CN115006384A - Application of iron death inhibitor in preparation of medicine for inhibiting cardiotoxicity caused by sorafenib - Google Patents
Application of iron death inhibitor in preparation of medicine for inhibiting cardiotoxicity caused by sorafenib Download PDFInfo
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- CN115006384A CN115006384A CN202210853102.2A CN202210853102A CN115006384A CN 115006384 A CN115006384 A CN 115006384A CN 202210853102 A CN202210853102 A CN 202210853102A CN 115006384 A CN115006384 A CN 115006384A
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Abstract
The invention provides an application of an iron death inhibitor in preparation of a medicine for inhibiting cardiotoxicity caused by sorafenib, and belongs to the technical field of medicines. Aiming at solving the problem that the existing clinic lacks of drugs for inhibiting cardiotoxicity caused by sorafenib. Experimental research proves that Ferrostatin-1 has a remarkable protective effect on cardiotoxicity caused by sorafenib. The research result shows that: ferrostatin-1 was able to significantly reduce the mortality rate in mice receiving sorafenib (30 mg/kg body weight) injection; can ameliorate sorafenib-induced cardiac decline; can reverse myocardial damage caused by sorafenib; at the in vivo level, iron death caused by sorafenib can be inhibited. The invention expands the clinical application of sorafenib, provides a foundation for the research and development of medicaments for inhibiting sorafenib cardiotoxicity, and has clinical practicability. The invention also expands the indication of the Ferrostatin-1 and improves the application potential of the Ferrostatin-1.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to an application of an iron death inhibitor in preparation of a medicine for inhibiting cardiotoxicity caused by sorafenib.
Background
Sorafenib is a common oral small-molecule multi-target Tyrosine Kinase Inhibitors (TKIs) clinically at present, and is used for treating hepatocellular carcinoma, renal cell carcinoma and well-differentiated thyroid carcinoma. As a multi-target receptor kinase inhibitor, it can target and inhibit vascular endothelial growth factor receptors (VEGFR2 and VEGFR3), platelet-derived growth factor receptors (PDGFR), Ras-related factor 1(RAF-1), protooncogene B-Raf and the like. From another perspective, however, multi-kinase target inhibitors have a greater risk of cardiotoxicity than targeted drugs that are targeted to a single target. Common cardiotoxicity of the sorafenib comprises heart failure, hypertension, ischemic heart disease, cardiac ischemia, myocardial infarction and the like, which not only greatly affects the life quality of patients, but also greatly limits the clinical application of the sorafenib.
Iron death (ferroptosis) is a novel mode of programmed cell death, different from other death pathways such as apoptosis, necrosis, autophagy, and the like. Iron death is characterized by: (1) in terms of cell morphology, iron death results in intact plasma membranes, increased density of mitochondrial membranes, decreased or absent mitochondrial ridges, and insignificant morphological changes in the nucleus; (2) cellular components, as evidenced by excessive accumulation of lipid reactive oxygen species, increase in ROS. (3) Some characteristic genes are changed, GPX4, ferrodeath suppressor protein (FSP 1) and the like. (4) Can be inhibited by iron chelators. Ferrostatin-1(Fer-1) is a currently accepted iron death inhibitor, and as a compound containing N-cyclohexyl, Ferrostatin-1 has higher affinity with a cell membrane phospholipid bilayer, can effectively eliminate lipid peroxidation of cell membranes, but does not change the content of iron, so that a plurality of clinical side effects caused by an iron chelator can be avoided. To date, there have been no reports of iron death and the effects of its inhibitors on sorafenib cardiotoxicity.
The prior art (CN 107007586A) discloses the application of an iron death inhibitor in the preparation of a drug for inhibiting cardiotoxicity caused by adriamycin, wherein the cardiotoxicity mechanism caused by adriamycin is described to be related to the overproduction of active oxygen, lipid peroxidation, DNA damage, accumulation of tumor suppressor protein and the like, and the fact that cardiac iron overload caused by adriamycin plays an extremely important role in cardiotoxicity is also described.
