scholarly journals SUN-211 Active Steroid Hormone Synthesis Renders Adrenocortical Cells Highly Susceptible to Type II Ferroptosis Induction

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Isabel Weigand ◽  
Jochen Schreiner ◽  
Florian Roehrig ◽  
Na Sun ◽  
Landwehr Laura-Sophie ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Treatment Options ◽  
Cortical Cell ◽  
Current Treatment ◽  
Adrenocortical Cells ◽  
Hormone Synthesis ◽  
Steroidogenic Cell ◽  
Coa Ligase ◽  
Dependent Form

Abstract Context: Cell death in the adrenal cortex is ill understood but of high clinical relevance. Resistance of adrenocortical carcinoma (ACC) to current treatment with mitotane and chemotherapy calls for an improved understanding of adrenal cortical cell death processes. Ferroptosis is an iron-dependent form of regulated cell death which is characterized by polyunsaturated lipids adrenic (AdA) and arachidonic acid (AA) peroxidation. Aim: To address the potential role of ferroptosis in the adrenal gland as a potential treatment target of ACC. Methods: Human ACC cells H295R, CU-ACC1 and 2 were used. Protein expression of key enzymes was determined by western blotting. Lipid peroxidation was quantified with BODIPY 581/591 and cell viability with CellTiterGlo after treatment with known inducers and inhibitors of ferroptosis and steroidogenesis, respectively. Results: Adrenocortical tissues are enriched in AdA and AA and express high levels of genes relevant to ferroptosis, such as glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4). Inhibition of GPX4 with RSL3 led to cell death in H295R, CU-ACC1 and 2 cells at EC50 values of 2.4x10-7, 8.1x10-7 and 1.5x10-8 M, respectively. The steroidogenesis inhibitor ketoconazole completely reversed RSL3 cytotoxicity in all three steroidogenic cell lines by reducing lipid peroxidation. Mitotane induced lipid peroxidation but inhibition of ferroptosis with liproxstatin did not protect mitotane-induced cell death. Conclusion: Adrenocortical cells are highly sensitive to ferroptosis due to active steroidogenesis. Triggering this form of cell death could present future novel treatment options against ACC.

scholarly journals Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ligia I. Bastea ◽  
Laeticia M. A. Hollant ◽  
Heike R. Döppler ◽  
Elizabeth M. Reid ◽  
Peter Storz
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Treatment Options ◽  
Histone H3 ◽  
Current Treatment ◽  
Cancer Cell Death ◽  
H3 Phosphorylation ◽  
Histone H3 Phosphorylation

Abstract Current treatment options for patients with pancreatic cancer are suboptimal, resulting in a five year survival rate of about 9%. Difficulties with treatment are due to an immunosuppressive, fibrotic tumor microenvironment that prevents drugs from reaching tumor cells, but also to the limited efficacy of existing FDA-approved chemotherapeutic compounds. We here show that the nucleoside analog Sangivamycin and its closely-related compound Toyocamycin target PDA cell lines, and are significantly more efficient than Gemcitabine. Using KINOMEscan screening, we identified the kinase Haspin, which is overexpressed in PDA cell lines and human PDA samples, as a main target for both compounds. Inhibition of Haspin leads to a decrease in Histone H3 phosphorylation and prevents Histone H3 binding to survivin, thus providing mechanistic insight of how Sangivamycin targets cell proliferation, mitosis and induces apoptotic cell death. In orthotopically implanted tumors in mice, Sangivamycin was efficient in decreasing the growth of established tumors. In summary, we show that Sangivamycin and derivatives can be an efficient new option for treatment of PDA.

scholarly journals Ferroptosis: the potential value target in atherosclerosis

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Siyu Ouyang ◽  
Jia You ◽  
Chenxi Zhi ◽  
Pin Li ◽  
Xiaoyan Lin ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Theoretical Basis ◽  
Vascular Endothelial Cells ◽  
Necrotic Core ◽  
Vascular Endothelial ◽  
Intracellular Iron ◽  
Future Studies ◽  
Dependent Form ◽  
Pathologic Processes

