CN-122005514-A - Application of isoliquiritigenin in preparation of medicines for treating 5-FU induced cardiotoxicity

Abstract

The invention discloses application of isoliquiritigenin in preparing a drug for treating 5-FU induced cardiotoxicity, belongs to the technical field of biomedicine, comprises isoliquiritigenin, improves oxidative stress and apoptosis induced by 5-FU by regulating an AhR-CYP1A1 channel, further improves the cardiotoxicity induced by 5-FU, analyzes from the whole level and the cellular molecular level to the mechanism, firstly discloses an action mechanism of isoliquiritigenin for improving the cardiotoxicity induced by 5-FU by inhibiting an AhR-CYP1A1 signal channel, verifies the application value of isoliquiritigenin in preparing the drug for treating 5-FU cardiotoxicity, provides a novel active ingredient and a novel technical scheme for preparing the drug for resisting 5-FU cardiotoxicity based on the complete analysis of the mechanism, lays a theoretical and experimental foundation for research and development of the drug for relieving 5-FU chemotherapy side effects, and has important drug development value.

Inventors

• LI XINZHI
• HOU XIANGHONG
• YANG RUI
• MA KETAO

Assignees

• 石河子大学

Dates

Publication Date

20260512

Application Date

20260414

Claims (10)

1. 1. The application of isoliquiritigenin in preparing a medicament for treating 5-FU induced cardiotoxicity is characterized in that the medicament comprises isoliquiritigenin, and the isoliquiritigenin improves 5-FU induced oxidative stress and apoptosis by regulating an AhR-CYP1A1 pathway, thereby improving 5-FU induced cardiotoxicity.
2. 2. The use according to claim 1, wherein the isoliquiritigenin down regulates the expression level of the target gene CYP1A1 downstream thereof by inhibiting the expression of an aromatic hydrocarbon receptor.
3. 3. The use according to claim 1, wherein the isoliquiritigenin reduces 5-FU induced myocardial oxidative stress injury by up-regulating expression levels of Nrf2, HO-1 and NQO1 antioxidant proteins in myocardial tissue.
4. 4. The use according to claim 1, wherein the isoliquiritigenin inhibits 5-FU induced myocardial apoptosis by up-regulating the expression level of anti-apoptotic protein Bcl-2, down-regulating the expression levels of pro-apoptotic proteins Bax and CLEAVED CASPASE-3.
5. 5. The use according to claim 1, wherein the isoliquiritigenin restores 5-FU-induced drop in mitochondrial membrane potential of cardiomyocytes and reduces active oxygen levels in the cardiomyocytes.
6. 6. The use according to claim 1, wherein the medicament further comprises an aromatic hydrocarbon receptor inhibitor as a synergistically active ingredient.
7. 7. The use according to claim 6, wherein the aromatic hydrocarbon receptor inhibitor is selected from CH-223191.
8. 8. The use according to claim 1, wherein the effective dose range of isoliquiritigenin is 20 mg/kg/day to 80 mg/kg/day for animals and 20 μm to 80 μm for cells.
9. 9. The use of claim 1, wherein the 5-FU-induced cardiotoxic manifestation comprises at least one of reduced ejection fraction, reduced fractional reduction, reduced cardiac output, increased myocardial zymogram, increased brain natriuretic peptide, myocardial fibrosis, myocardial apoptosis, and myocardial histopathological injury.
10. 10. The use according to any one of claims 1 to 9, wherein the medicament comprises isoliquiritigenin and pharmaceutically acceptable excipients, the excipients being any pharmaceutically acceptable carrier or excipient.