However, sorafenib is a TKIs medicament, adriamycin belongs to anthracycline antitumor drugs, and the complete molecular mechanism of sorafenib for inducing heart injury at present is not clear, so that the TKIs medicament has the property of being cardiotropic and is easy to stay in myocardial cells, heart tissues lack catalase, and the antioxidant activity is weak. In addition, myocardial cells are rich in mitochondria and are also a source for generating ROS, and TKIs have high affinity for cardiolipin and can enter the mitochondria to combine with the cardiolipin to inhibit a respiratory chain, so that heart damage is caused.
In recent years, sorafenib is discovered to be a liver cancer cell iron death inducer, the main mechanism is that the activity of glutathione peroxidase (GPX 4) is influenced by inhibiting cystine/glutamic acid antiporter (systemXC-), the oxidation resistance of cells is reduced, and Reactive Oxygen Species (ROS) is increased, so that cell iron death is induced. However, whether sorafenib can induce myocardial cell iron death and play a role through what molecular mechanism, and no research report exists at home and abroad at present.
Disclosure of Invention
The technical problem to be solved by the invention is as follows:
the problem of lack of cardiotoxic drugs caused by inhibition of sorafenib in clinic at present.
The invention adopts the technical scheme for solving the technical problems that:
the invention provides an application of an iron death inhibitor in preparation of a medicine for inhibiting cardiotoxicity caused by sorafenib, wherein the iron death inhibitor is Ferrostatin-1.
The in vivo study of mice proves that Ferrostatin-1 has a remarkable protective effect on cardiotoxicity caused by sorafenib, and can be used for relieving the cardiotoxicity caused by sorafenib. In the research, the usage and the dosage of the Ferrostatin-1 are that the Ferrostatin-1(1 mg/kg body weight) is injected into the abdominal cavity every day, and 14 days are a course of treatment; the research result shows that: ferrostatin-1 was able to significantly reduce the mortality rate in mice receiving sorafenib (30 mg/kg body weight) injection; can improve sorafenib-induced cardiac function decline; can reverse myocardial damage caused by sorafenib.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides an application of a ferroptosis inhibitor in preparation of a medicine for inhibiting cardiotoxicity caused by sorafenib, wherein during the use process of the sorafenib, when cardiotoxicity occurs, such as myocardial ischemia or myocardial infarction, a patient needs to temporarily or permanently stop the treatment of the sorafenib, and the clinical application of the sorafenib is greatly limited. The research proves that the iron death inhibitor has a remarkable protection effect on the cardiotoxicity caused by sorafenib, and the iron death inhibitor can be used for relieving the cardiotoxicity induced by sorafenib, so that the clinical application of the sorafenib is expanded, a foundation is provided for the research and development of medicaments for inhibiting the sorafenib cardiotoxicity, and the iron death inhibitor has clinical practicability. The invention also expands the indication of the Ferrostatin-1 and improves the application potential of the Ferrostatin-1.
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FIG. 1 is a schematic diagram showing the protective effect of Ferrostatin-1 on the mouse Sorafenib cardiotoxicity in terms of survival rate in the examples of the present invention;
FIG. 2 is a schematic diagram showing the protective effect of Ferrostatin-1 on the mouse Sorafenib cardiotoxicity in terms of cardiac function in the example of the present invention;
FIG. 3 is a graph showing how Ferrostatin-1 induces myocardial damage and fibrosis levels (brain natriuretic peptide (BNP) (A), Atrial Natriuretic Peptide (ANP) (B), collagen I (Col I) (C), creatine kinase isoenzyme MB (CK-MB) (D), and Lactate Dehydrogenase (LDH) (E), hematoxylin-eosin (HE) staining (F), Masson staining (G), and Masson staining quantification (H) in Sorafenib in mice according to an embodiment of the present invention;
FIG. 4 is a schematic diagram of how Ferrostatin-1 reverses Sorafenib-induced cardiac death of mice (indicated by an electron microscope (A), GPX4 mRNA (B), FSP1 mRNA (C) and serum malondialdehyde MDA (D)) in an example of the present invention.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below.