AbstractIn advanced atherosclerosis (AS), defective function-induced cell death leads to the formation of the characteristic necrotic core and vulnerable plaque. The forms and mechanisms of cell death in AS have recently been elucidated. Among them, ferroptosis, an iron-dependent form of necrosis that is characterized by oxidative damage to phospholipids, promotes AS by accelerating endothelial dysfunction in lipid peroxidation. Moreover, disordered intracellular iron causes damage to macrophages, vascular smooth muscle cells (VSMCs), vascular endothelial cells (VECs), and affects many risk factors or pathologic processes of AS such as disturbances in lipid peroxidation, oxidative stress, inflammation, and dyslipidemia. However, the mechanisms through which ferroptosis initiates the development and progression of AS have not been established. This review explains the possible correlations between AS and ferroptosis, and provides a reliable theoretical basis for future studies on its mechanism.

scholarly journals Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy

2022 ◽  
Vol 15 (1) ◽  
pp. 91
Author(s):  
Mike-Andrew Westhoff ◽  
Marie Schuler-Ortoli ◽  
Daniela Zerrinius ◽  
Amina Hadzalic ◽  
Andrea Schuster ◽  
...  
Keyword(s):  
Cell Death ◽  
Combination Therapy ◽  
Treatment Options ◽  
Cell Number ◽  
Current Treatment ◽  
Model Systems ◽  
Intrinsic Resistance ◽  
Therapeutic Benefits ◽  
Experimental Tumour ◽  
Sensitizing Effect

Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells’ intrinsic resistance to therapy-induced cell death should lead to less aggressive and more effective treatment options. In other tumour entities, this has been achieved by modulating the balance between the various pro- and anti-apoptotic members of the Bcl-2 family with small molecule inhibitors. To evaluate the therapeutic benefits of ABT-199 (Venetoclax), a Bcl-2 inhibitor, and ABT-263 (Navitoclax), a dual Bcl-XL/Bcl-2 inhibitor, increasingly more relevant model systems were investigated. Starting from established MB cell lines, progressing to primary patient-derived material and finally an experimental tumour system imbedded in an organic environment were chosen. Assessment of the metabolic activity (a surrogate readout for population viability), the induction of DNA fragmentation (apoptosis) and changes in cell number (the combined effect of alterations in proliferation and cell death induction) revealed that ABT-263, but not ABT-199, is a promising candidate for combination therapy, synergizing with cell death-inducing stimuli. Interestingly, in the experimental tumour setting, the sensitizing effect of ABT-263 seems to be predominantly mediated via an anti-proliferative and not a pro-apoptotic effect, opening a future line of investigation. Our data show that modulation of specific members of the Bcl-2 family might be a promising therapeutic addition for the treatment of MB.

Ferroptosis Is Regulated by Mitochondria in Neurodegenerative Diseases

2020 ◽  
Vol 20 (1) ◽  
pp. 20-34 ◽  
Author(s):  
Juepu Zhou ◽  
Yao Jin ◽  
Yuhong Lei ◽  
Tianyi Liu ◽  
Zheng Wan ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Iron Homeostasis ◽  
Cell Metabolism ◽  
Lipid Peroxide ◽  
Mitochondrial Damage ◽  
Mitochondrial Activity ◽  
Dependent Form

Background: Neurodegenerative diseases are characterized by a gradual decline in motor and/or cognitive function caused by the selective degeneration and loss of neurons in the central nervous system, but their pathological mechanism is still unclear. Previous research has revealed that many forms of cell death, such as apoptosis and necrosis, occur in neurodegenerative diseases. Research in recent years has noticed that there is a new type of cell death in neurodegenerative diseases: ferroptosis. An increasing body of literature provides evidence for an involvement of ferroptosis in neurodegenerative diseases. Summary: In this article, we review a new form of cell death in neurodegenerative diseases: ferroptosis. Ferroptosis is defined as an iron-dependent form of regulated cell death, which occurs through the lethal accumulation of lipid-based reactive oxygen species when glutathione-dependent lipid peroxide repair systems are compromised. Several salient and established features of neurodegenerative diseases (including lipid peroxidation and iron dyshomeostasis) are consistent with ferroptosis, which means that ferroptosis may be involved in the progression of neurodegenerative diseases. In addition, as the center of energy metabolism in cells, mitochondria are also closely related to the regulation of iron homeostasis in the nervous system. At the same time, neurodegenerative diseases are often accompanied by degeneration of mitochondrial activity. Mitochondrial damage has been found to be involved in lipid peroxidation and iron dyshomeostasis in neurodegenerative diseases. Key Messages: Based on the summary of the related mechanisms of ferroptosis, we conclude that mitochondrial damage may affect neurodegenerative diseases by regulating many aspects of ferroptosis, including cell metabolism, iron dyshomeostasis, and lipid peroxidation.

