Application of artesunate in prevention or treatment of chemotherapeutic drug-induced cardiotoxicity

Abstract

The present invention relates to the use of artesunate for the prevention or treatment of chemotherapeutic drug induced cardiotoxicity. Artesunate improves the cardiac function of a mouse with chemotherapeutic drug induced cardiotoxicity; the chemotherapeutic drug-induced myocardial injury can be repaired, and the chemotherapeutic drug-induced myocardial fibrosis can be inhibited; the content of myocardial injury markers creatine kinase and lactic dehydrogenase in body serum can be reduced.

Description

Technical Field

[0001] The present invention relates to the field of medical research, and in particular to use of artesunate for preventing or treating chemotherapy-induced cardiotoxicity. Background Art

[0002] Doxorubicin (DOX) is an anthracycline compound widely used in chemotherapy for a variety of malignancies, including breast cancer, lung cancer, and lymphoma. As a chemotherapeutic drug, DOX not only kills tumor cells but also is toxic to normal cardiomyocytes, leading to cardiotoxicity as a major side effect. Doxorubicin-induced cardiotoxicity (DIC) manifests primarily as cardiomyocyte apoptosis, myocardial dysfunction, and heart failure. This toxicity can develop in a subacute, acute, or chronic manner, with risk factors including cumulative dose, drug administration rate, preexisting heart disease, and hypertension. Studies have found that the risk of death from drug-related cardiotoxicity in cancer patients exceeds the risk of death from the tumor itself or from tumor recurrence. Currently, dexrazoxane is the only FDA-approved drug for the prevention of DIC. However, due to its side effects and strict indications, the European Medicines Agency does not recommend this treatment. Consequently, the prevention and treatment of DIC faces a clinical dilemma, with a lack of available drugs. The development of more effective and safer preventive and treatment drugs is a current research priority.

[0003] As a unique health resource in my country, traditional Chinese medicine has important application value in anti-tumor treatment and reducing the toxic side effects of chemotherapy drugs. Artesunate is a derivative of artemisinin and a first-line antimalarial drug. It has been proven to have multiple biological functions such as antiviral, anti-inflammatory, anti-angiogenic, and anti-cancer. Artesunate, also known as dihydroartemisinin-10α-succinate monoester, has a molecular formula of C 19 H 28 O8, with a molecular weight of 384.42, has the following structural formula:

[0004] Summary of the Invention

[0005] To this end, the present invention provides the use of artesunate for preventing or treating chemotherapy-induced cardiotoxicity.

[0006] In one embodiment, the chemotherapeutic agent is an anthracycline.

[0007] In one embodiment, the chemotherapeutic agent is doxorubicin hydrochloride.

[0008] In one embodiment, the artesunate improves cardiac function in mice with chemotherapeutic drug-induced cardiotoxicity.

[0009] In one embodiment, the artesunate is capable of repairing myocardial damage induced by chemotherapy drugs.

[0010] In one embodiment, the artesunate is capable of inhibiting chemotherapeutic drug-induced myocardial fibrosis.

[0011] In one embodiment, the artesunate is capable of reducing the levels of creatine kinase and lactate dehydrogenase, markers of myocardial injury, in the serum of the body.

[0012] In one embodiment, the artesunate is used as the sole active ingredient in a medicament for preventing or treating chemotherapeutic drug-induced cardiotoxicity.

[0013] In one embodiment, the drug for preventing or treating chemotherapeutic drug-induced cardiotoxicity further comprises a pharmaceutically acceptable excipient.

[0014] In one embodiment, the artesunate has the following structural formula:

[0015]

[0016] The artesunate of the present invention can significantly reduce the cardiotoxicity induced by adriamycin and has a significant effect of improving cardiac function. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0018] Figure 1 Representative ultrasound images of cardiac function of mice in each group are shown, where Vehicle represents the blank group; DOX represents the doxorubicin group; DOX+LowART represents the low-dose artesunate group; DOX+HighART represents the high-dose artesunate group; and DOX+Dex represents the dexrazoxane group.