Example 1
18 male C57BL/6 mice were randomly divided into 3 groups, namely a control group, a sorafenib group and a combination of sorafenib + Ferrostatin-1, wherein 6 mice in each group were administrated by intraperitoneal injection. The control group was given 10% DMSO + 40% PEG300+ 5% Tween-80+ 45% physiological saline, sorafenib (MedChemExpress, # HY-10201) was given at a dose of 30mg/kg/day (cosolvent is control group solvent), and Ferrostatin-1(MedChemExpress, # HY-100579) was given at a dose of 1mg/kg/day (cosolvent is control group solvent), and the administration doses of sorafenib and Ferrostatin-1 were calculated based on the mass of solid drug administered.
The administration was continued for 2 weeks, and mice were observed daily for death at regular intervals, and after two weeks, cardiac function was examined in each group of mice using echocardiography. The myocardial injury biochemical markers CK-MB, LDH value and MDA level in serum are detected by using an orbital blood collection mode, then the mice are sacrificed, the heart is dissected, weighed, the visceral organ index is examined, and the mRNA level in myocardial tissue is detected by Real-time fluorescence quantitative PCR (Real-time PCR).
As shown in figure 1, the results show that the survival rate of the combined group is remarkably higher than that of the sorafenib group, and the fact that Ferrostatin-1 can inhibit cell damage and cell death caused by sorafenib at the in vivo level is suggested.
As shown in A-C in FIG. 2, the echocardiogram test results show that the left ventricular Ejection Fraction (Ejection Fraction) of the cardiac function index of the control group, the sorafenib group and the combination of sorafenib + Ferrostatin-1 are 76.19 +/-3.12, 60.81 +/-6.20 and 76.78 +/-3.33 respectively; the short-axis Shortening rates (Fractional Shortening) of the left ventricle are 39.03 +/-2.66, 27.70 +/-4.03 and 39.64 +/-2.77 respectively, which shows that the sorafenib can cause the reduction of the heart function of the mouse, and the reduction of the heart function induced by the sorafenib is improved after the Ferrostatin-1 is used together.
As shown in D in FIG. 2, the heart weight/body weight ratio (HW/BW) of each group was 7.07 + -1.09, 4.51 + -0.21, and 6.42 + -0.45, respectively, indicating that the decrease in HW/BW values induced by sorafenib after combination with Ferrostatin-1 was significantly reversed.
As shown in A-C in figure 3, Real-time PCR (polymerase chain reaction) is used for detecting myocardial tissues, and the results show that the levels of Sorafenib BNP, ANP and Col ImRNA are obviously increased, and combined use of Ferrostatin-1 can obviously reverse the indexes, which indicates that Ferrostatin-1 can inhibit myocardial damage caused by Sorafenib at the in-vivo level.
As shown in D-E in FIG. 3, the values of CK-MB, a biochemical marker of myocardial injury in serum, were 15.23 + -2.50, 29.31 + -7.98 and 15.92 + -1.53, respectively; LDH values are 8.95 +/-0.05, 13.49 +/-2.18 and 8.08 +/-1.56 respectively, which indicates that sorafenib can cause myocardial damage of mice, and the combination of Ferrostatin-1 can reverse the myocardial damage caused by sorafenib.
As shown in F in figure 3, HE staining further proves that heart damage caused by sorafenib, myocardial disturbance caused by sorafenib groups, myocardial cell enlargement, obvious nucleus fragmentation and obvious myocardial damage degree reduction after combination of Ferrostatin-1.
As shown in G-H in figure 3, collagen deposition and fibrosis of myocardial tissues are observed by Masson staining, after sorafenib is injected into the abdominal cavity, the collagen content and fibrosis in the heart tissues of mice are increased, and the degree of myocardial fibrosis is obviously reduced after Ferrostatin-1 is combined. Taken together, these findings indicate that Ferrostatin-1 can prevent sorafenib-induced myocardial injury and cardiac fibrosis.
