CN110538172B - Application of iron death inhibitor in preparation of medicine for treating auranofin hepatotoxicity - Google Patents
Application of iron death inhibitor in preparation of medicine for treating auranofin hepatotoxicity Download PDFInfo
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Abstract
The invention discloses application of an iron death inhibitor in preparing a medicament for treating auranofin hepatotoxicity, wherein the iron death inhibitor is Ferrostatin-1. The invention provides evidence of Ferrostatin-1 in inhibiting iron death process caused by auranofin, provides theoretical basis for treating auranofin liver injury with iron death as target, and especially provides basis for combined administration of auranofin and iron death inhibitor in clinical process.
Description
Technical Field
The invention relates to application of an iron death inhibitor Ferrostatin-1 in treatment of auranofin hepatotoxicity.
Background
Iron death (Ferroptosis) is an iron-dependent cell death pathway, different from other death pathways such as apoptosis, necrosis, autophagy, etc. The iron death is expressed by the comprehensive change of multiple indexes such as cell lipid peroxidation level, increase of the expression level of the marker gene Ptgs2 and the like, and can be specifically inhibited by the iron ion chelating agent.
Ferrostatin-1 is currently recognized as an inhibitor of iron death. As a compound containing N-cyclohexyl, ferrostatin-1 has higher affinity with a cell membrane phospholipid bilayer and can effectively eliminate lipid peroxidation of cell membranes. In vitro experiments, ferrostatin-1 acts on cancer cells to inhibit Erastin-induced cytoplasm and lipid ROS accumulation, and further inhibit iron death. Ferrostatin-1 inhibits neuronal iron death caused by glutamate toxicity in the Huntington's chorea model; in hereditary hemochromatosis, ferrostatin-1 inhibits iron death of hepatocytes by iron overload.
The invention of application number 201710919871.7, application of an iron death inhibitor in preparation of a medicine for preventing myocardial ischemia-reperfusion injury, the invention of application number 201710137097.4, application of an iron death inhibitor in preparation of a medicine for inhibiting cardiotoxicity caused by adriamycin, and the invention of patent number 201610307748.5, application of an iron death inhibitor in preparation of a medicine for treating iron overload diseases disclose corresponding effects of Ferrostatin-1.
In addition, ferrostatin-1 is unable to inhibit extracellular signal-regulated kinase (ERK) phosphorylation or chelate iron, indicating that Ferrostatin-1 inhibits iron death by modulating MEK/ERK pathway, cellular iron levels or inhibiting protein synthesis. Similar to reducing agents such as tocopherol, ferrostatin-1 is unstable and readily oxidized to the stable 2, 2-diphenyl-1-picrylhydrazine (DPPH).
Auranofin (Auranofin) is a class of oral gold preparations developed by Smith Kline & French specifically for the treatment of rheumatoid arthritis. Auranofin is slightly soluble in water and readily soluble in lipid. Approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis in 1985. After oral administration of auranofin, 15% -25% of the drug can be detected in blood plasma, and the drug is mainly combined with albumin. The half-life period of the plasma of the medicine is 15 to 25 days, and the medicine is almost completely discharged out of the body after 55 to 80 days. 85% of auranofin is excreted via feces and only 15% is excreted via urine, while only 0.4% of the administered dose will accumulate in the kidney. The incidence rate of adverse reactions of auranofin reaches 30-50%, and the adverse reactions mostly occur within 3 months after the administration, mainly manifested as hepatotoxicity, hematopoietic suppression and the like. To date, auranofin has gradually quit clinical first-line administration.
The reason for Auranofin (Auranofin) hepatotoxicity is not clear at present, and no relevant report about the relevance of iron death and Auranofin toxicity in vivo exists, and whether high-dose Auranofin injection can cause Ferroptosis is unknown; that is, there is currently no literature reporting a link between auranofin and hemochromatosis or iron death. At present, no medicine capable of effectively treating/relieving Auranofin (Auranofin) toxicity exists, and clinical treatment for Auranofin toxicity is usually carried out.
