Application of przewatanshinone A in preparation of medicine for treating anti-tumor medicine cardiotoxicity
By using tanshinone A as the single active ingredient, the cardiotoxicity problem caused by anthracyclines has been solved, achieving significant antioxidant and anti-inflammatory effects, improving cardiac function, and providing a new means of prevention and treatment.
Patent Information
- Application Number
- CN202511574997.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-31
- Publication Date
- 2026-01-09
AI Technical Summary
Existing technologies for preventing and treating cardiotoxicity caused by anthracyclines have limited efficacy, significant side effects, and unclear mechanisms, resulting in a lack of effective prevention and treatment methods.
Using tanshinone A as the single active ingredient, extracted from tanshinone, it has antioxidant and anti-inflammatory activities and is used to prevent and treat cardiotoxicity caused by anthracyclines. Through multi-target synergistic effects, it inhibits oxidative stress in myocardial cells and reduces inflammatory responses.
It significantly inhibits oxidative stress in cardiomyocytes, reduces inflammatory response, protects cardiomyocyte function, improves cardiac contractile function and electrical activity, and reduces myocardial tissue damage, providing a treatment option with definite efficacy and high safety.
Smart Images
Figure CN121287722A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of tanshinone A in the preparation of drugs for treating cardiotoxicity of antitumor drugs. Background Technology
[0002] Anthracycline-induced cardiotoxicity (AIC) is one of the major limiting factors in its clinical application. AIC is a pathological process of cardiac dysfunction and myocardial damage induced by anthracyclines, and its mechanism involves the combined effects of multiple factors, including oxidative stress, inflammatory response, and cardiomyocyte apoptosis. As a type of cardiac injury caused by chemotherapy drugs, AIC not only significantly affects patients' cardiac health but also greatly reduces their quality of life and survival, becoming one of the leading causes of death in cancer patients. Although various prevention and treatment strategies have been adopted clinically, including reducing the dosage of anthracyclines, changing the administration method, and using cardioprotective drugs, current treatment methods still have limitations. Therefore, how to effectively prevent the occurrence of AIC, reduce cardiac damage, and improve patient prognosis has become one of the important clinical problems that urgently need to be solved.
[0003] Currently, clinical drug treatment options for preventing and treating anthracycline-induced cardiotoxicity are very limited. Dexrazoxane is a commonly used cardioprotective drug, and although it has some effect in reducing AIC, its significant side effects, limited efficacy, and high cost restrict its widespread use. Furthermore, commonly used cardioprotective drugs such as β-blockers, ACE inhibitors, and antioxidants, while able to reduce cardiac damage to some extent, have broad mechanisms of action and lack specific targeted interventions on the key mechanisms of AIC. Traditional Chinese medicine compound formulas have complex components, unclear effective ingredients, ambiguous mechanisms of action, and difficulties in quality control.
[0004] Therefore, existing technologies still have significant limitations in preventing and treating cardiotoxicity caused by anthracyclines, and there is an urgent need to develop a new treatment regimen that is highly effective, safe, and has a clear mechanism of action. Summary of the Invention
[0005] Based on this, the purpose of the present invention is to provide the application of tanshinone A in the preparation of a drug for treating cardiotoxicity of antitumor drugs, thereby solving the problems in the prior art.
[0006] To achieve the above objectives, the present invention adopts the following technical solution.
[0007] This invention provides the application of tanshinone A in the preparation of a drug for treating cardiotoxicity of antitumor drugs.
[0008] In some embodiments of the present invention, the cardiotoxicity of the antitumor drug is the cardiotoxicity caused by anthracycline drugs.
[0009] Przewaquinone A (PA) is an important active ingredient in Danshen (Salvia miltiorrhiza) with strong antioxidant and anti-inflammatory activities. However, no studies have yet reported its application in preventing and treating anthracycline-induced cardiotoxicity. This invention experimentally verifies that Przewaquinone A has a multi-target synergistic effect, significantly inhibiting myocardial oxidative stress, reducing inflammatory responses, and protecting myocardial cell function, thereby effectively preventing and treating anthracycline-induced cardiotoxicity (AIC). The single herbal ingredient provided by this invention is an effective component extracted from the pure natural medicinal plant Danshen, possessing advantages such as definite efficacy, low toxicity, and a clear mechanism of action. As a single active ingredient, Przewaquinone A has a well-defined chemical structure and easily established quality control standards, offering significant advantages in pharmacological mechanism research, drug development, and clinical application, providing a novel solution for the clinical prevention and treatment of anthracycline-induced cardiotoxicity.
[0010] In some embodiments of the present invention, the anthracycline drug includes: doxorubicin.
[0011] In some embodiments of the present invention, the drug is used to improve the physiological state of cardiotoxic mice and enhance cardiac contractile function.
[0012] In some embodiments of the present invention, the drug is used to correct abnormal electrocardiographic activity in cardiotoxic mice and reduce myocardial tissue inflammation and oxidative stress levels.
[0013] In some embodiments of the present invention, the content of tanshinone A in the drug is 1wt% to 99wt%.
[0014] In some embodiments of the present invention, the drug is a tablet, granule, capsule, or injection.
[0015] In some embodiments of the present invention, the drug further includes other pharmaceutically acceptable excipients.
[0016] In some specific embodiments of the present invention, the other pharmaceutically acceptable excipients include solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, anti-adhesion agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and anti-flocculation agents, filter aids, and release inhibitors.
[0017] In some specific embodiments of the present invention, the filler is selected from starch, sucrose, lactose, or microcrystalline cellulose; the binder is selected from cellulose derivatives, alginate, gelatin, or polyvinylpyrrolidone; the wetting agent is selected from water, glycerin, ethanol, methylcellulose, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, or hydroxypropyl methylcellulose; the disintegrant is selected from sodium carboxymethyl starch, hydroxypropyl cellulose, cross-linked carboxymethyl cellulose, agar, calcium carbonate, or sodium bicarbonate; the absorption promoter is a quaternary ammonium compound; the surfactant is selected from hexadecyl alcohol or sodium dodecyl sulfate; the adsorbent carrier is selected from kaolin or soap clay; the lubricant is selected from talc, calcium and magnesium stearate, micronized silica gel, or polyethylene glycol; and the flavoring agent is selected from sucrose, simple syrup, aromatic syrup, glycerin, sorbitol, or mannitol.
[0018] In some embodiments of the present invention, the drug further includes a drug carrier.
[0019] In some embodiments of the present invention, the drug carrier comprises one of microcapsules, microspheres, nanoparticles, and liposomes.
[0020] Based on the technical solution of the present invention, the present invention has the following beneficial effects compared with the prior art:
[0021] This invention marks the first application of tanshinone A in the prevention and treatment of anthracycline-induced cardiotoxicity. Tanshinone A is a natural active ingredient extracted from Salvia miltiorrhiza, possessing strong antioxidant and anti-inflammatory activities. This invention, by applying tanshinone A to the prevention and treatment of anthracycline-induced cardiotoxicity (AIC), provides a novel treatment regimen with significant efficacy, high safety, and a clearly defined mechanism of action. It effectively overcomes the limitations of existing technologies in preventing and treating anthracycline-induced cardiotoxicity and has significant clinical application value.
[0022] This invention experimentally verifies that tanshinone A has a multi-target synergistic effect, significantly inhibiting myocardial oxidative stress, reducing inflammatory responses, and protecting myocardial cell function, thereby effectively preventing and treating anthracycline-induced cardiotoxicity (AIC). The traditional Chinese medicine monomer provided by this invention is an effective component extracted from the pure natural medicinal plant *Salvia miltiorrhiza*, possessing advantages such as definite efficacy, minimal toxicity, and a clear mechanism of action. As a single active ingredient, tanshinone A has a well-defined chemical structure and easily established quality control standards, offering significant advantages in pharmacological mechanism research, drug development, and clinical application, providing a novel solution for the clinical prevention and treatment of anthracycline-induced cardiotoxicity. Attached Figure Description
[0023] Figure 1 The image shows the results of tanshinone A improving the general condition of DOX mice; among them... Figure 1 In the diagram, A represents a gross view of the heart of a mouse in each group; Figure 1 In this context, B represents the change in body weight of mice in each group after DOX induction.
[0024] Figure 2 The images show the cardiac ultrasound images (short axis sections) of mice in each group after treatment with tanshinone A.
[0025] Figure 3 The graph shows the left ventricular ejection fraction of mice in each group after treatment with tanshinone A.
[0026] Figure 4 The image shows the results of tanshinone A improving abnormal cardiac electrical activity; among which... Figure 4 In the figure, A represents a comparison of the QT intervals in the electrocardiograms of different groups of mice; Figure 4 In the figure, B represents a comparison of the corrected QT interval (QTc) of the electrocardiograms of the mice in each group.
[0027] Figure 5 H&E staining images of heart tissue from mice in each group after treatment with tanshinone A (×200).
[0028] Figure 6 The figure shows the results of tanshinone A improving myocardial oxidative stress in mice; among them Figure 6 In the diagram, A represents the ROS fluorescence staining image of the heart tissue of mice in each group; Figure 6 In the figure, B represents the statistical graph of the average fluorescence intensity of ROS in the heart tissue of mice in each group. Detailed Implementation
[0029] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.
[0030] The following description is based on specific embodiments.
[0031] Example 1
[0032] 1. Medicine
[0033] The standard of tanshinone A was purchased from Chengdu Zhibiaohua Pure Biotechnology Co., Ltd., CAS No.: 76843-23-7.
[0034] 2. Experimental Animals: Eight-week-old male SPF-grade C57BL / 6J mice (weighing 18-22 g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. All mice were housed in an SPF-grade animal facility under the following conditions: temperature 22±2℃, humidity 50±5%, 12-hour light-dark cycle (light time 8:00-20:00), and provided with free access to standard rodent food and sterile drinking water. Mice were acclimatized for one week, during which their condition was observed daily. Modeling was performed only after confirming the absence of abnormalities.
[0035] 3. Construction of an acute cardiotoxicity model
[0036] Mice were randomly divided into an acute cardiotoxicity model group and a normal control group;
[0037] Acute cardiotoxicity model group (DOX group): 24 animals, who received a single intravenous injection of doxorubicin (DOX) solution (manufacturer: McLean, catalog number: D807083) via tail vein. The DOX solution concentration was 4 mg / ml, the injection dose was 20 mg / kg, and it was injected once.
[0038] Normal control group (CON group): 6 animals, injected with physiological saline with an equal volume of doxorubicin via tail vein.
[0039] Baseline body weight was measured for all mice before modeling. After modeling, body weight was monitored daily, and mental status, feeding, fur condition, activity level, and survival were observed.
[0040] 4. Grouping and Dosing
[0041] Mice with acute cardiotoxicity were randomly divided into five groups: normal control group (CON group): injected with the same amount of physiological saline as doxorubicin at the time of modeling; model group (DOX group): DOX modeling + physiological saline gavage; low-dose tanshinone A group (PA-L group): DOX modeling + tanshinone A (10 mg / kg) gavage; high-dose tanshinone A group (PA-H group): DOX modeling + tanshinone A (20 mg / kg) gavage; positive control drug pravastatin group (PRAVA group): DOX modeling + pravastatin (40 mg / kg) gavage.
[0042] The administration regimen consisted of prophylactic and therapeutic administration, starting with gavage two days before modeling, once daily; and continuing for three days after modeling (total intervention period of 5 days). The administration volume was uniform (10 ml / kg), with the CON and DOX groups receiving the same dose of distilled water by gavage. Gavage was performed at a fixed time, once daily, for 5 consecutive days. During the treatment period, mice in all groups had free access to water and food.
[0043] 5. General condition monitoring
[0044] During the experiment, the growth, food and water intake, coat color and luster, mental state and other general conditions of the mice in each group were observed and their body weight was recorded.
[0045] 6. Cardiac function assessment
[0046] On the third day after modeling, the short-axis M-shaped images of the left ventricle of each group of mice were examined, and the left ventricular ejection fraction (LVEF%) was measured. The average value was taken for three cardiac cycles for each mouse.
[0047] 7. Electrocardiogram (ECG) function assessment
[0048] Electrocardiogram (ECG) tests were performed on the third day of modeling. After mice were anesthetized with isoflurane, electrodes were connected to the limbs, and standard lead II ECGs were recorded. Parameters such as QT interval (QT) and corrected QT interval (QTc) were analyzed, and the presence of arrhythmias was recorded.
[0049] 8. Cardiac Pathological Analysis
[0050] Mice were sacrificed at the end of the experiment, and heart tissue was quickly collected, fixed in 4% paraformaldehyde, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (HE). Cardiac cell arrangement, inflammatory cell infiltration, and degree of necrosis were observed under a light microscope.
[0051] 9. Inflammation and Oxidative Stress Detection
[0052] The level of reactive oxygen species (ROS) in myocardium was detected by DHE fluorescence staining. After staining, the slides were photographed, and the fluorescence intensity was semi-quantitatively analyzed using ImageJ software.
[0053] 10. Experimental Results
[0054] (1) Modeling results
[0055] like Figure 1 As shown, compared with the normal control group (CON group), the doxorubicin model group (DOX group) mice exhibited significant systemic toxicity and cardiac injury characteristics after administration, indicating that the acute cardiotoxicity model was successfully established. The body weight of the DOX group mice decreased significantly after administration (P<0.01). Figure 1 (B) The mice exhibited a series of significant adverse effects, including lethargy, significantly reduced activity, rough and frizzy fur, and decreased food and water intake; some mice even died. These typical behavioral and physiological changes, combined with the severe impairment of cardiac function (such as significantly reduced LVEF), electrocardiographic abnormalities (QT interval prolongation), and myocardial tissue pathological damage observed in subsequent echocardiography and myocardial marker tests, collectively confirmed the successful establishment of an doxorubicin-induced acute cardiotoxicity model, which can be used for subsequent pharmacodynamic evaluation.
[0056] (2) The effect of tanshinone on improving the general condition of DOX mice
[0057] like Figure 1 As shown in Figures A and B, the normal control group (CON group) mice were more active and had glossy fur; the doxorubicin model group (DOX group) mice showed a significant decrease in body weight (P<0.01), accompanied by lethargy, dull fur, and reduced activity. After intervention with tanshinone A, the above symptoms were significantly alleviated, the weight loss slowed down, and the mental state and activity level improved, with effects similar to those of the positive control drug pravastatin group (PRAVA group).
[0058] (3) Salvia miltiorrhiza extract improves cardiac contractile function
[0059] like Figure 2 and Figure 3 As shown, ultrasound examination revealed that the LVEF in the DOX group was significantly lower than that in the CON group (P<0.01). Both the PA-L and PA-H groups significantly improved LVEF (P<0.05) and enhanced cardiac contractile function, comparable to the pravastatin group.
[0060] (4) Salvia miltiorrhiza extract improves abnormal cardiac electrical activity.
[0061] like Figure 4 As shown in A and B, the QT interval and QTc were significantly prolonged in the DOX group mice (P<0.01), indicating cardiac electrical activity disorder. After intervention, the QT and QTc were significantly shortened in the PA-L and PA-H groups, with statistically significant differences (P<0.01), but there was no significant difference compared to the PRAVA group.
[0062] (5) Salvia miltiorrhiza extract improves myocardial pathological tissue structure
[0063] like Figure 5 As shown, HE staining of myocardial tissue revealed significant cardiomyocyte disorder, inflammatory cell infiltration, and focal necrosis in the DOX group. The PA-H group significantly alleviated pathological damage while maintaining the integrity of myocardial tissue; the PA-L group also showed a mitigating effect, with pathological manifestations superior to the DOX group, and the effect was comparable to that of the PRAVA group.
[0064] (6) Tanshinone A improves myocardial oxidative stress in mice
[0065] like Figure 6 As shown in Figures A and B, ROS fluorescence staining results revealed a significant increase in ROS levels in the myocardial tissue of DOX-treated mice, indicating significant activation of oxidative stress. After intervention with tanshinone A, the ROS fluorescence intensity in the PA-H and PA-L groups was significantly reduced, exhibiting potent antioxidant effects, with statistically significant differences (P<0.01), comparable to the pravastatin positive control group (PRAVA).
[0066] In summary, this invention is the first to propose a technical solution for treating anthracycline-induced cardiotoxicity using the traditional Chinese medicine monomer tanshinone A, and confirms its multi-dimensional and multi-target cardioprotective effects. Tanshinone A can effectively improve the general physiological state of mice with doxorubicin-induced cardiotoxicity, enhance cardiac contractile function, correct abnormal cardiac electrical activity, and reduce myocardial tissue inflammation and oxidative stress, thereby exerting a preventive and therapeutic effect against anthracycline-induced cardiotoxicity. This technical solution not only provides an effective and feasible natural active ingredient for the prevention and treatment of DOX cardiotoxicity, but also has a good pharmacological basis and development prospects, making it suitable for development into a safe, convenient, orally administered cardioprotective dosage form, expanding its application potential in the field of adjuvant chemotherapy.
[0067] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0068] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.
Claims
1. Application of tanshinone A in the preparation of drugs for treating cardiotoxicity of antitumor drugs.
2. The application as described in claim 1, characterized in that, The cardiotoxicity of the antitumor drugs mentioned refers to the cardiotoxicity caused by anthracyclines.
3. The application as described in claim 1, characterized in that, The anthracycline drugs include: doxorubicin.
4. The application as described in claim 1, characterized in that, The drug is used to improve the physiological state of cardiotoxic mice and enhance cardiac contractile function.
5. The application as described in claim 1, characterized in that, The drug was used to correct abnormal electrocardiographic activity in cardiotoxic mice and reduce myocardial tissue inflammation and oxidative stress levels.
6. The application as described in claim 1, characterized in that, The content of tanshinone A in the drug is 1wt%~99wt%.
7. The application as described in claim 1, characterized in that, The drug is in the form of tablets, granules, capsules, or injections.
8. The application as described in claim 1, characterized in that, The drug also includes other pharmaceutically acceptable excipients.
9. The application as described in claim 1, characterized in that, The drug also includes a drug carrier.
10. The application as described in claim 9, characterized in that, The drug carrier comprises one of microcapsules, microspheres, nanoparticles, and liposomes.