Application of flavin adenine dinucleotide in preparation of medicine for preventing and / or treating doxorubicin-induced cardiotoxicity

Abstract

The invention discloses application of flavin adenine dinucleotide in preparation of a medicine for preventing and / or treating doxorubicin-induced cardiotoxicity, and relates to the technical field of biological medicines. Experimental verification shows that the flavin adenine dinucleotide can effectively improve the myocardial atrophy condition by inhibiting DOX-induced myocarditis reaction, fibrosis process and oxidative stress level, and plays an important role in prevention and / or treatment of DOX-induced cardiotoxicity. According to the invention, the action mechanism and potential value of the flavin adenine dinucleotide in prevention and / or treatment of DOX-induced cardiotoxicity are defined, and a new potential target and means are provided for reconstruction of related treatment strategies.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to the use of flavin adenine dinucleotide in the preparation of a drug for preventing and / or treating doxorubicin-induced cardiotoxicity. Background Art

[0002] In recent years, tremendous changes in the field of tumor treatment have significantly improved the long-term prognosis of tumor patients. However, with the extension of treatment time and survival period, as well as the widespread use of targeted drugs, there are more and more studies on complications such as drug-induced heart failure, hypertension, thromboembolism, and arrhythmia. In addition to recurrence and metastasis, cardiovascular disease has become the second leading cause of death in tumor patients. Data show that the current 5-year survival rate of cancer patients is close to 80%. However, the risk of hospitalization for cardiovascular disease in cancer survivors is significantly increased. Compared with the general population of matched age, cancer survivors have a 7-fold higher risk of premature death due to cardiac causes. Therefore, for cancer patients, clinicians should not only pay attention to the effectiveness of tumor treatment, but also focus on the prevention and treatment of cardiovascular comorbidities and complications.

[0003] At present, the toxicity of anti-tumor drugs is divided into two types according to pathological changes and clinical manifestations: type I and type II. Type I cardiotoxicity is often accompanied by irreversible myocardial damage, which is dose-dependent and more likely to lead to heart failure. It is more common in traditional chemotherapy drugs, such as anthracyclines. Type II cardiotoxicity can lead to temporary loss of myocardial contractility without ultrastructural abnormalities, is non-dose-dependent, and is mostly reversible, such as trastuzumab. Anthracyclines, such as doxorubicin (DOX), are widely used to treat hematological malignancies and solid tumors, such as acute leukemia, lymphoma, breast cancer, pancreatic cancer, gastric cancer, soft tissue sarcoma, and ovarian cancer. Doxorubicin has a wide anti-tumor spectrum, strong anti-tumor effect, and definite efficacy, but its toxic side effects cannot be ignored. Cardiotoxicity is the most serious toxic side effect of doxorubicin, which is clinically called "doxorubicin-induced cardiotoxicity" (DIC).

[0004] At the same time, heart failure caused by doxorubicin differs significantly from heart failure related to hypertension, diabetes or myocardial infarction in terms of pathogenesis, clinical features and treatment strategies. Doxorubicin mainly causes heart failure through direct myocardial toxicity, and its mechanism involves the massive generation of reactive oxygen species (ROS), mitochondrial damage and DNA repair inhibition, leading to myocardial cell apoptosis and necrosis, which is manifested pathologically as myofibril loss and cavitation, and eventually progresses to dilated cardiomyopathy (mainly with contractile dysfunction, HFrEF), and is dose-dependent (cumulative dose > 300 mg / m 2The risk is significantly increased), and some patients even develop delayed heart failure several years after chemotherapy. In contrast, heart failure related to hypertension is mostly caused by long-term pressure load leading to left ventricular hypertrophy and myocardial fibrosis, mainly manifested as diastolic dysfunction (HFpEF) in the early stage; diabetes causes diabetic cardiomyopathy through hyperglycemia-induced oxidative stress, lipotoxicity and microvascular lesions, often combined with HFpEF; while heart failure after myocardial infarction results from acute myocardial ischemia necrosis, secondary ventricular remodeling (scar formation, ventricular dilation), manifested as HFrEF, and segmental wall motion abnormalities can be seen by imaging. In terms of diagnosis, doxorubicin-induced heart failure needs to be combined with the chemotherapy history and cumulative dose, and cardiac MRI can detect myocardial edema or fibrosis at an early stage, while for heart failure caused by hypertension and diabetes, attention should be paid to the control of the primary disease (such as blood pressure, blood sugar), and heart failure after myocardial infarction depends on coronary angiography to clarify the ischemic cause. In terms of treatment, doxorubicin-induced heart failure requires immediate drug withdrawal and the use of dexrazoxane for prevention, supplemented with standard heart failure drugs (such as ACEI, β-blockers), but the cardiac function damage of some patients is irreversible and the prognosis is poor; while for heart failure caused by hypertension and diabetes, blood pressure and blood sugar control need to be strengthened (ARNI and SGLT2i are preferred), and heart failure after myocardial infarction requires revascularization and anti-ischemic treatment. Appropriate control of the primary disease can significantly improve the prognosis. Generally speaking, doxorubicin-induced heart failure emphasizes early monitoring and prevention more, while heart failure caused by other etiologies focuses on multi-dimensional intervention of the primary disease, and there are essential differences between the two in the pathological process and clinical management strategies.

[0005] It is estimated that the mortality rate of cancer patients with DIC is increasing year by year. Therefore, seeking effective treatment methods for DIC is a common and urgent research direction in the fields of cancer and cardiovascular diseases. Summary of the Invention

[0006] The purpose of the present invention is to provide the application of flavin adenine dinucleotide in the preparation of drugs for preventing and / or treating doxorubicin-induced cardiotoxicity, so as to solve the problems existing in the above-mentioned prior art. The present invention's research found that flavin adenine dinucleotide (FAD) can effectively improve myocardial atrophy by inhibiting DOX-induced myocardial inflammatory response, fibrosis process and oxidative stress level, and plays an important role in preventing and / or treating DOX-induced cardiotoxicity.

[0007] To achieve the above purpose, the present invention provides the following solutions:

[0008] The present invention provides the application of flavin adenine dinucleotide in the preparation of drugs for preventing and / or treating doxorubicin-induced cardiotoxicity.

[0009] Furthermore, the doxorubicin-induced cardiotoxicity includes heart failure caused by myocardial atrophy.

[0010] Furthermore, the drug improves myocardial atrophy by inhibiting doxorubicin-induced myocardial inflammatory response, fibrosis process, and oxidative stress level, thereby preventing and / or treating doxorubicin-induced cardiotoxicity.

[0011] The present invention also provides a drug for preventing and / or treating doxorubicin-induced cardiotoxicity, and the active ingredient of the drug includes flavin adenine dinucleotide.

[0012] Furthermore, the drug further includes pharmaceutically acceptable excipients.

[0013] Furthermore, the excipients include solubilizers, excipients, disintegrants, preservatives, colorants, or glidants.

[0014] Furthermore, the dosage form of the drug is powder, tablet, capsule, granule, suspension, or injection.

[0015] The present invention also provides an anti-tumor composition, including doxorubicin and flavin adenine dinucleotide.

[0016] The present invention also provides the application of the above composition in the preparation of anti-tumor drugs.

[0017] The present invention also provides an anti-tumor drug, and the active ingredient includes the above composition.

[0018] The present invention discloses the following technical effects:

[0019] Experimental verification of the present invention shows that flavin adenine dinucleotide can effectively improve myocardial atrophy by inhibiting DOX-induced myocardial inflammatory response, fibrosis process, and oxidative stress level, and plays an important role in preventing and / or treating DOX-induced cardiotoxicity. The present invention clarifies the mechanism of action and potential value of flavin adenine dinucleotide in preventing and / or treating DOX-induced cardiotoxicity, and provides new potential targets and means for the reconstruction of related treatment strategies. Description of the Drawings

[0020] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required in the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0021] Figure 1 Western Blot detection results (A) and statistical chart (B) of the protein expression levels of NLRP3 and β-actin;

[0022] Figure 2Statistical chart of LDH secretion in each group of cells;

[0023] Figure 3 Statistical chart of 8-OH-dG secretion in each group of cells;

[0024] Figure 4 WGA staining images (A) and statistical chart of cross-sectional area of cardiomyocytes (B) of paraffin pathological sections of the hearts of mice in each group;

[0025] Figure 5 Masson staining images (A) and statistical chart of fibrotic area (B) of paraffin pathological sections of the hearts of mice in each group;

[0026] Figure 6 DHE staining images (A) and statistical chart of relative DHE intensity (B) of paraffin pathological sections of the hearts of mice in each group. Detailed implementation manners

[0027] Now, various exemplary implementation manners of the present invention will be described in detail. This detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics, and implementation schemes of the present invention.