Disclosure of Invention
The invention aims to solve the technical problem of providing the application of the iron death inhibitor Ferrostatin-1 in preparing the medicine for treating auranofin hepatotoxicity, and provides a basis for the research and development of new medicines and innovative therapy.
In order to solve the technical problems, the invention provides an application of an iron death inhibitor in preparing a medicament for treating/relieving auranofin hepatotoxicity, wherein the iron death inhibitor is Ferrostatin-1.
Although iron death is the pathogenic mechanism of many liver injury diseases, there are many forms of hepatotoxicity caused by drugs, such as antineoplastic chemotherapeutic drugs, antituberculosis drugs, antipyretic analgesics, immunosuppressants, hypoglycemic and hypolipidemic drugs, antibacterial, antifungal and antiviral drugs, etc. that vary; therefore, known Ferrostatin-1 can not provide the technical suggestion for the invention to inhibit the death of liver cell iron caused by iron overload.
In the course of the invention, the inventors found that high doses of auranofin lead to iron death; the inventor finds that Ferrostatin-1 can obviously inhibit iron death caused by auranofin in the Huh7 liver cancer cell line. The mouse model proves that Ferrostatin-1 can obviously inhibit iron death and liver injury caused by auranofin. The research result provides a theoretical basis for Ferrostatin-1 to relieve the toxic side effect of the auranofin, and particularly provides a basis for combined administration of the auranofin and the iron death inhibitor in the clinical process.
In the course of the invention, it was found that the mode of intraperitoneal administration of Ferrostatin-1 can not effectively treat hepatotoxicity caused by the antitumor chemotherapeutic drugs, antituberculosis drugs, antipyretic analgesics, immunosuppressants and the like.
The use and dosage of the iron death inhibitor Ferrostatin-1 in treating auranofin toxicity are as follows: ferrostatin-1 (1 mg/kg body weight) is injected intramuscularly or intravenously every day, and 3 weeks are a course of treatment.
Auranofin is a medicine for clinically treating rheumatoid arthritis, but has side effects such as liver injury and the like, so that the clinical application of auranofin is limited at present. Experiments prove that ferrostatin-1 can effectively prevent hepatotoxic side effects of auranofin (figure 2).
In conclusion, the invention provides application of an iron death inhibitor in treating auranofin hepatotoxicity, and particularly, the iron death inhibitor Ferrostatin-1 can be used for preparing a medicine for treating/relieving auranofin hepatotoxicity or a supplement for preventing iron death hepatotoxicity by combining with auranofin. The invention has the following beneficial effects: the invention provides evidence of Ferrostatin-1 in inhibiting iron death process caused by auranofin, provides theoretical basis for treating auranofin liver injury with iron death as target, and especially provides basis for combined administration of auranofin and iron death inhibitor in clinical process.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 is a graph of Ferrostatin-1 inhibiting aurora-induced iron death in vitro;
a: the primary liver cells of mice were co-treated for 24 hours with blank treatment (Con), auranofin (2.5. Mu.M) plus dimethyl sulfoxide (DMSO), auranofin (2.5. Mu.M) plus Ferrostatin-1 (2. Mu.M), auranofin (2.5. Mu.M) plus apoptosis inhibitor Z-VAD-FMK (10. Mu.g/mL), auranofin (2.5. Mu.M) plus necrosis inhibitor Necrostatin-1 (10. Mu.g/mL), and the rescue effect on cell viability was obtained.
