scholarly journals Metabolic Regulation of Ferroptosis in Cancer

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 83
Author(s):  
Min Ji Kim ◽  
Greg Jiho Yun ◽  
Sung Eun Kim
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Lipid Metabolism ◽  
Metabolic Pathways ◽  
Metabolic Regulation ◽  
Organ Damage ◽  
Cell Death Mechanism ◽  
Therapeutic Uses ◽  
Unique Cell ◽  
Excessive Accumulation

Ferroptosis is a unique cell death mechanism that is executed by the excessive accumulation of lipid peroxidation in cells. The relevance of ferroptosis in multiple human diseases such as neurodegeneration, organ damage, and cancer is becoming increasingly evident. As ferroptosis is deeply intertwined with metabolic pathways such as iron, cyst(e)ine, glutathione, and lipid metabolism, a better understanding of how ferroptosis is regulated by these pathways will enable the precise utilization or prevention of ferroptosis for therapeutic uses. In this review, we present an update of the mechanisms underlying diverse metabolic pathways that can regulate ferroptosis in cancer.

scholarly journals Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers

2019 ◽  
Vol 31 (2) ◽  
pp. 280-296 ◽  
Author(s):  
Eikan Mishima ◽  
Emiko Sato ◽  
Junya Ito ◽  
Ken-ichi Yamada ◽  
Chitose Suzuki ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cytochrome P450 ◽  
Liver Injury ◽  
Peroxyl Radical ◽  
Organ Damage ◽  
Peroxyl Radicals ◽  
Radical Scavengers ◽  
Lipid Peroxyl Radicals ◽  
Elevated Lipid

BackgroundFerroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation via obscure mechanisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals.MethodsUsing a cell-based assay, we screened cytochrome P450 substrate compounds to identify drugs with antiferroptotic activity and investigated the underlying mechanism. To evaluate radical-scavenging activity, we used electron paramagnetic resonance–spin trapping methods and a fluorescence probe for lipid radicals, NBD-Pen, that we had developed. We then assessed the therapeutic potency of these drugs in mouse models of cisplatin-induced AKI and LPS/galactosamine-induced liver injury.ResultsWe identified various US Food and Drug Administration–approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, propranolol, estradiol, and thyroid hormones. The antiferroptotic drug effects were closely associated with the scavenging of lipid peroxyl radicals but not significantly related to interactions with other radicals. The elevated lipid peroxyl radical levels were associated with ferroptosis onset, and known ferroptosis suppressors, such as ferrostatin-1, also functioned as lipid peroxyl radical scavengers. The drugs exerted antiferroptotic activities in various cell types, including tubules, podocytes, and renal fibroblasts. Moreover, in mice, the drugs ameliorated AKI and liver injury, with suppression of tissue lipid peroxidation and decreased cell death.ConclusionsAlthough elevated lipid peroxyl radical levels can trigger ferroptosis onset, some drugs that scavenge lipid peroxyl radicals can help control ferroptosis-related disorders, including AKI.

scholarly journals Anthracyclins increase free PUFAs and etherPEs with PUFAs as potential hallmarks of lipid peroxidation and ferroptosis

2021 ◽  
Author(s):  
David Balgoma ◽  
Fredrik Kullenberg ◽  
Carlemi Calitz ◽  
Maria Kopsida ◽  
Femke Heindryckx ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cell Lines ◽  
Metabolic Pathways ◽  
De Novo ◽  
Primary Liver Cancer ◽  
De Novo Lipogenesis ◽  
Liver Cancer Cell ◽  
The Individual ◽  
The Relationship

AbstractMetabolic and personalized interventions in cancer treatment require a better under-standing of the relationship between the induction of cell death and metabolism. Consequently, we treated three primary liver cancer cell lines with two anthracyclins (doxorubicin and idarubin) and studied the changes of the lipidome. We found that both anthracyclins in the three cell lines increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethano-lamines (etherPEs) with PUFAs. As PUFAs and alkylacylglycerophospholipids with PUFAs are fundamental in lipid peroxidation during ferroptotic cell death, our results suggests supplementa-tion with PUFAs and/or etherPEs with PUFAs as a potential general adjuvant of anthracyclins. In contrast, neither the markers of de novo lipogenesis nor cholesterol lipids presented the same trend in all cell lines and treatments. In agreement with previous research, this suggests that modulation of the metabolism of cholesterol could be considered a specific adjuvant of anthracyclins depend-ing on the type of tumor and the individual. Finally, we discuss the changes in the lipidome in re-lation to the endoplasmic reticulum stress and the sensitivity to anthracyclins of the different cells. In conclusion, our results suggest that the modulation of different lipid metabolic pathways may be considered for generalized and personalized metabochemotherapies.

scholarly journals Is Ferroptosis a Future Direction in Exploring Cryptococcal Meningitis?

2021 ◽  
Vol 12 ◽  
Author(s):  
Xianbin Xu ◽  
Danfeng Lin ◽  
Sheng Tu ◽  
Shiqi Gao ◽  
Anwen Shao ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cryptococcal Meningitis ◽  
Treatment Strategies ◽  
Therapeutic Strategies ◽  
Molecular Pattern ◽  
Immunodeficiency Virus ◽  
Future Direction ◽  
Unique Cell ◽  
The Brain

Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.

scholarly journals DDRE-23. A COMPREHENSIVE CHARACTERIZATION OF THE GBM LIPIDOME REVEALS A MOLECULARLY-DEFINED SUB-GROUP WITH HEIGHTENED SENSITIVITY TO LIPID PEROXIDATION INDUCED CELL DEATH

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i11-i11
Author(s):  
Danielle Morrow ◽  
Jenna Minami ◽  
Nicholas Bayley ◽  
Kevin Williams ◽  
Steven Bensinger ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Lipid Metabolism ◽  
Membrane Phospholipids ◽  
Molecular Alterations ◽  
Tumor Microenvironments ◽  
Novel Association ◽  
Therapeutic Opportunity

Abstract Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth and promote survival. However, the full extent to which lipid content is altered across molecularly heterogeneous patient tumors has yet to be fully elucidated. Additionally, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of an extensive library of molecularly diverse patient-derived GBM tumors across tumor microenvironments both in vivo (n=23) and in vitro (n=30). Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Triacylglycerides (TAGs) enriched in polyunsaturated fatty acids (PUFAs) were among the most significantly altered lipids between the two groups of GBM tumors. TAGs are the main components of lipid droplets, which have been shown to sequester PUFAs away from membrane phospholipids where their sensitivity to peroxidation leads to cell death. The GBM subgroup with a depletion of PUFA TAGs showed heightened sensitivity to lipid peroxidation both under basal conditions and in response to pro-oxidant compounds in vitro. Our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and lipid peroxidation-induced cell death. This relationship may present a new therapeutic opportunity to target reprogrammed lipid metabolism in a molecularly-defined subset of GBMs.

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