CN118178618A - Application of semaglutin in preparation of medicine for preventing and treating heart toxicity induced by anti-tumor medicine - Google Patents
Application of semaglutin in preparation of medicine for preventing and treating heart toxicity induced by anti-tumor medicine Download PDFInfo
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- CN118178618A CN118178618A CN202410362863.7A CN202410362863A CN118178618A CN 118178618 A CN118178618 A CN 118178618A CN 202410362863 A CN202410362863 A CN 202410362863A CN 118178618 A CN118178618 A CN 118178618A
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Abstract
The invention belongs to the technical field of biological pharmacy, and discloses application of GLP-1 analogue semaglutin in preparation of a medicine for preventing and treating heart toxicity induced by an anti-tumor medicine. The semaglutin can improve the survival rate, cardiac function, myocardial injury markers and apoptosis of doxorubicin cardiomyopathy; can inhibit the expression of myocardial mitochondrial BNIP3 and improve myocardial mitochondrial dysfunction in doxorubicin cardiomyopathy, and provides a novel and safe cardioprotectant for the anti-tumor drug-induced cardiotoxicity.
Description
Technical Field
The invention relates to the technical field of biological pharmacy, in particular to application of semaglutin in preparing medicines for preventing and treating heart toxicity induced by anti-tumor medicines.
Background
The independent application or combined chemoradiotherapy of the anti-tumor drugs is the most important and powerful anticancer tool at present, but the cardiotoxicity is always one of serious adverse reactions occurring in the application process of the anti-tumor drugs and is also a key factor for influencing the prognosis of tumors. Antitumor drugs have various damage mechanisms and different clinical manifestations to the heart, and have obvious effects on survival and prognosis of patients.
With the gradual increase of the incidence rate of tumors, cardiovascular complications caused by tumor treatment are rapidly increasing, wherein the anthracycline doxorubicin (DOX, chemical formula C 27H29NO11) is widely used for the chemotherapy of various malignant tumors, and the cardiotoxicity of the anthracycline doxorubicin is one of the important factors for death of cancer patients. The incidence of cardiotoxicity was 3%, 7.5% and 18% when patients received cumulative doses of 400, 550 and 700mg/m2 of doxorubicin, respectively. At present, no treatment method or medicine for effectively relieving the anthracycline-induced cardiotoxicity exists, and related researches on anti-tumor medicine cardiotoxicity prevention and treatment medicines are urgently needed to be developed.
Doxorubicin-induced cardiotoxicity is a complex multifactorial process involving multiple mechanisms. Previous studies have shown that metabolic dysfunction is a key mechanism for myocardial injury caused by doxorubicin. Thus, intervention against myocardial metabolism is a key target for improving doxorubicin cardiotoxicity. Glucagon-like peptide-1 (glp-1), a hormone produced mainly by intestinal L cells, has the basic function of promoting insulin synthesis and secretion, inhibiting glucagon secretion, and thus lowering blood glucose levels. In addition, it is involved in metabolic regulation of various cells such as adipocytes, cardiomyocytes, etc., promotion of oxidation of fatty acids and inhibition of fat synthesis. GLP-1 thus also plays an important cardioprotective role. However, myocardial toxicity of tumor chemotherapeutic drugs is obviously different from that of traditional heart failure in etiology, mechanism and treatment. Although many researches on traditional heart failure prove that GLP-1 has an improvement effect on traditional heart failure, heart failure related to heart toxicity of an anti-tumor drug is different from the traditional heart failure, the traditional heart failure resistant drug has little effect in treating heart failure related to heart toxicity of the anti-tumor drug, and a novel hypoglycemic drug, namely, a Semiglutide (GLP-1 receptor agonist), has not been researched in heart toxicity heart failure of the anti-tumor drug.
Current treatment regimens for doxorubicin-induced cardiotoxicity are: (1) drug treatment: with cardioprotective agents, dexrazoxane is currently the only cardioprotective agent approved by the U.S. food and drug administration specifically for anthracycline chemotherapy patients. (2) adjusting a treatment regimen: depending on the patient's specific situation, the dosage, mode of administration or treatment cycle of doxorubicin is adjusted to reduce the risk of cardiotoxicity. (3) symptomatic treatment: if the patient has developed cardiotoxic reaction, corresponding symptomatic treatment measures are taken according to specific situations, such as diuretics, cardiotonic agents and the like are used for relieving symptoms and protecting cardiac functions. However, these treatment regimens have shortcomings: the adverse reaction of the dexrazoxane is serious, and the adverse reaction such as bone marrow suppression, hepatotoxicity, secondary malignant tumor development and the like can be possibly caused, so that the application value of the medicine is severely limited; adjusting the dose of doxorubicin may affect the therapeutic effect of the tumor, increasing the risk of tumor progression in the patient; symptomatic treatment, while alleviating or improving symptoms, does not radically cure the root cause of the disease, and may also bring side effects, dependencies and other risks.
Disclosure of Invention
The invention aims at solving the problems and provides application of GLP-1 analogue semaglutin in preparing medicines for preventing and treating anti-tumor drug-induced cardiotoxicity.
In order to achieve the purpose, the invention adopts the following technical scheme:
use of GLP-1 analogue semaglutin in the preparation of a medicament for preventing or treating anti-tumor drug-induced cardiotoxicity.
In the above technical scheme, the antitumor drug is an anthracycline drug.
In the above technical scheme, the antitumor drug is doxorubicin.
In the technical scheme, the application of the GLP-1 analogue semaglutin in preparing medicines for treating doxorubicin-induced cardiomyopathy is preferred.
Wherein, the semaglutin improves myocardial mitochondrial dysfunction in doxorubicin cardiomyopathy.
Wherein, the semaglutinin inhibits the expression of myocardial mitochondrial BNIP3 and reduces mitochondrial damage and cardiomyopathy induced by doxorubicin.
In the technical scheme, the semaglutin reduces the myocardial injury markers of the doxorubicin cardiomyopathy, improves the cardiac function, the myocardial structure, the myocardial fibrosis and the myocardial apoptosis, and improves the survival rate of the doxorubicin cardiomyopathy.
In the technical scheme, the medicine further comprises a pharmaceutically acceptable carrier or auxiliary material.
In the technical scheme, the dosage forms of the medicine comprise injection, tablet, granule, pill and capsule.
The beneficial effects of the invention are as follows:
The experimental study proves that the invention has the following advantages: GLP-1 analogue semeglutide can improve the survival rate of doxorubicin cardiomyopathy, cardiac function, myocardial injury markers and apoptosis; can inhibit the expression of myocardial mitochondrial BNIP3, improve myocardial mitochondrial dysfunction in doxorubicin cardiomyopathy, and provide a novel and safe cardioprotectant for anti-tumor drug-induced cardiotoxicity.
Drawings
FIG. 1 shows the results of GLP-1 experiments for improving doxorubicin cardiomyopathy cardiac dysfunction: panel A is an ultrasonic index of cardiac function after 6 weeks of GLP-1 treatment: (A1) Each group of mouse cardiac ultrasound representative graphs, (A2) left ventricular ejection fraction (LVEF%), (A3) left ventricular foreshortening fraction (LVFS%), (A4) left ventricular endocrinopathy (LVIDs), (A5) left ventricular diastole endocrinopathy (LVIDd), (n=6); panel B is survival, (n=15); panel C is the effect of semaglutinin on doxorubicin-induced cardiotoxicity mouse serological index: (C1) Lactate Dehydrogenase (LDH), (C2) creatine kinase isoenzyme (CK-MB), (C3) Brain Natriuretic Peptide (BNP), (n=6); panel D shows myocardial apoptosis staining: (D1) Staining pattern, (D2) apoptosis staining positive cell statistics pattern.
FIG. 2 shows mitochondrial function indicators, wherein FIG. A shows Mitochondrial Membrane Potential (MMP) JC-1 staining representative graph (A1) (scale: 50 μm) and statistical graph (A2), and FIG. B shows fluorescence representative graph (B1) (scale: 50 μm) and statistical graph (B2) of mitochondrial permeability transition pore (PT-pore).
FIG. 3 shows the experimental results of GLP-1 analogues on cardiomyocyte BNIP3 expression: panel A shows differentially expressed genes: (A1) The first 10 differentially expressed genes, (A2) the first 10 differentially expressed genes qPCR (n=4); panel B shows BNIP3 expression levels (B1) and statistics (B2) (n=4) for different groups of animal models, and panel C shows BNIP3 co-localization with mitochondrial fluorescence (C1) and statistics (C2) (n=5) (scale of 10 μm).
Detailed Description
The invention is further illustrated, but is not limited, by the following examples.
The experimental methods in the following examples are conventional methods unless otherwise specified.
The main reagent sources are as follows:
GLP-1 analog semaglutin (Semaglutide): novel glucagon-like peptide-1receptor agonist (Glucagon-likepeptide-1receptor agonist,GLP-1 RA), CAS no: 99291-20-0, molecular formula:
C 42H69N9O14 S. In the embodiment of the invention, the semaglycone Lu Taigou is subcutaneously injected (diluted by normal saline) from a mouse, and the dosage is as follows: 12. Mu.g/kg.
Example 1
1 Experimental method
1.1GLP-1 improving Adriamycin cardiomyopathy cardiac dysfunction
C57 mice were randomly divided into four groups, control group: GLP-1 (SEMA) group, doxorubicin cardiomyopathy group (DOX) doxorubicin cardiomyopathy+GLP-1 group (DOX+SEMA). The doxorubicin cardiomyopathy group and the doxorubicin cardiomyopathy+glp-1 group were given doxorubicin (CAS accession number 23214-92-8) 5mg/kg once per week to mice, and were intraperitoneally injected for 4 weeks to induce doxorubicin cardiomyopathy. The doxorubicin cardiomyopathy plus GLP-1 group was subcutaneously injected daily with 12 μg/kg of the GLP-1 analog semaglutinin (Semaglutide) for 6 weeks before and after the doxorubicin injection period.
And (3) heart function detection: echocardiographic examination was performed using a high resolution ultrasound imaging system (Vevo 2100, visual sonic Inc., canada). Briefly, mice were anesthetized with 1.5% isoflurane and 98.5% oxygen, supine on a temperature controlled heated platform to maintain body temperature at 37 ℃. The contractile function index was calculated using the parasternal long axis plane during M-type measurements using the Vevo analysis software (Vevo LAB 5.5.1), and an average of at least three consecutive heartbeats was taken.
Myocardial injury marker measurement: serum levels of BNP (HB 533-Mu, henghai Biotechnology Co., china), CK-MB (HB 761-Mu, hengyuan Biotechnology Co., ltd.) and LDH (HB 1402-Mu, hengyuan Biotechnology Co.) were measured using commercial kits. All commercial kits were used according to the manufacturer's instructions.
Apoptosis detection: the heart sections were stained with TUNEL in situ apoptosis kit (E-CK-a 331, wuhan biosciences ltd, china) using a one-step procedure. Images were obtained using an olympus SLIDEVIEWVS microscope.
1.2 Administration of GLP-1 analog to ameliorate myocardial mitochondrial dysfunction in Adriamycin cardiomyopathy
Mitochondrial analysis: mitochondrial Membrane Potential (MMP) was measured using JC-1 mitochondrial membrane potential detection kit (C2003S, beyotime). After washing once with PBS, 500. Mu.L of staining solution was added to each well and incubated at room temperature for 20 minutes. The mixture was washed twice with a staining buffer solution, covered with a solution and then replaced with DMEM medium (11965092, sesameiser technology). Finally, the cell fluorescence was observed under a fluorescence microscope.
The open status of the PT-pore was detected using a mitochondrial permeability transition pore (PT-pore) detection kit (C2009S, beyotime). mu.L of staining working solution was added to each well, and incubated at 37℃for 30 minutes in the absence of light. The staining working solution was changed to a pre-heated DMEM medium and incubated at 37 ℃ for 30 minutes in the absence of light. The nuclei were counterstained with Hoechst33342 (C1017, beyotime). After washing twice with PBS, the cells were observed for fluorescence under a fluorescence microscope.
Prior to immunofluorescence experiments, viable cells were pre-stained with Mitotracker Red (M7512, sammer feichi technology). Immunocytochemistry experiments were then performed. The fluorescence intensity was analyzed quantitatively blindly with Image J software.
1.3 Administration of GLP-1 analog inhibits expression of myocardial mitochondrial BNIP3
Primary cardiomyocyte extraction: new Sprague-Dawley rats were used to isolate primary ventricular cardiomyocytes. Briefly, neonatal rats were anesthetized, then anesthetized with isoflurane, and then euthanized with cervical mating. The heart was removed and immediately placed in pre-cooled ADS buffer (consisting of 120mmol/LNaCl,20mmol/LHEPES,8mmol/LNaH 2PO4, 6mmol/L glucose, 5mmol/L KCl,0.8mmol/L MgSO 4, pH 7.4). The heart was then transferred to fresh ADS buffer and cut into small pieces of less than 1mm 3. Subsequently, the heart tissue is repeatedly rinsed with sterile ADS until the rinse becomes transparent. Tissues were collected and placed in a 25ml sterile bottle containing 2ml collagenase II solution and 2ml ADS. The digestion process was carried out by continuously stirring the mixture at 37℃at 180rpm for 8 minutes. The suspension was filtered into a 50ml centrifuge tube previously placed on ice. To each centrifuge tube was added 1ml of fetal bovine serum (FBS, gibco). After centrifugation at 2000g for 5 minutes, the supernatant was discarded. The pellet was suspended in FBS and subsequently seeded into petri dishes. The cells were incubated at 37℃and 5% CO 2 for 2 hours. This process separates cardiomyocytes from fibroblasts. The supernatant was then carefully transferred to a 50ml centrifuge tube. High purity cardiomyocytes were isolated from fibroblasts by using a Percoll gradient (GE 17-0891-01, sigma-Aldrich) in sterile ADS buffer. After centrifugation at 1800g for 45 minutes, cardiomyocytes were isolated and placed in the middle layer. Isolated cells were cultured in DMEM medium containing 10% fbs and 1% penicillin-streptomycin at 37 ℃ in a 5% co 2 incubator for 24 hours.
BNIP3 screening and verification: RNA-Seq analysis, heart of C57/BL6J mice, isolation of tissue RNA, quality control, library construction and sequencing were performed by Shanghai applied protein technologies. After library preparation, sequencing was performed on Illumina Novaseq 6000 platforms. Subsequent bioinformatics analysis was performed on RStudio (version 2022.07.2Build 576). Differential expression analysis was performed using DESeq2 (R package version v1.38.1) with 1.5 fold change and P <0.0518 as significance threshold. Pathway enrichment analysis was performed using a cluster Profiler (R package version v4.6.0) to examine KEGG pathways. Enrichment analysis of Gene Ontology (GO) was performed by GSEABase (R package version v1.60.0). Maps were generated using enrichplot (v1.18.3), ggplot2 (v3.4.1), cowplot (v1.1.1) and pheatmap (v1.0.12) packages. Real-time fluorescent quantitative PCR after total RNA was extracted from hearts using RNAiso plus reagents (9108, taKaRa, daidan, china) according to the manufacturer's instructions 21, cDNA was obtained using PRIMESCRIPTTM RT kit (RR 047A, takara, china) with GDNAERASER. Subsequently, real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed using SYBR Premix Ex Taq II (RR 820A, taKaRa, china) to detect the level of target mRNA in the 7900HT Fast RealTime PCR system (Applied Biosystems). GAPDH was used as an internal control. Each reaction was repeated three times. Values were normalized to GAPDH to calculate relative RNA expression levels. Primer sequences for mRNA expression detection are shown in table 1.
TABLE 1 primer sequences
Mitochondrial isolation and Western blot analysis: mitochondrial and cytoplasmic fractions were extracted from cardiomyocytes using Cell Mitochondria Isolation kit (C3601, beyotime Biotechnology). Protein expression levels in myocardial tissue and NRVMs were determined using Western blot analysis. Total protein samples were collected and their concentrations were determined using the BCA protein assay kit (PC 0020, solarbio). A50 mg sample of the protein was then subjected to SDS-PAGE and transferred to nitrocellulose (GE HEALTHCARE LIFE SCIENCES, logan, UT). Non-specific binding was blocked by incubation with the corresponding antibody overnight at 4 ℃. Subsequently, the primary antibody was detected with a fluorescent-labeled goat anti-rabbit IgG (5151,Cell Signalling Technology) and the results were visualized with Odyssey Western Blot Detection System (LI-COR Biotechnology, lincoln, nebraska, NE). The relative protein expression level was determined from the gray scale intensity of the bands. Immunofluorescent staining: the heart slices were dewaxed and rehydrated using gradient elution. Antigen retrieval was performed by incubation in citrate antigen retrieval buffer (P0081, beyotime) at 95 ℃ for 20 min. Cells were fixed with 4% glutaraldehyde for 15 min at room temperature. Prepared heart sections and cells were blocked with QuickBlockTM immunostaining blocking kit (P0260, beyotime) for 30 min at 37 ℃ and then incubated overnight at 4 ℃ with a primary antibody to BNIP3 (1:200, ab109362, abcam). The slides were then incubated with AlexaFluor488 TM secondary antibody (1:200, A-11008, siemens technology) in the dark for 1 hour. Nuclei were counterstained with DAPI (C1006, beyotime, china). After each step, the cells were washed three times for 5 minutes with PBS. Images were captured using a laser confocal microscope and analyzed using olympus Fluoview FV300 version 3C acquisition software. Fluorescence intensity was quantitatively analyzed blindly using Image J software.