Description

Application of isoliquiritigenin in preparation of medicines for treating 5-FU induced cardiotoxicity Technical Field The invention relates to the technical field of medicines, in particular to a novel medical application of isoliquiritigenin, and particularly relates to an application of isoliquiritigenin in preparation of a medicine for treating 5-FU induced cardiotoxicity. Background 5-Fluorouracil (5-Fluorouracil, 5-FU) is a classical antimetabolite chemotherapeutic agent, and is widely applied to the treatment of colorectal cancer, gastric cancer, breast cancer, head and neck cancer and other solid tumors, and is still a basic stone drug of many solid tumor combined chemotherapy schemes. However, 5-FU has been increasingly focused on clinical use for its cardiotoxicity while exerting an antitumor effect. Epidemiological studies have shown that 5-FU induced cardiotoxicity occurs at a rate of 10% -35% depending on the chemotherapeutic regimen, the dose administered, and whether the patient is suffering from cardiovascular disease. 5-FU has become the second most common anti-tumor drug causing cardiotoxicity next to anthracyclines. Clinically, the 5-FU related cardiotoxicity can be expressed in various forms such as angina pectoris, myocardial ischemia, myocardial infarction, arrhythmia, heart failure, sudden cardiac death and the like, seriously influences the treatment compliance and the life quality of patients, even forces the interruption of chemotherapy and restricts the clinical application of the patients. Aiming at the heart toxicity induced by 5-FU, a specific prevention and treatment means is lack in clinic at present. The existing intervention strategies mainly comprise vasodilating drugs such as calcium channel blockers, nitric acid esters and the like, and antioxidants such as N-acetylcysteine and the like, but the intervention measures have the problems of inaccurate curative effect, large tolerance difference of patients and the like in clinical application, are mostly limited to symptomatic treatment, and cannot fundamentally block occurrence and development of cardiotoxicity. Therefore, the development of a novel intervention drug capable of effectively relieving the heart toxicity of 5-FU has important clinical significance. Isoliquiritigenin (isoliquiritigenin, ISL) is a natural flavonoid extracted from Glycyrrhrizae radix and other medicinal plants, and has various biological activities including antiinflammatory, antioxidant, antitumor, and antidiabetic effects. In the aspect of cardiovascular protection, patent CN115919850A discloses a traditional Chinese medicine monomer composition for resisting adriamycin cardiotoxicity, which is prepared from Songshengling, 8-gingerol and isoliquiritigenin according to specific parts by weight and is used for relieving the cardiotoxicity induced by adriamycin. The patent shows that isoliquiritigenin is used as one of the components of the composition, and is synergistic with Songshenling and 8-gingerol, and the expression of mitochondrial energy metabolism related enzyme and mitochondrial dynamics related protein is regulated, so that the effect of resisting the toxicity of doxorubicin heart is exerted. However, the indication of this patent is doxorubicin-induced cardiotoxicity and does not relate to 5-FU-induced cardiotoxicity. The pathogenesis of cardiotoxicity of doxorubicin and 5-FU are different classes of chemotherapeutic drugs, and the intervention strategy for cardiotoxicity of doxorubicin cannot be directly deduced and its effectiveness on 5-FU cardiotoxicity is not obvious. Based on the above, the invention provides the application of isoliquiritigenin in preparing medicaments for treating 5-FU induced cardiotoxicity, so as to fill the technical blank. Disclosure of Invention The invention aims to provide an application of isoliquiritigenin in preparing a drug for treating 5-FU induced cardiotoxicity, so as to solve the technical problems that a specific drug for preventing and treating 5-FU cardiotoxicity is lacking in the prior art, the application of natural isoliquiritigenin in the indication is blank, the action mechanism of the isoliquiritigenin is not yet elucidated, and the like. The invention discloses that isoliquiritigenin improves myocardial oxidative stress and apoptosis induced by 5-FU through inhibiting an aromatic hydrocarbon receptor (AhR) -cytochrome P450 family 1 subfamily A member 1 (CYP 1A 1) signal pathway for the first time, thereby relieving the action mechanism of 5-FU cardiotoxicity, and provides the independent application of isoliquiritigenin and the novel pharmaceutical application of combined aromatic hydrocarbon receptor inhibitors based on the action mechanism, thus providing a technical foundation for preventing and treating cardiotoxicity caused by chemotherapy. In order to achieve the above object, the present invention provides the following solutions: The key point of the application of the isoliqu