B: blank treatment (Con), auranofin (2.5 mu M) added with dimethyl sulfoxide (DMSO), auranofin (2.5 mu M) added with Ferrostatin-1 (2 mu M), auranofin (2.5 mu M) added with apoptosis inhibitor Z-VAD-FMK (10 mu g/mL), auranofin (2.5 mu M) added with necrosis inhibitor Necrostatin-1 (10 mu g/mL) to co-treat primary mouse hepatocytes for 12 hours, and the inhibitory effect on cell lipid peroxidation is achieved;
c: blank treatment (Con), auranofin (2.5 mu M) added with dimethyl sulfoxide (DMSO), auranofin (2.5 mu M) added with Ferrostatin-1 (2 mu M), auranofin (2.5 mu M) added with apoptosis inhibitor Z-VAD-FMK (10 mu g/mL), auranofin (2.5 mu M) added with necrosis inhibitor Necrostatin-1 (10 mu g/mL) to co-treat the primary mouse hepatocytes for 12 hours, and the inhibition effect on cell Ptgs2 mRNA expression is achieved;
FIG. 2 shows that intraperitoneal administration of Ferrostatin-1 inhibited iron death and ameliorated liver injury in hemochromatosis mice;
a, ferrostatin-1 (Ferr-1, 1mg/kg body weight per day) is injected into the abdominal cavity for 6 weeks, and male and female Hfe are injected into the abdominal cavity -/- A mouse lethality curve;
description of the invention: in the right panel, AF + Ferr1 and control are completely overlapped, indicating that the two effects are the same;
b, injecting Ferrostatin-1 (Ferr-1, 1mg/kg body weight per day) into abdominal cavity for 3 weeks, and male Hfe -/- Mouse liver Malondialdehyde (MDA) content;
c, ferrostatin-1 (Ferr-1, 1mg/kg body weight per day) was injected intraperitoneally for 3 weeks, male Hfe -/- Mouse liver Ptgs2 mRNA expression levels;
d, intraabdominal injection of Ferrostatin-1 (Ferr-1, 1mg/kg body weight per day) for 3 weeks, male Hfe -/- Mouse liver sirius red staining.
AF stands for auranofin.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of protection of the invention is not limited thereto:
example 1:
1. materials and methods:
1.1 Experimental materials preparation:
the compound monomers auranofin, available from MedChemexpress, ferrostatin-1, Z-VAD-FMK and Necrostatin-1, were dissolved in sterile dimethyl sulfoxide DMSO to the desired concentrations.
1.2 Huh7 hepatoma cell line:
culture conditions of the Huh7 liver cancer cell line: DMEM high-glucose medium (GIBCO) containing 10% FBS (GIBCO), 37 ℃,5% CO2 saturation humidity incubator. After the cells adhered to the wall, DMSO, auranofin (2.5. Mu.M, final concentration, same below) + DMSO, auranofin (2.5. Mu.M) + apoptosis inhibitor (10. Mu.g/mL), auranofin (2.5. Mu.M) + necrosis inhibitor (10. Mu.g/mL), auranofin (2.5. Mu.M) + Ferrostatin-1 (2. Mu.M) were added to the medium, respectively. Cell viability was measured by MTT 24 hours after treatment (see 1.3). After 12 hours of treatment, cells were harvested and subjected to Real-time PCR (see 1.4) and cell membrane lipid peroxidation level determination (see 1.5).
The apoptosis inhibitor is Z-VAD-FMK; the necrosis inhibitor is Necrostatin-1.
1.3 cell viability assay (MTT):
huh7 cells treated with drug for 24 hours were tested for cell viability by MTT colorimetry, and MTT kits were purchased from Bilun sky.
1.4 RNA extraction and Real-time PCR:
the Trizol (Life Technologies) method extracts RNA from cells and tissues, and the specific procedures were performed as described in the specification. RNA purity (OD 260/OD 280. Apprxeq.1.9-2.1) and RNA concentration (ng/. Mu.l) were determined on a Nanodrop1000Spectrophotometer, adjusting the RNA concentration to 1. Mu.g/. Mu.l.
