Discovery of Novel Potent Covalent Glutathione Peroxidase 4 Inhibitors as Highly Selective Ferroptosis Inducers for the Treatment of Triple-Negative Breast Cancer
Tingting ChenJiafu LengJun TanYongjun ZhaoShanshan XieShifang ZhaoXiangyu YanLiqiao ZhuJun LuoLingyi KongYong Yin
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Abstract:
Glutathione peroxidase 4 (GPX4) is a promising target to induce ferroptosis for the treatment of triple-negative breast cancer (TNBC). We designed and synthesized a novel series of covalent GPX4 inhibitors based on RSL3 and ML162 by structural integration and simplification strategies. Among them, compound C18 revealed a remarkable inhibitory activity against TNBC cells and significantly inhibited the activity of GPX4 compared to RSL3 and ML162. Moreover, it was identified that C18 could notably induce ferroptosis with high selectivity by increasing the accumulation of lipid peroxides (LPOs) in cells. Further study demonstrated that C18 covalently bound to the Sec46 of GPX4. Surprisingly, C18 exhibited an outstanding potency of tumor growth inhibition in the MDA-MB-231 xenograft model with a TGI value of 81.0%@20 mg/kg without obvious toxicity. Overall, C18 could be a promising GPX4 covalent inhibitor to induce ferroptosis for the treatment of TNBC.Keywords:
GPX4
Triple-negative breast cancer
GPX4
Phospholipid-hydroperoxide glutathione peroxidase
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Objectives This experimental study was performed to investigate the continuous anti-bacterial potency of Coptidis rhizoma extract on cultivation of Staphylococcus species(S. aureus, S. epidermidis) that induce eye disease. Methods Minimal inhibitory concentration(MIC) was measured by dropping to diluted Coptidis rhizoma extract(100%, 10%, 1%, 0.1%) on S. aureus, S. epidermidis that were cultivated from 2 to 6 days. Anti-bacterial potency was measured by the size of inhibition zone with change of volume(). Results 1. Anti-bacterial potency of Coptidis rhizoma extract on S. aureus was appeared in 100%, 10% and was the same as anti-bacterial potency of 2 days and 6 days. Anti-bacterial potency with change of volume(100%) was increased in propotion to increase volume on all samples. Anti-bacterial potency with change of volume(10%) was increased in propotion to increase volume on all samples except . Anti-bacterial potency of Coptidis rhizoma extract on S. aureus was appeared continuous. 2. Anti-bacterial potency of Coptidis rhizoma extract on S. epidermidis was appeared in 100%, 10% and was the same as anti-bacterial potency of 2 days and 6 days. Anti-bacterial potency with change of volume(100%) was increased in propotion to increase volume on all samples. Anti-bacterial potency with change of volume(10%) was appeared in . Anti-bacterial potency of Coptidis rhizoma extract on S. epidermidis was appeared continuous. Conclusions Anti-bacterial potency of Coptidis rhizoma extract on cultivation of S. aureus & S. epidermidis was showed continuous.
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Phospholipid-hydroperoxide glutathione peroxidase
GPX3
GPX6
GPX4
GPX1
Affect
Glutathione reductase
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GPX1
GPX4
GPX3
Phospholipid-hydroperoxide glutathione peroxidase
Knockout mouse
Selenoprotein
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Significance Ferroptosis is a regulated form of cell death induced by loss of glutathione peroxidase 4 (GPX4) phospholipid peroxidase activity and lethal accumulation of reactive oxygen species. Small-molecule inhibitors of GPX4 induce ferroptosis; however, the interaction between these inhibitors and GPX4 has remained elusive, as has the identity of the reactive oxygen species that drive execution of ferroptosis. We identified here a ligand-binding site on GPX4 and determined the specific lipids oxidized during ferroptosis. We further identified two key drivers of lipid peroxidation during ferroptosis: lipoxygenases and phosphorylase kinase G2. These findings reveal a previously enigmatic mechanism of ferroptotic lipid peroxide generation and suggest new strategies for pharmacological control of ferroptosis and diseases associated with this mode of cell death.
GPX4
Phospholipid-hydroperoxide glutathione peroxidase
Lipid peroxide
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Glutathione reductase
GPX4
GPX3
GPX6
GPX1
Glutaredoxin
Cumene hydroperoxide
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GPX4
Lipid peroxide
Glutathione reductase
GPX3
Glutathione S-transferase
GPX1
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Summary: Glutathione peroxidase (GPx) catalyzes the reduction of hydroperoxides, including hydrogen peroxides, by reduced glutathione and functions to protect the cell from oxidative damage. With the exception of phospholipid-hydroperoxide GPx, a monomer, all of the GPx enzymes are tetramers of four identical subunits. Each subunit contains a selenocysteine in the active site which participates directly in the two-electron reduction of the peroxide substrate. The enzyme uses glutathione as the ultimate electron donor to regenerate the reduced form of the selenocysteine. The Cayman Chemical Glutathione Peroxidase Assay Kit measures GPx activity indirectly by a coupled reaction with glutathione reductase (GR). Oxidized glutathione (GSSG), produced upon reduction of an organic hydroperoxide by GPx, is recycled to its reduced state by GR and NADPH. The oxidation of NADPH to NADP+ is accompanied by a decrease in absorbance at 340 nm. The rate of decrease in the A340 is directly proportional to the GPx activity in the sample. The Cayman GPx Assay Kit can be used to measure all of the glutathione- dependent peroxidases in plasma, erythrocyte lysates, tissue homogenates, and cell lysates.
Glutathione reductase
GPX4
GPX3
GPX1
Phospholipid-hydroperoxide glutathione peroxidase
GPX6
Selenocysteine
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The Effects of Hyperthyroidism on Lipid Peroxidation, Erythrocyte Glutathione and Glutathione Peroxidase The aim of this study was to determine if lipid peroxidation, glutathione, and glutathione peroxidase levels can be effected by hyperthyroidism. Twenty-three subjects with hyperthyroidism (18 females/5 males), and 19 euthyroid subjects (11 females/8 males) were examined in this study. Plasma and erythrocytes malondialdehyde (MDA), erythrocytes glutathione (GSH) and glutathione peroxidase (GSH-PX) were measured. Results show that an increase in lipid peroxidation was observed in the hyperthyroid patients (p < 0.001). This was accompanied by a decrease in glutathione and glutathione peroxidase in the same subjects (p < 0.001). The results suggest that hyperthyroidism has some effects on lipid peroxidation and free radical scavengers.
GPX4
Malondialdehyde
Glutathione reductase
GPX3
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