2 Experimental results
2.1GLP-1 improving Adriamycin cardiomyopathy cardiac dysfunction
The results of the echocardiography of fig. 1 show that those mice that received doxorubicin showed a significant decrease in the left ventricular short axis reduction rate (FS) and Ejection Fraction (EF) compared to the control group, while the left ventricular systolic inner diameter (LVIDs) and the left ventricular diastolic inner diameter (LVIDd) were significantly increased (fig. 1A), indicating that doxorubicin resulted in impaired left ventricular systolic function in the mice, and congestive heart failure was present. However, these previously reduced indicators all appear to rise significantly when semaglutin is co-treated. This change suggests that semaglutinin has an improving effect on doxorubicin-induced loss of cardiac function in mice. Survival of mice was observed over 6 weeks and recorded and found that semaglutinin significantly reversed the reduced survival of doxorubicin-injured mice as shown in fig. 1B. The result shows that the semaglutin can effectively reduce the death rate of mice damaged by the doxorubicin.
LDH, CK-MB and BNP are important biochemical indicators for assessing myocardial damage and heart failure. As shown in the data presented in fig. 1C, there was a significant increase in the concentration of LDH, CK-MB and BNP in doxorubicin-treated mice serum, further confirming the condition of myocardial damage. However, these mice with elevated serum biochemical marker levels due to doxorubicin were effectively reduced upon treatment with semaglutinin. This indicates that the semaglutin has potential therapeutic effects in protecting cardiac muscle and relieving heart failure.
We showed by TUNEL staining that myocardial apoptosis was significantly increased in doxorubicin-treated mice, while semaglutinin reduced the increase in myocardial apoptosis (fig. 1D), which at least partially explained the protective effect of semaglutinin on doxorubicin-induced cardiotoxicity.
2.2 Mitochondrial function index
Doxorubicin induced cardiomyocyte mitochondrial membrane potential loss (fig. 2A) and sustained mitochondrial permeability transition pore opening (fig. 2B) were found by Mitochondrial Membrane Potential (MMP) detection and mitochondrial permeability transition pore (PT-pore) opening, MMP and PT-pore indicated that doxorubicin caused mitochondrial perturbation, whereas in the presence of semaglutinin, the above changes were improved, indicating that semaglutinin ameliorates doxorubicin-induced cardiac injury by improving mitochondrial function.
2.3 Effect of GLP-1 analogs on myocardial BNIP3 expression
To further explore the mechanism of protective effect of semaglutinin on doxorubicin-induced cardiotoxicity, doxorubicin-injured mice with semaglutinin treatment were subjected to RNAseq, and the most significant changes in BNIP3 were found to be most significant by the top ten genes with most significant changes and qPCR verification (fig. 3A), and in vivo and in vitro models were further confirmed by western immunoblotting that semaglutinin inhibited the expression of BNIP3 that was elevated by doxorubicin induction (fig. 3B). Doxorubicin induced high expression of BNIP3 on mitochondria by co-localization of BNIP3 with mitochondrial fluorescence, whereas semaglutinin inhibited expression of BNIP3 on mitochondria (fig. 3C). Thus we believe that semaglutin improves mitochondrial function by inhibiting BNIP3 expression on mitochondria.
Claims (9)
- Use of glp-1 analogue semaglutin in the preparation of a medicament for the prevention or treatment of anti-tumor drug induced cardiotoxicity.
- 2. The use according to claim 1, characterized in that: the antitumor drug is anthracycline drug.
- 3. The use according to claim 2, characterized in that: the antitumor drug is doxorubicin.
- 4. The use according to claim 1, characterized in that: application of GLP-1 analogue semaglutin in preparing medicine for treating doxorubicin-induced cardiomyopathy.
- 5. The use according to claim 4, characterized in that: semaglutin improves myocardial mitochondrial dysfunction in doxorubicin cardiomyopathy.
- 6. The use according to claim 5, characterized in that: the semaglutin inhibits the expression of myocardial mitochondrial BNIP3, and reduces mitochondrial damage and cardiomyopathy induced by doxorubicin.
- 7. The use according to claim 6, characterized in that: the semaglutin reduces the myocardial injury markers of the doxorubicin cardiomyopathy, improves the cardiac function, the myocardial structure, the myocardial fibrosis and the myocardial apoptosis, and improves the survival rate of the doxorubicin cardiomyopathy.
- 8. Use according to any one of claims 1 to 7, characterized in that: the medicine also comprises a pharmaceutically acceptable carrier or auxiliary material.
- 9. The use according to claim 8, characterized in that: the dosage forms of the medicine comprise injection, tablet, granule, pill and capsule.
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