阅读说明：本技术 铁死亡抑制剂在制备治疗金诺芬肝毒性的药物中的应用 (Application of iron death inhibitor in preparation of medicine for treating auranofin hepatotoxicity ) 是由 王福俤 王浩 杨磊 闵军霞 于 2019-09-28 设计创作，主要内容包括：本发明公开了铁死亡抑制剂在制备治疗金诺芬肝毒性的药物中的应用,该铁死亡抑制剂为Ferrostatin-1。本发明提供了Ferrostatin-1在抑制金诺芬导致的铁死亡过程的证据,为以铁死亡为靶点的金诺芬肝损伤的治疗提供了理论依据,特别是对临床过程中金诺芬与铁死亡抑制剂联合用药提供了基础。(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 the process of inhibiting iron death caused by auranofin, provides a theoretical basis for treating auranofin liver injury taking iron death as a target, and particularly provides a basis for combined administration of auranofin and an iron death inhibitor in a clinical process.)

1. The application of an iron death inhibitor in preparing a medicament for treating auranofin hepatotoxicity is disclosed, wherein the iron death inhibitor is Ferrostatin-1.

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, and the like. The iron death is expressed by the comprehensive changes of multiple indexes such as the peroxidation level of cell lipid, the increase of the expression level of a marker gene Ptgs2 and the like, and can be specifically inhibited by an 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 No. 201710919871.7, namely application of an iron death inhibitor in preparing a medicament for preventing myocardial ischemia-reperfusion injury, the invention of application No. 201710137097.4, namely application of the iron death inhibitor in preparing a medicament for inhibiting cardiotoxicity caused by adriamycin, and the invention of patent No. 201610307748.5, namely application of the iron death inhibitor in preparing a medicament 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. Like reducing agents such as tocopherol, Ferrostatin-1 is unstable and is easily oxidized to 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 medicine plasma is 15-25 days, and the medicine plasma is almost completely discharged out of the body after 55-80 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 cause of 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 injection of Auranofin 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 no medicine is usually taken for clinically treating Auranofin toxicity.

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 Huh7 liver cancer cell lines. 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 auranofin, and particularly provides a basis for combined administration of auranofin and an iron death inhibitor in a 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(1mg/kg body weight) is injected intramuscularly or intravenously every day, and 3 weeks are a course of treatment.

the auranofin is a medicament for clinically treating rheumatoid arthritis, but has side effects of 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 an 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 the process of inhibiting iron death caused by auranofin, provides a theoretical basis for treating auranofin liver injury taking iron death as a target, and particularly provides a basis for combined administration of auranofin and an iron death inhibitor in a 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 mouse hepatocytes 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 the primary mouse liver cells for 12 hours, and the inhibition 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 can suppress iron death and ameliorate liver injury in hemochromatosis mice;

Ferrostatin-1(Ferr-1, 1mg/kg body weight per day) is injected into the abdominal cavity for 6 weeks, and the male and female Hfe-/-mouse lethal curve;

description of the drawings: in the right panel, AF + Ferr1 completely overlaps with control, indicating that both are equally effective;

b, injecting Ferrostatin-1(Ferr-1, 1mg/kg body weight per day) into abdominal cavity for 3 weeks, wherein the liver Malondialdehyde (MDA) content of male Hfe-/-mice;

C, injecting Ferrostatin-1(Ferr-1, 1mg/kg body weight every day) into the abdominal cavity for 3 weeks, and obtaining the expression level of male Hfe-/-mouse liver Ptgs2 mRNA;

D, injecting Ferrostatin-1(Ferr-1, 1mg/kg body weight every day) into the abdominal cavity for 3 weeks, and staining the liver of the male Hfe-/-mouse with sirius red.

AF stands for auranofin.

Detailed Description

the invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto: