Application of trimetazidine hydrochloride in medicine for preventing and treating melanoma and brain glioma

Abstract

The invention discloses application of trimetazidine hydrochloride in preparation of medicines for treating glioma, melanoma and other solid tumors, and belongs to the technical field of medicines. The invention also discloses application of a pharmaceutical composition containing the trimetazidine hydrochloride as an active component in preparation of drugs for treating glioma and melanoma, wherein the trimetazidine hydrochloride is a compound shown in the formula (I). # imgabs0 #

Description

Technical Field

[0001] The invention relates to use of trimetazidine hydrochloride in preparing medicines for preventing and treating brain gliomas, melanomas and other solid tumors, and belongs to the technical field of medicines. Background Art

[0002] Gliomas are the most common primary tumors in the brain, accounting for 81% of central nervous system (CNS) malignancies. They usually originate from glial cells or precursor cells and develop into astrocytomas, oligodendrogliomas, ependymomas, or oligoastrocytomas. According to the WHO classification, gliomas are divided into 4 grades, of which grade 1 and 2 gliomas represent low-grade gliomas, and grade 3 and 4 gliomas represent high-grade gliomas. In general, relatively high grades are associated with poor prognosis. The 10-year survival rate of low-grade gliomas is 11%, and the median survival is 11.6 years. For HGG, the median OS survival time for patients with grade 3 gliomas is about 4 years, while the median OS survival time for grade 4 gliomas is poor, at 15 months. Glioblastoma (GBM) is the most common type of grade 4 glioma.

[0003] Glioma is a malignant tumor with a high incidence, short survival and high degree of poor prognosis. However, at present, the standard care for glioma includes maximal surgical resection, combined with temozolomide radiotherapy and chemotherapy within 30 days after surgery. In addition to TMZ, bevacizumab and tumor treatment fields (TTF) have been approved by the FDA for the treatment of glioblastoma. Bevacizumab is a synthetic monoclonal antibody that targets vascular endothelial growth factor (VEGF). TTF is an electromagnetic field therapy that selectively damages proliferating cells by applying a low-intensity, medium-frequency alternating electric field. A phase III clinical trial showed that TTF combined with TMZ can significantly prolong the progression-free survival and OS of GBM patients. Considering the limited resources for the treatment of glioma, more research is needed to study new methods to combat this malignancy. However, the high price of monoclonal antibodies and the common side effects of alkylating agents such as bone marrow transplantation, nausea, and vomiting that may be caused by taking TMZ make the glioma drug market still need great development.

[0004] Melanoma, other than glioma, is the most serious type of skin cancer. It is caused by mutation of melanocytes and turns into melanoma tumors with high recurrence and high metastasis. As the tumor grade increases, the 5-year survival rate of melanoma patients drops from 90% to less than 5% in stage IV. For patients in stage I and II, surgical resection is mostly used for treatment, while patients with higher grades are currently treated with PD-1 monoclonal antibodies or other biological agents. Some patients are also troubled by high prices and injection pain. Therefore, the treatment of various solid tumors represented by glioma and melanoma requires further research and development.

[0005] Trimetazidine is a long-chain 3-ketoacyl-CoA-thiolase inhibitor. It selectively inhibits intracellular fatty acid β-oxidation, stimulates glucose oxidation, improves cellular energy metabolism, increases myocardial oxygen utilization, reduces oxygen consumption, reduces vascular resistance, and increases coronary microcirculatory blood flow. It is clinically used as an anti-myocardial ischemia drug for long-term anti-angina treatment. Trimetazidine hydrochloride has been used for many years, and the only side effect reported is rare gastrointestinal discomfort (nausea, vomiting). Extremely rare Parkinson's symptoms, such as tremor, rigidity and akinesia, can be restored after drug discontinuation, with excellent drug safety.

[0006] Our previous studies have shown that trimetazidine hydrochloride, as a commonly used anti-angina drug, can not only act on myocardial cells, but also inhibit tumor growth, including but not limited to gliomas and melanomas. Based on this, the inventors used mouse ectopic and orthotopic tumor inoculation models to explore the therapeutic effects of trimetazidine hydrochloride on gliomas and melanomas, and evaluated the biological effects of trimetazidine hydrochloride in the occurrence and development of gliomas and melanomas in depth, thereby completing the present invention, providing new treatment options for various solid tumors such as gliomas and melanomas, and providing a theoretical basis for treating solid tumors with energy metabolism as a target. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide the use of trimetazidine hydrochloride in preparing a medicine for treating glioma, melanoma and other solid tumors.

[0008] In order to solve the above technical problems of the present invention, the present invention provides the following technical solutions:

[0009] In a first aspect, the present invention provides the use of trimetazidine hydrochloride or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and treating brain glioma, melanoma and various solid tumors, wherein the trimetazidine hydrochloride is a compound represented by formula (I):

[0010]

[0011] In a second aspect, the present invention provides a use of a pharmaceutical composition in the preparation of a drug for treating glioma, melanoma and various solid tumors, wherein the pharmaceutical composition contains a therapeutically effective amount of trimetazidine hydrochloride or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein trimetazidine hydrochloride is a compound represented by formula (I).

[0012] The trimetazidine hydrochloride of the present invention can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining trimetazidine hydrochloride or a pharmaceutically acceptable salt thereof represented by formula (I) of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of trimetazidine hydrochloride represented by formula (I) of the present invention in its pharmaceutical composition is generally 0.1-99.8% by weight.

[0013] The trimetazidine hydrochloride represented by formula (I) of the present invention or the pharmaceutical composition containing it can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc. The dosage form can be a liquid dosage form, a solid dosage form or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w type, w / o type and multiple emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.; semisolid dosage forms can be ointments, gels, pastes, etc. The aminopropylene glycol derivatives of the present invention can be made into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.

[0014] The dosage of trimetazidine hydrochloride shown in formula (I) of the present invention can vary widely according to the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and the dosage form. Generally speaking, the suitable daily dosage range of trimetazidine hydrochloride of the present invention is 0.01-600 mg / Kg body weight, preferably 0.1-300 mg / Kg body weight, more preferably 0.1-150 mg / Kg body weight, orally twice a day, and most preferably 0.3-150 mg / Kg body weight, orally twice a day. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the doctor's clinical experience and the dosage regimen including the use of other treatment methods.

[0015] The trimetazidine hydrochloride represented by formula (I) of the present invention or the pharmaceutical composition containing it can be taken alone or used in combination with other therapeutic drugs or symptomatic drugs. When the trimetazidine hydrochloride represented by formula (I) of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0016] Beneficial effects: The trimetazidine hydrochloride represented by formula (I) of the present invention has significant therapeutic effects on mouse glioma (orthotopic and ectopic) and melanoma (ectopic) models, can significantly delay tumor growth, reduce tumor volume, maintain mouse body weight, maintain immune cell levels, is safe and non-toxic, and provides a new drug option for the clinical treatment of glioma, melanoma and various solid tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1. Effect of trimetazidine hydrochloride on body weight of mice ectopically inoculated with G422 glioma;

[0018] Figure 2. Effects of trimetazidine hydrochloride on tumor volume and weight of ectopically inoculated G422 glioma;

[0019] Figure 3. Effect of trimetazidine hydrochloride on body weight of mice orthotopically inoculated with G422 glioma;

[0020] Figure 4. Effect of trimetazidine hydrochloride on tumor size of orthotopically inoculated G422 glioma (MRI detection);

[0021] Figure 5. Effects of trimetazidine hydrochloride on the five types of peripheral blood inoculated with G422 in situ;

[0022] Figure 6. Effect of trimetazidine hydrochloride on body weight of mice ectopically inoculated with B16F10 melanoma;

