |
DHODH | Dihydroorotate dehydrogenase |
DMT1 | Divalent metal transporter 1 |
ECM | Extracellular matrix |
Fe2+ | Ferrous cations |
Fe3+ | Ferric cations |
FTH1 | Ferritin heavy chain 1 |
FXR1 | Fragile-X mental retardation autosomal 1 |
GCL | Glutamate cysteine ligase |
GCS | Glutamylcysteine synthetase |
Glu | Glutamic acid |
Gly | Glycine |
GPX | Glutathione peroxidase |
GPX4 | Glutathione peroxidase 4 |
GSH | Glutathione |
GSSG | Glutathione disulfide |
H2O2 | Hydrogen per-oxide |
HMOX1 | P53-heme oxygenase 1 |
HP | Hephaestin |
HSP90 | Heat shock protein 90 |
HSPA5 | Heat shock protein family A member 5 |
IECs | Intestinal epithelium cells |
IL-13Rα2 | Interleukin receptor-13alpha2 |
IONPs | Iron oxide nanoparticles |
IREB2 | Iron responsive element binding protein 2 |
LOXs | Lipoxygenases |
LPC | Lysophosphatidylcholine |
LPCAT3 | Lysophosphatidylcholine acyltransferase 3 |
MDSCs) | Myeloid-derived suppressor cells |
MLKL | Mixed lineage kinase-like |
MTOR | Mammalian target of rapamycin |
NADPH | Nicotinamide adenine dinucleotide phosphate |
NCOA4 | Nuclear receptor coactivator 4 |
OS | Overall survival |
PCBP2 | Poly(C)-binding protein 2 |
PE-PUFA | Phosphatidylethanolamine polyunsaturated fatty acid |
PLOHs | Phospholipid alcohols |
PLOOHs | Phospholipid hydroperoxides |
PUFAs | Polyunsaturated fatty acids |
RCD | Regulated cell death |
ROS | Reactive oxygen species |
SLC3A2 | Solute carrier family 3 member 2 |
SLC7A11 | Solute carrier family 7 member 11 |
STEAP3 | 6-transmembrane epithelial antigen of the prostate 3 |
STING | Stimulator of interferon gene |
TAMs | Tumor-associated macrophages |
Tf | Transferrin |
Tfh | Follicular helper T cell |
TfR | Transferrin receptor |
TIME | Tumor immune microenvironment |
TMZ | Temozolomide |
Treg | Regulatory T |
VEGF | Vascular endothelial-derived growth factor |
WHO | World Health Organization |
xCT | Cysteine/glutathione antiporter system Xc− |
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Morphological Features | Biochemical Features | Common Inspection Indicators | ||
---|---|---|---|---|
Ferroptosis | cell membrane | plasma membrane integrity | Iron accumulation and lipid peroxidation | GSH, GPX4, MDA, SLC7A11, NRF2, ACSL4, FSP1,LPO |
Cell cytoplasm | small mitochondria and increased mitochondrial membrane densities | |||
Cell nucleus | no obvious alteration | |||
Apoptosis | Cell membrane | plasma membrane disruption, | DNA fragmentation | Caspase, Bcl-2, TUNEL,Annexin-V JC-1 |
Cell cytoplasm | cell volume reduction | |||
Cell nucleus | nuclear volume reduction chromatin agglutination | |||
Necroptosis | Cell membrane | plasma membrane disruption, | Drop in ATP levels | RIP1, RIP3 Calcein-AM |
Cell cytoplasm | generalized swelling of the cytoplasm and organelles | |||
Cell nucleus | oderate chromatin condensation and leakage of cellular constituents | |||
Autophagy | Cell membrane | no obvious alteration | Increased lysosomal activity | LC3, ATG family proteins(ATG5, ATG7) |
Cell cytoplasm | formation of double-membraned autolysosomes | |||
Cell nucleus | no chromatin agglutination |
Nanocarrier | Coating | Outcome | Reference |
---|---|---|---|
Cisplatin-Fe3O4 /Gd2O3 | LF + RGD dimer | Increased accumulation in tumor Released Fe2+ and Fe3+ | [160] |
Iron oxide | NIR-fluorescent silica | Visualized tumor-associated macrophage populations | [161] |
PEG | Doxorubicin | Increased drug diffusion across BBB | [162] |
PEtOz-SS-PCL micelle | Doxorubicin | Increased drug diffusion across BBB | [163] |
Liposome | Temozolomide | Enhanced antitumor activity | [164] |
OX26-PLGA | Temozolomide | Enhanced permeability Improved cellular uptake | [165] |
Fa-PEG-PCL | Luteolin | Prolonged survival time Enhanced antitumor activity | [166] |
Anti-miR-21-PLA | Temozolomide | Increased apoptotic cell death | [167] |
Transferrin-PEG-PLA | Resveratrol | Improved drug accumulation | [168] |
Albumin | Paclitaxel and fenretinide | Increased drug diffusion across BBB Increased survival rate | [169] |
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Luo, Y.; Tian, G.; Fang, X.; Bai, S.; Yuan, G.; Pan, Y. Ferroptosis and Its Potential Role in Glioma: From Molecular Mechanisms to Therapeutic Opportunities. Antioxidants 2022, 11, 2123. https://doi.org/10.3390/antiox11112123
Luo Y, Tian G, Fang X, Bai S, Yuan G, Pan Y. Ferroptosis and Its Potential Role in Glioma: From Molecular Mechanisms to Therapeutic Opportunities. Antioxidants. 2022; 11(11):2123. https://doi.org/10.3390/antiox11112123
Chicago/Turabian StyleLuo, Yusong, Guopeng Tian, Xiang Fang, Shengwei Bai, Guoqiang Yuan, and Yawen Pan. 2022. "Ferroptosis and Its Potential Role in Glioma: From Molecular Mechanisms to Therapeutic Opportunities" Antioxidants 11, no. 11: 2123. https://doi.org/10.3390/antiox11112123