Theoretical insights into the mechanism of ferroptosis suppression via inactivation of a lipid peroxide radical by liproxstatin-1

2017 ◽  
Vol 19 (20) ◽  
pp. 13153-13159 ◽  
Author(s):  
Xiehuang Sheng ◽  
Chao Shan ◽  
Jianbiao Liu ◽  
Jintong Yang ◽  
Bin Sun ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Lipid Peroxide ◽  
Membrane Lipid ◽  
Peroxide Radical ◽  
Membrane Lipid Peroxidation ◽  
Pathological Conditions ◽  
Dependent Form ◽  
The Brain

Ferroptosis is a recently discovered iron-dependent form of non-apoptotic cell death caused by the accumulation of membrane lipid peroxidation products, which is involved in various pathological conditions of the brain, kidneys, liver and heart.

scholarly journals Laurinterol from Laurencia johnstonii eliminates Naegleria fowleri triggering PCD by inhibition of ATPases

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Iñigo Arberas-Jiménez ◽  
Sara García-Davis ◽  
Aitor Rizo-Liendo ◽  
Ines Sifaoui ◽  
María Reyes-Batlle ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Treatment Options ◽  
Opportunistic Pathogen ◽  
Current Treatment ◽  
Ion Pump ◽  
Naegleria Fowleri ◽  
Trophozoite Stage ◽  
Nægleria Fowleri

Abstract Primary amoebic encephalitis (PAM) is a lethal disease caused by the opportunistic pathogen, Naegleria fowleri. This amoebic species is able to live freely in warm aquatic habitats and to infect children and young adults when they perform risk activities in these water bodies such as swimming or splashing. Besides the need to increase awareness of PAM which will allow an early diagnosis, the development of fully effective therapeutic agents is needed. Current treatment options are amphotericin B and miltefosine which are not fully effective and also present toxicity issues. In this study, the in vitro activity of various sesquiterpenes isolated from the red alga Laurencia johnstonii were tested against the trophozoite stage of a strain of Naegleria fowleri. Moreover, the induced effects (apoptotic cell death) of the most active compound, laurinterol (1), was evaluated by measuring DNA condensation, damages at the mitochondrial level, cell membrane disruption and production of reactive oxygen species (ROS). The obtained results demonstrated that laurinterol was able to eliminate the amoebae at concentrations of 13.42 ± 2.57 µM and also to induced programmed cell death (PCD) in the treated amoebae. Moreover, since ATP levels were highly affected and laurinterol has been previously reported as an inhibitor of the Na+/K+-ATPase sodium–potassium ion pump, comparison with known inhibitors of ATPases were carried out. Our results points out that laurinterol was able to inhibit ENA ATPase pump at concentrations 100 times lower than furosemide.

scholarly journals Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics

2019 ◽  
Author(s):  
Lohans Pedrera ◽  
Rafael A. Espiritu ◽  
Uris Ros ◽  
Anja Schmitt ◽  
Stephan Hailfinger ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Plasma Membrane ◽  
Membrane Damage ◽  
Protective Mechanism ◽  
Membrane Repair ◽  
Plasma Membrane Damage ◽  
Molecular Events ◽  
Regulated Necrosis ◽  
Dependent Form

SummaryFerroptosis is an iron-dependent form of regulated necrosis associated with lipid peroxidation. Despite its key role in the inflammatory outcome of ferroptosis, little is known about the molecular events leading to the disruption of the plasma membrane during this type of cell death. Here we show that a sustained increase in cytosolic Ca2+ is a hallmark of ferroptosis that precedes complete bursting of the cell. We report that plasma membrane damage leading to ferroptosis is associated with membrane nanopores of few nanometers in radius and that ferroptosis, but not lipid peroxidation, can be delayed by osmoprotectants. Importantly, Ca2+ fluxes during ferroptosis correlate with the activation of ESCRT-III-mediated membrane repair, which counterbalances the kinetics of cell death and modulates the inflammatory signature of ferroptosis. Our findings with ferroptosis provide a unifying concept that sustained high levels of cytosolic Ca2+ prior to plasma membrane disruption are a common feature of regulated necrosis and position ESCRT-III as a general protective mechanism in these inflammatory cell death pathways.