Mu.g of RNA was treated with DNase (Promega) and then reverse transcribed with M-MLV reverse transcriptase (Promega) and Oligo (dT) 18primer (Takara Bio Inc.). Realtime PCR was performed in CFX96 Real-Time System (Bio-Rad), the iQ SYBR Green Supermix (Bio-Rad) was used as a reagent, and the reaction System was 10. Mu.l, including SYBGREN 5. Mu.l, cDNA 1. Mu.l, primers 2. Mu.l, ddH 2 O2. Mu.l. The Real-Time program was 95 ℃ pre-denaturation for 3 minutes, 40 cycles (95 ℃ for 10 seconds per cycle, 60 ℃ for 15 seconds during detection of fluorescence), and the dissolution curve was examined. The primer sequences are as follows:
Mouse Actb(β-actin):
forward：AAATCGTGCGTGACATCAAAGA
reverse：GCCATCTCCTGCTCGAAGTC
mouse Ptgs2:
forward：CTGCGCCTTTTCAAGGATGG
reverse：GGGGATACACCTCTCCACCA。
1.5 cell membrane lipid peroxidation level assay:
the Huh7 cells after 12 hours of drug treatment were trypsinized into a single cell suspension. C11-BODIPY (10. Mu.M) was incubated for 30 minutes at room temperature in the dark, washed 3 times with PBS and detected by flow cytometry. C11-BODIPY was purchased from Invitrogen.
Mouse liver tissue is homogenized by PBS, and the content of Malondialdehyde (MDA) which is a lipid peroxidation product is detected by a colorimetric method. MAD kits were purchased from petunia.
1.6 Experimental animals:
hfe knockout (Hfe-/-) mice are a classical hemochromatosis animal model with phenotypes similar to the symptoms of HFE-HH patients, manifested by an abnormal decrease in hepcidin expression and systemic iron overload. Hfe-/-mice had no symptoms and associations of liver damage and iron death.
Hfe -/- Mice were bred to 8 weeks of age in an SPF environment and randomly divided into three groups by weight, with 8 males and females in each group. According to experimental design, three groups were administered daily i.p. saline, i.p. auranofin (25 mg/kg body weight) + Ferrostatin-1 (1 mg/kg body weight), for a total of 6 weeks, and mice lethal curve was recorded.
Hfe -/- Mice were raised to 8 weeks of age in an SPF environment and randomly divided into three groups by weight, each group containing 6 males. According to the experimental design, three groups were administered daily i.p. saline, i.p. auranofin (25 mg/kg body weight) + Ferrostatin-1 (1 mg/kg body weight), respectively, for a total of 3 weeks. After 5% chloral hydrate abdominal anesthesia, blood was collected from the heart, serum was separated, liver, spleen and kidney tissues were collected (stored in liquid nitrogen), and liver lipid peroxidation level (method 1.5), fibrosis index (see 1.7) and liver Ptgs2 expression level (method 1.4) were examined.
1.7 detection of liver injury indexes:
liver fibrosis is often used clinically to measure the level of liver damage. Liver fibrosis was obtained by sirius red staining of paraffin sections of liver, the red stained area was the liver fibrosis product-collagen, sirius red dye purchased from Sigma, and the staining method was according to the instructions.
1.8 statistical methods
The statistics used were analyzed using R software and the experimental data are expressed as Mean ± SEM. The Tukey's test (ANOVA) was used for comparison between cells and animals, and Student's t-test was used for comparison between groups, where P <0.05 was considered statistically significant and the letters were different, indicating P <0.05.
2. As a result, the
2.1 Ferrostatin-1 inhibits aurora-induced iron death in Huh7 hepatoma cells
Huh7 cells were cultured in vitro, and DMSO, auranofin (2.5. Mu.M, final concentration, the same applies hereinafter) + DMSO, auranofin (2.5. Mu.M) + apoptosis inhibitor Z-VAD-FMK (10. Mu.g/mL), auranofin (2.5. Mu.M) + necrosis inhibitor Neostatin-1 (10. Mu.g/mL), auranofin (2.5. Mu.M) + Ferrosstatin-1 (2. Mu.M) were added to the culture medium, respectively. Cell viability was measured after 24 hours. After 12 hours, iron death indicators, including cell membrane lipid peroxidation, ptgs2 mRNA levels, were measured. Each treatment was performed in 3 duplicate wells and the experiment was repeated three times.