As shown in fig. 4, when changes in the ultrastructure of cardiomyocytes were detected by transmission electron microscopy, cell death, mitochondrial atrophy, increase in mitochondrial membrane density, and disappearance of mitochondrial cristae occurred in sorafenib; real-time PCR (polymerase chain reaction) is used for detecting myocardial tissues, and the Sorafenib GPX4 and FSP1 mRNA level is found to be remarkably reduced; serum MDA is detected by a malondialdehyde method, and the MDA level of the sorafenib group is found to be remarkably increased, which indicates that the sorafenib can induce lipid peroxidation and iron death in vivo. The combined use of Ferrostatin-1 can obviously reverse the indexes, which shows that the Ferrostatin-1 can inhibit the iron death caused by sorafenib at the in vivo level.
Based on the experimental results, it can be proved that Ferrostatin-1 has a good inhibition effect on the cardiotoxicity caused by sorafenib. Although the present disclosure has been described above, the scope of the present disclosure is not limited thereto. Various changes and modifications may be effected therein by one of ordinary skill in the pertinent art without departing from the spirit and scope of the present disclosure, and these changes and modifications are intended to be within the scope of the present disclosure.
Claims (3)
1. The application of the iron death inhibitor in preparing the medicine for inhibiting the cardiotoxicity caused by sorafenib is disclosed, wherein the iron death inhibitor is Ferrostatin-1.
2. Use according to claim 1, characterized in that the iron death inhibitor and sorafenib are in a dosage ratio of 1: 30.
3. Use according to claim 1, characterized in that the medicament is prepared from an inhibitor of iron death and pharmaceutically acceptable excipients.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210853102.2A CN115006384A (en) | 2022-07-20 | 2022-07-20 | Application of iron death inhibitor in preparation of medicine for inhibiting cardiotoxicity caused by sorafenib |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210853102.2A CN115006384A (en) | 2022-07-20 | 2022-07-20 | Application of iron death inhibitor in preparation of medicine for inhibiting cardiotoxicity caused by sorafenib |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107007586A (en) * | 2017-03-09 | 2017-08-04 | 浙江大学 | Iron death inhibitor is preparing the application in suppressing cardiotoxicity caused by doxorubicin medicine |
| CN107496401A (en) * | 2017-09-30 | 2017-12-22 | 浙江大学 | Iron death inhibitor is preparing the application in preventing medicament for myocardial ischemia-reperfusion injury |
| CN112915196A (en) * | 2021-03-15 | 2021-06-08 | 中国人民解放军北部战区总医院 | Medical application of CREG1 protein in preventing or treating sorafenib-induced myocardial injury |
| CA3171430A1 (en) * | 2020-03-13 | 2021-09-16 | Brent R. Stockwell | Gpx4 compounds and compositions and methods of treatment using same |
| JP2021147375A (en) * | 2020-03-23 | 2021-09-27 | 国立大学法人 岡山大学 | Agent for improving or preventing cardiotoxicity and autophagy abnormality related state by anticancer agent |
-
2022
- 2022-07-20 CN CN202210853102.2A patent/CN115006384A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107007586A (en) * | 2017-03-09 | 2017-08-04 | 浙江大学 | Iron death inhibitor is preparing the application in suppressing cardiotoxicity caused by doxorubicin medicine |
| CN107496401A (en) * | 2017-09-30 | 2017-12-22 | 浙江大学 | Iron death inhibitor is preparing the application in preventing medicament for myocardial ischemia-reperfusion injury |
| CA3171430A1 (en) * | 2020-03-13 | 2021-09-16 | Brent R. Stockwell | Gpx4 compounds and compositions and methods of treatment using same |
| JP2021147375A (en) * | 2020-03-23 | 2021-09-27 | 国立大学法人 岡山大学 | Agent for improving or preventing cardiotoxicity and autophagy abnormality related state by anticancer agent |
| CN112915196A (en) * | 2021-03-15 | 2021-06-08 | 中国人民解放军北部战区总医院 | Medical application of CREG1 protein in preventing or treating sorafenib-induced myocardial injury |
Non-Patent Citations (1)
| Title |
|---|
| 康传杰;张相彤;马威;: "细胞铁死亡发生与调控机制的研究进展", 中国病理生理杂志 * |
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