An Overview of Dementias

2012 ◽  
Vol 21 (3) ◽  
pp. 75-84
Author(s):  
Venkata Vijaya K. Dalai ◽  
Jason E. Childress ◽  
Paul E Schulz
Keyword(s):  
Clinical Presentation ◽  
Treatment Options ◽  
Current Treatment ◽  
Great Variability ◽  
Health Concern ◽  
Public Health Concern ◽  
Life Threatening ◽  
The Common ◽  
Neurodegenerative Dementias ◽  
Made In

Dementia is a major public health concern that afflicts an estimated 24.3 million people worldwide. Great strides are being made in order to better diagnose, prevent, and treat these disorders. Dementia is associated with multiple complications, some of which can be life-threatening, such as dysphagia. There is great variability between dementias in terms of when dysphagia and other swallowing disorders occur. In order to prepare the reader for the other articles in this publication discussing swallowing issues in depth, the authors of this article will provide a brief overview of the prevalence, risk factors, pathogenesis, clinical presentation, diagnosis, current treatment options, and implications for eating for the common forms of neurodegenerative dementias.

Melatonin reduces high levels of lipid peroxidation induced by potassium iodate in porcine thyroid

2019 ◽  
pp. 1-7 ◽  
Author(s):  
Paulina Iwan ◽  
Jan Stepniak ◽  
Malgorzata Karbownik-Lewinska
Keyword(s):  
Lipid Peroxidation ◽  
Oxidative Damage ◽  
Membrane Lipids ◽  
Chemical Properties ◽  
Iodine Concentration ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Protective Effects ◽  
Potassium Iodate ◽  
Hormone Synthesis

Abstract. Iodine is essential for thyroid hormone synthesis. Under normal iodine supply, calculated physiological iodine concentration in the thyroid is approx. 9 mM. Either potassium iodide (KI) or potassium iodate (KIO3) are used in iodine prophylaxis. KI is confirmed as absolutely safe. KIO3 possesses chemical properties suggesting its potential toxicity. Melatonin (N-acetyl-5-methoxytryptamine) is an effective antioxidant and free radical scavenger. Study aims: to evaluate potential protective effects of melatonin against oxidative damage to membrane lipids (lipid peroxidation, LPO) induced by KI or KIO3 in porcine thyroid. Homogenates of twenty four (24) thyroids were incubated in presence of either KI or KIO3 without/with melatonin (5 mM). As melatonin was not effective against KI-induced LPO, in the next step only KIO3 was used. Homogenates were incubated in presence of KIO3 (200; 100; 50; 25; 20; 15; 10; 7.5; 5.0; 2.5; 1.25 mM) without/with melatonin or 17ß-estradiol. Five experiments were performed with different concentrations of melatonin (5.0; 2.5; 1.25; 1.0; 0.625 mM) and one with 17ß-estradiol (1.0 mM). Malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA) concentration (LPO index) was measured spectrophotometrically. KIO3 increased LPO with the strongest damaging effect (MDA + 4-HDA level: ≈1.28 nmol/mg protein, p < 0.05) revealed at concentrations of around 15 mM, thus corresponding to physiological iodine concentrations in the thyroid. Melatonin reduced LPO (MDA + 4-HDA levels: from ≈0.97 to ≈0,76 and from ≈0,64 to ≈0,49 nmol/mg protein, p < 0.05) induced by KIO3 at concentrations of 10 mM or 7.5 mM. Conclusion: Melatonin can reduce very strong oxidative damage to membrane lipids caused by KIO3 used in doses resulting in physiological iodine concentrations in the thyroid.

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