As shown in fig. 1, the experiment results show that compared with Control, auranofin + DMSO stimulation can significantly kill cells (fig. 1A); up-regulation of iron death indicators, including cell membrane lipid peroxidation levels (figure 1B) and Ptgs2 mRNA expression (figure 1C); indicating that in vitro cellular levels of auranofin trigger iron death. Compared with auranofin and DMSO, auranofin and Ferrostatin-1 treatment can obviously save cell viability (figure 1A) and inhibit auranofin from up-regulating lipid peroxidation (figure 1B) and Ptgs2 expression (figure 1C); however, auranofin + apoptosis inhibitor Z-VAD-FMK and auranofin + necrosis inhibitor Necrostatin-1 had no effect on cell viability (fig. 1A), lipid peroxidation (fig. 1B) and Ptgs2 expression level (fig. 1C) compared to auranofin + DMSO treatment. This suggests that the mode of cell death caused by auranofin is iron death, rather than modulation of apoptosis or necrosis. Ferrostatin-1 inhibits aurora-induced iron death at in vitro levels.
2.2 Ferrostatin-1 inhibits auranofin toxicity
Hfe 8 weeks old -/- Mice were randomly divided into three groups (8 males and females in each group), and were intraperitoneally injected with normal saline, auranofin (25 mg/kg body weight), and auranofin (25 mg/kg body weight) + Ferrostatin-1 (1 mg/kg body weight) daily, respectively. Mice lethal curve was recorded at 6 weeks of treatment; liver MDA content, ptgs2 mRNA level and liver fibrosis were measured at 3 weeks of treatment.
The results in figure 2A show that all 100% of the auranofin-treated mice died within 5 weeks after injection, regardless of male or female mice, whereas the combined treatment with Ferrostatin-1+ auranofin significantly delayed and reduced the death of the mice (figure 2A). In terms of physiological and biochemical indexes of iron death, the mouse liver MDA content (figure 2B), ptgs2 mRNA level (figure 2C) and liver fibrosis level (figure 2D) are obviously increased after the auronofin is injected for 3 weeks compared with a normal saline group (control), which indicates that the in vivo treatment of the auronofin can cause iron death. Compared with the group treated by auranofin alone, the combination treatment of auranofin and Ferrostatin-1 can obviously restore the MDA content of the liver (figure 2B), the Ptgs2 mRNA level (figure 2C) and the liver fibrosis level (figure 2D), which shows that the Ferrostatin-1 can inhibit iron death caused by auranofin and improve liver damage caused by iron death at the in vivo level.
Based on this, ferrostatin-1 inhibition of iron death is a therapeutic approach to treat auranofin hepatotoxicity. Therefore, the iron death is taken as a target, and the iron death caused by the auranofin is targeted and inhibited by the iron death inhibitor, so that the method has important significance for treating auranofin hepatotoxicity and safely using auranofin.
Finally, it is also noted that the above-mentioned list is only a few specific embodiments of the present invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.
Sequence listing
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Application of <120> iron death inhibitor in preparation of medicine for treating auranofin hepatotoxicity
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Claims (1)
1. The application of an iron death inhibitor in preparing a medicament for treating auranofin hepatotoxicity is that the iron death inhibitor is Ferrostatin-1, and Ferrostatin-1 can obviously inhibit iron death and liver injury caused by auranofin.
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Non-Patent Citations (4)
| Title |
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| In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake;Johnson J. Liu 等;《Journal of Inorganic Biochemistry》;20070926;第102卷;第303-310页 * |
| THE MODULATION OF REDOX HOMEOSTASIS AND INDUCTION OF FERROPTOTIC CELL DEATH IN HEPATOCELLULAR CARCINOMA AS AN ANTICANCER STRATEGY;J Liese 等;《ESMO Open》;20180629;第3卷;第A192页 * |
| 新型细胞死亡方式ferroptosis在肝疾病机制中的研究前景;俞鸿敏 等;《药学学报》;20171231;第52卷(第12期);第1783-1790页 * |
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