[0019] Figure 2 The results of the cardiac function parameters of each group of mice are shown in the statistical chart, where Vehicle represents the blank group; DOX represents the doxorubicin group; DOX+LowART represents the low-dose artesunate group; DOX+HighART represents the high-dose artesunate group; and DOX+Dex represents the dexrazoxane group. Note: Compared with the model group, *P<0.05, **P<0.01, ***P<0.001, n=6;

[0020] Figure 3HE staining images of the heart morphology of mice in each group are shown, wherein Vehicle represents the blank group; DOX represents the doxorubicin group; DOX+LowART represents the low-dose artesunate group; DOX+HighART represents the high-dose artesunate group; DOX+Dex represents the dexrazoxane group;

[0021] Figure 4 The Masson staining images of mice in each group are shown, wherein Vehicle represents the blank group; DOX represents the doxorubicin group; DOX+LowART represents the low-dose artesunate group; DOX+HighART represents the high-dose artesunate group; DOX+Dex represents the dexrazoxane group;

[0022] Figure 5 Figure 2 shows the levels of cardiac injury markers in the serum of mice in each group. Vehicle represents the blank group; DOX represents the doxorubicin group; DOX+LowART represents the low-dose artesunate group; DOX+HighART represents the high-dose artesunate group; and DOX+Dex represents the dexrazoxane group. Note: *P<0.05, **P<0.01, ***P<0.001 compared with the model group, n=6. DETAILED DESCRIPTION

[0023] The following examples are provided for a better understanding of the present invention and are not intended to limit the best mode of implementation. They do not limit the content and scope of protection of the present invention. Any product identical or similar to the present invention obtained by anyone under the guidance of the present invention or by combining the features of the present invention with other prior arts shall fall within the scope of protection of the present invention.

[0024] Example

[0025] Experimental drugs

[0026] The drugs used in this experiment are as follows:

[0027] Doxorubicin hydrochloride was purchased from Shanghai Yuanye Biotechnology Co., Ltd., batch number S17092, 25 mg / bottle. Doxorubicin hydrochloride is referred to as doxorubicin (abbreviated as DOX);

[0028] Artesunate, standard product, purchased from Chengdu Desite Biotechnology Co., Ltd., batch number DA0040, 5 mg / vial;

[0029] Dexrazoxane hydrochloride was purchased from GlpBio, batch number GC11619, 50 mg / bottle. This dexrazoxane hydrochloride is referred to as dexrazoxane (abbreviated as DEX).

[0030] Establishment of a mouse model of doxorubicin-induced cardiotoxicity

[0031] 6-8 week old male C57BL / 6 mice were used for doxorubicin-induced cardiotoxicity modeling as follows: after 3 days of adaptive feeding, the mice were randomly divided into a blank group, a doxorubicin group, a low-dose artesunate group (25 mg / kg), a high-dose artesunate group (50 mg / kg), and a dexrazoxane group (30 mg / kg, positive drug), with 6 mice in each group.

[0032] The blank group received sterile saline via the tail vein, while all other groups received 5 mg / kg of doxorubicin via the tail vein once weekly for four weeks (cumulative dose of 20 mg / kg) to establish a cardiotoxicity model. The dexrazoxane group received a tail vein injection of 30 mg / kg of dexrazoxane 30 minutes before model establishment and then once weekly (as close as possible) for four weeks. Doses were calculated based on clinically used doses. The artesunate group received daily intraperitoneal injections of the corresponding concentration of artesunate for 28 consecutive days.

[0033] Echocardiography in mice

[0034] After anesthesia, mice were skinned on the left chest and placed on an ultrasound table with their limbs pressed against copper plates and coated with coupling agent. Left ventricular internal dimension (LVID) diastole (d) and left ventricular internal dimension (LVID) systole (s) were measured using the Vevo2100 small animal ultrasound imaging system. Ejection fraction (EF) and fractional shortening (FS) were calculated using ultrasound data analysis software to assess cardiac function.

[0035] Experimental results:

[0036] Compared with the blank group, the left ventricular ejection fraction EF and left ventricular fractional shortening FS of mice in the doxorubicin group were decreased (P<0.001), indicating that doxorubicin injection caused impaired cardiac function in mice.

[0037] Compared with the model group, the EF values ​​of mice in the low-dose artesunate group (25 mg / kg) and the high-dose artesunate group (50 mg / kg) increased significantly after 28 days of artesunate intervention (P<0.001), indicating that artesunate can significantly alleviate the decline in cardiac function induced by adriamycin. In addition, artesunate can significantly reduce the left ventricular end-diastolic diameter (LVID; d) value and the left ventricular end-systolic diameter (LVID; s) value, indicating that artesunate can improve the dilation of the left ventricle in mice and improve cardiac function. The positive drug dexrazoxane also has the same effect (such as Figure 1 and Figure 2 shown).

[0038] Observation of pathological changes in mouse heart tissue by HE staining

[0039] The heart tissue was immersed in 4% paraformaldehyde solution and embedded in paraffin 24 hours later. After dewaxing, the sections were stained with hematoxylin for 2 minutes, rinsed with running water for 5 minutes, stained with eosin for 90 seconds, rinsed with running water for 10 minutes, and dried in a 60℃ oven for 30 minutes. The sections were sealed with neutral resin, and the pathological changes of the heart tissues in each group were observed under a microscope.

