Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis

Belavgeni, Alexia; Bornstein, Stefan R.; Mäßenhausen, Anne von; Tonnus, Wulf; Stumpf, Julian; Meyer, Claudia; Othmar, Evelyn; Latk, Markus; Kanczkowski, Waldemar; Kroiß, Matthias; Hantel, Constanze; Hugo, Christian; Faßnacht, Martin; Ziegler, Christian; Schally, Andrew V.; Krone, Nils; Linkermann, Andreas

doi:10.1073/pnas.1912700116

Cited by 84 publications

(76 citation statements)

References 52 publications

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“…1k) and an increased sensitivity to RSL3 treatment (Fig. 2g), which is in line with a very recently published study 40 . NCI-H295R cells without Se, although more sensitive to RSL3, were still not as sensitive as CU-ACC2 cells (Fig.…”

Section: Discussionsupporting

confidence: 92%

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

et al. 2020

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Conditions of impaired adrenal function and tissue destruction, such as in Addison's disease, and treatment resistance of adrenocortical carcinoma (ACC) necessitate improved understanding of the pathophysiology of adrenal cell death. Due to relevant oxidative processes in the adrenal cortex, our study investigated the role of ferroptosis, an irondependent cell death mechanism and found high adrenocortical expression of glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4) genes, key factors in the initiation of ferroptosis. By applying MALDI mass spectrometry imaging to normal and neoplastic adrenocortical tissue, we detected high abundance of arachidonic and adrenic acid, two long chain polyunsaturated fatty acids which undergo peroxidation during ferroptosis. In three available adrenal cortex cell models (H295R, CU-ACC1 and CU-ACC-2) a high susceptibility to GPX4 inhibition with RSL3 was documented with EC 50 values of 5.7 × 10 −8 , 8.1 × 10 −7 and 2.1 × 10 −8 M, respectively, while all nonsteroidogenic cells were significantly less sensitive. Complete block of GPX4 activity by RSL3 led to ferroptosis which was completely reversed in adrenal cortex cells by inhibition of steroidogenesis with ketoconazole but not by blocking the final step of cortisol synthesis with metyrapone. Mitotane, the only approved drug for ACC did not induce ferroptosis, despite strong induction of lipid peroxidation in ACC cells. Together, this report is the first to demonstrate extraordinary sensitivity of adrenal cortex cells to ferroptosis dependent on their active steroid synthetic pathways. Mitotane does not induce this form of cell death in ACC cells.

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Section: Discussionsupporting

confidence: 92%

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

et al. 2020

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“…A study found that significant increases in the expression of GPX4 and sensitivity to ferroptosis in ACCs, suggesting that inducing ferroptosis may be a promising approach for the treatment of ACCs. In addition, ferroptosis inducers may be more effective and less toxic than mitotane in treating ACC patients 50 .…”

Section: Adrenocortical Carcinomas (Accs)mentioning

confidence: 99%

Ferroptosis: past, present and future

et al. 2020

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Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases. Facts Ferroptosis is a new type of programmed cell death, which occurs with iron dependence. Ferroptosis plays an important regulatory role in the occurrence and development of many diseases, such as tumors, neurological diseases, acute kidney injury, ischemia/reperfusion, etc. Activating or blocking the ferroptosis pathway to alleviate the progression of the disease, which provides a promising therapeutic strategy for many diseases. Open questions What is the relationship between ferroptosis and other types of cell death? Is it synergy or antagonism? Is iron necessary to promote the production of lipid peroxides, or can other substances take the place of iron in ferroptosis? What is the downstream regulation mechanism of iron in ferroptosis? How can ferroptosis promote the development of inflammation?

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“…The bmMSC control group displayed no green fluorescence (Figure 2A), suggesting no LPO accumulation. Similar to the control group, the positive control group (ferrostatin-1) [63,64] also showed negligible green fluorescence ( Figure 2C). This result indicates that LPO accumulation is effectively inhibited by ferrostatin-1-a widely used ferroptosis-inhibitor-by targeting LPO [10,63,64].…”

Section: Resultsmentioning

confidence: 65%

Inhibitory Effect and Mechanism of Action of Quercetin and Quercetin Diels-Alder anti-Dimer on Erastin-Induced Ferroptosis in Bone Marrow-Derived Mesenchymal Stem Cells

Zeng

Liu

et al. 2020

Antioxidants

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In this study, the anti-ferroptosis effects of catecholic flavonol quercetin and its metabolite quercetin Diels-Alder anti-dimer (QDAD) were studied using an erastin-treated bone marrow-derived mesenchymal stem cell (bmMSCs) model. Quercetin exhibited higher anti-ferroptosis levels than QDAD, as indicated by 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-undecanoic acid (C11-BODIPY), 2′,7′-dichlorodihydrofluoroscein diacetate (H2DCFDA), lactate dehydrogenase (LDH) release, cell counting kit-8 (CCK-8), and flow cytometric assays. To understand the possible pathways involved, the reaction product of quercetin with the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH●) was measured using ultra-performance liquid-chromatography coupled with electrospray-ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS). Quercetin was found to produce the same clusters of molecular ion peaks and fragments as standard QDAD. Furthermore, the antioxidant effects of quercetin and QDAD were compared by determining their 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide radical-scavenging, Cu2+-reducing, Fe3+-reducing, lipid peroxidation-scavenging, and DPPH●-scavenging activities. Quercetin consistently showed lower IC50 values than QDAD. These findings indicate that quercetin and QDAD can protect bmMSCs from erastin-induced ferroptosis, possibly through the antioxidant pathway. The antioxidant pathway can convert quercetin into QDAD—an inferior ferroptosis-inhibitor and antioxidant. The weakening has highlighted a rule for predicting the relative anti-ferroptosis and antioxidant effects of catecholic flavonols and their Diels-Alder dimer metabolites.

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Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis

Cited by 84 publications

References 52 publications

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

Ferroptosis: past, present and future

Inhibitory Effect and Mechanism of Action of Quercetin and Quercetin Diels-Alder anti-Dimer on Erastin-Induced Ferroptosis in Bone Marrow-Derived Mesenchymal Stem Cells

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