[0028] It should be understood that the terms described in the present invention are only for describing specific implementation manners and are not used to limit the present invention. Additionally, for the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0029] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein can also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In case of conflict with any incorporated document, the content of this specification shall prevail.

[0030] Without departing from the scope or spirit of the present invention, various improvements and changes can be made to the specific implementation manners of the specification of the present invention, which are obvious to those skilled in the art. Other implementation manners obtained from the specification of the present invention are obvious to those skilled in the art. The specification and examples of the present invention are only exemplary.

[0031] Regarding the terms "comprising", "including", "having", "containing", etc. used in this article, they are all open-ended terms, meaning including but not limited to.

[0032] Example 1

[0033] 1. Experimental method

[0034] (1) Experimental grouping

[0035] Cultured neonatal rat cardiomyocytes were divided into three groups: control group, DOX group, and FAD + DOX group. Among them, in the DOX group, 0.5 μmol / L DOX was applied for 24 hours, and in the FAD + DOX group, after pretreatment with 10 μmol / L FAD for 24 hours, it was then incubated with 0.5 μmol / L DOX for 24 hours.

[0036] (2) Index detection

[0037] The protein expression levels of NLRP3 and β-actin were detected by Western Blot; the secretion of LDH was detected using an LDH kit; the secretion of 8-OH-dG was detected by ELISA.

[0038] 2. Experimental results

[0039] The results of index detection for each experimental group are shown in Figure 1 . The results showed that DOX could promote the expression of NLRP3 in neonatal rat cardiomyocytes, while the addition of FAD inhibited the expression of NLRP3 (A and B in Figure 1 ). Next, the effects of FAD and DOX on ox-mtDNA were analyzed. The results showed that DOX could promote the secretion of 8-hydroxydeoxyguanosine (8-OH-dG) and lactate dehydrogenase (LDH), while the addition of FAD inhibited the secretion of 8-OH-dG and LDH ( Figures 2 - 3 ).

[0040] Example 2

[0041] 1. Experimental method

[0042] (1) Experimental grouping

[0043] The experiment was divided into 4 groups, and the experimental operations for each group are shown in Table 1.

[0044] Table 1 Experimental grouping

[0045]

[0046] (2) Index detection

[0047] After the administration treatment of each group was completed, the heart was dissected, and paraffin pathological sections of the heart were prepared. Then, WGA staining, Masson staining, and DHE staining were performed respectively to detect the myocardial atrophy, myocardial fibrosis level, and myocardial oxidative stress level in mice.

[0048] 2. Experimental results

[0049] The results of WGA staining showed that FAD could significantly alleviate DOX-induced myocardial cell atrophy ( Figure 4 ). The results of Masson staining showed that FAD could significantly alleviate DOX-induced myocardial fibrosis level ( Figure 5 ). The results of DHE staining showed that FAD could significantly alleviate DOX-induced myocardial oxidative stress level ( Figure 6 ).

[0050] The embodiments described above are only for describing the preferred mode of the present invention, and do not limit the scope of the present invention. Without departing from the design spirit of the present invention, various deformations and improvements made by those of ordinary skill in the art to the technical solutions of the present invention shall fall within the protection scope determined by the claims of the present invention.

Claims

1. Use of flavin adenine dinucleotide in the preparation of a drug for preventing and / or treating doxorubicin-induced cardiotoxicity.

2. The use according to claim 1, characterized in that: The doxorubicin-induced cardiotoxicity includes myocardial atrophy leading to heart failure.

3. The use according to claim 2, characterized in that: The drug improves myocardial atrophy by inhibiting adriamycin-induced myocardial inflammatory response, fibrosis process and oxidative stress level, thereby preventing and / or treating adriamycin-induced cardiotoxicity.

4. A drug for preventing and / or treating doxorubicin-induced cardiotoxicity, characterized in that: The active ingredient of the drug includes flavin adenine dinucleotide.

5. The drug according to claim 4, characterized in that The drug also includes pharmaceutically acceptable excipients.

6. The drug according to claim 5, characterized in that The auxiliary materials include solubilizers, excipients, disintegrants, preservatives, colorants or glidants.

7. The drug according to claim 5, characterized in that The dosage form of the medicine is powder, tablet, capsule, granule, suspension or injection.

8. An anti-tumor composition, characterized in that: Includes doxorubicin and flavin adenine dinucleotide.

9. Use of the composition according to claim 8 in the preparation of anti-tumor drugs.

10. An anti-tumor drug, characterized in that: The active ingredient comprises the composition according to claim 8.

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