[0040] Experimental results:

[0041] The myocardial cells of the mice in the blank group were intact in morphology, arranged neatly and orderly, and evenly colored. There were no obvious structural changes in the cell nuclei and no inflammatory cell infiltration. The myocardial cells of the mice in the doxorubicin group were obviously loosely and disorderly arranged, the myocardial fiber striations were unclear or even disappeared, the cell nuclei were condensed or ruptured, inflammatory cells infiltrated in the myocardial interstitium, and the normal structure was lost. Compared with the doxorubicin group, the disordered arrangement of myocardial tissue and the rupture and dissolution of myocardial fibers in the mice in the low-dose artesunate group (25 mg / kg) and the high-dose artesunate group (50 mg / kg) were improved. Only a small number of cells lost their normal structure, and occasionally there was infiltration of inflammatory cells (such as Figure 3 The results showed that artesunate could repair doxorubicin-induced myocardial damage.

[0042] Masson staining

[0043] Paraffin sections were dewaxed; the nuclei were stained with hematoxylin solution for 5–10 min; the sections were differentiated in 1% hydrochloric acid alcohol for 5–15 s and rinsed with water; the sections were kept in 0.1%–1% lithium carbonate for 5 min to increase the degree of blueing, and rinsed with water; the sections were stained with Ponceau acid fuchsin solution for 5–10 min for tissue structure, and rinsed with weak acid working solution (2% glacial acetic acid aqueous solution) for 1 min; the sections were differentiated with 1% phosphomolybdic acid aqueous solution for 3–5 min and rinsed with weak acid working solution for 1 min; the sections were stained with aniline blue aqueous solution for 1–2 min and rinsed with weak acid working solution for 1 min; the sections were dehydrated, sealed, and observed under a microscope.

[0044] Experimental results:

[0045] The myocardial cell tissue of the mice in the blank group was dense and neatly arranged, and no obvious collagen deposition was observed. The myocardial tissue of the mice in the doxorubicin group was disordered and loose, with a large amount of collagen deposition forming scars, and the degree of fibrosis was significantly aggravated. The collagen deposition of myocardial cells of the mice in the low-dose artesunate group (25 mg / kg) and the high-dose artesunate group (50 mg / kg) was significantly reduced. The results show that artesunate can reduce collagen deposition in myocardial tissue and reduce the degree of myocardial fibrosis ( Figure 4 ).

[0046] In addition, compared with the doxorubicin group, the levels of myocardial injury markers creatine kinase CK-MB and lactate dehydrogenase LDH in the serum of mice in the low-dose artesunate group (25 mg / kg) and the high-dose artesunate group (50 mg / kg) were significantly reduced ( Figure 5 ).

[0047] In order to better illustrate the purpose, complete technical route and advantages of the present invention, the present invention will be further described in detail below with reference to specific embodiments and drawings. However, the embodiments described below are only part of the embodiments of the present invention and do not include all embodiments. Based on the embodiments of the present invention, other embodiments that can be obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0048] In the examples described below, unless otherwise specified, the conventional methods used are technical means generally recognized or commonly used by those skilled in the art, and the instruments, reagents, consumables, etc. used in the examples of the present invention can be obtained through regular commercial channels.

Claims

1. Use of artesunate in the preparation of a medicament for preventing or treating chemotherapy-induced cardiotoxicity.

2. The use according to claim 1, characterized in that: The chemotherapy drug is an anthracycline drug.

3. The use according to claim 1 or 2, characterized in that: The chemotherapy drug is doxorubicin hydrochloride.

4. The use according to claim 1, characterized in that Artesunate improves cardiac function in mice with chemotherapy-induced cardiotoxicity.

5. The use according to claim 4, characterized in that The artesunate can repair myocardial damage induced by chemotherapy drugs.

6. The use according to claim 4, characterized in that The artesunate can inhibit myocardial fibrosis induced by chemotherapy drugs.

7. The use according to claim 4, characterized in that The artesunate can reduce the content of creatine kinase and lactate dehydrogenase, which are myocardial injury markers, in the body's serum.

8. The use according to claim 1, characterized in that The artesunate is used as the sole active ingredient in a drug for preventing or treating chemotherapy-induced cardiotoxicity.

9. The use according to claim 1, characterized in that The drug for preventing or treating chemotherapy-induced cardiotoxicity further comprises a pharmaceutically acceptable excipient.

10. The use according to claim 1, characterized in that The artesunate has the following structural formula:

Images