[0023] Figure 7. Effects of trimetazidine hydrochloride on tumor volume and weight of ectopically inoculated B16F10 melanoma cells;

[0024] Figure 8: Effects of trimetazidine hydrochloride on immune cells of melanoma ectopically inoculated with B16F10 (flow cytometry); A: Effects of trimetazidine hydrochloride on lymphocytes ectopically inoculated with B16F10; B: Effects of trimetazidine hydrochloride on B cells ectopically inoculated with B16F10; C: Effects of trimetazidine hydrochloride on NK cells ectopically inoculated with B16F10; D: Effects of trimetazidine hydrochloride on T cells and their subtypes ectopically inoculated with B16F10; E: Effects of trimetazidine hydrochloride on tumor-associated macrophages ectopically inoculated with B16F10; F: Effects of trimetazidine hydrochloride on granuloid myeloid-derived suppressor cells ectopically inoculated with B16F10; G: Effects of trimetazidine hydrochloride on monocytic myeloid-derived suppressor cells ectopically inoculated with B16F10. DETAILED DESCRIPTION

[0025] In order to enable those skilled in the art to fully understand the present invention, the present invention is further described below through specific examples, but those skilled in the art should be aware that the examples of the present invention do not limit the present invention in any way.

[0026] Experimental Example 1: Pharmacodynamic study of trimetazidine hydrochloride on ectopic inoculation of G422

[0027] Experimental method: The pharmacodynamic effect of trimetazidine hydrochloride on glioma was evaluated by using an animal model of ectopic inoculation of G422 glioma in ICR mice. 3×10 6 G422 tumor cells were grouped and administered on the first day after modeling, and were divided into a control group (model), a temozolomide group (TMZ), a trimetazidine hydrochloride 7.5 mg / kg twice daily administration group (7.5 mg / kg b.id), a trimetazidine hydrochloride 15 mg / kg twice daily administration group (15 mg / kg b.id), a trimetazidine hydrochloride 30 mg / kg daily single administration group (30 mg / kg q.d.), and a trimetazidine hydrochloride 60 mg / kg daily single administration group (60 mg / kg q.d.), with 7 animals in each group, wherein the model group was given an equal volume of solvent control-0.5% sodium carboxymethyl cellulose, and the temozolomide group was given an oral administration of 50 mg / kg for five consecutive days and then stopped. The experiment was terminated on the 17th day after modeling, and the mouse body weight, tumor volume, and tumor weight were evaluated according to methods known in the art.

[0028] Experimental results: During the experiment, trimetazidine hydrochloride can maintain the body weight of ectopically inoculated G422 mice (see Figure 1) At the end of the experiment 17 days after modeling, the average tumor weight of the model group animals reached 1.68g. Trimetazidine hydrochloride can significantly inhibit tumor growth, and the tumor inhibition effect of twice-daily administration is better than that of single daily administration. As the dosage increases, the tumor growth slows down and the weight decreases (see Figure 2) The 15mg / kgb.id group had the best tumor treatment effect, with a tumor inhibition rate of 60.3%. The above research results suggest that trimetazidine hydrochloride can treat ectopically inoculated G422 tumors and has good safety, and is very likely to become a drug for the treatment of G422.

[0029] Table 1 The inhibitory effect of trimetazidine hydrochloride on the growth of subcutaneous tumors of mouse brain glioma cells G422

[0030]

[0031] Experimental Example 2: Pharmacodynamic Study of Trimetazidine Hydrochloride on In situ Inoculation of G422

[0032] Experimental method: The pharmacodynamic effect of trimetazidine hydrochloride on glioma was evaluated by using an animal model of ectopic inoculation of G422 glioma in ICR mice. 2×10 5 G422 tumor cells were grouped and administered on the first day after modeling, and were divided into a control group (model), a temozolomide group (TMZ), a trimetazidine hydrochloride 7.5 mg / kg twice daily administration group (7.5 mg / kgb.id), a trimetazidine hydrochloride 15 mg / kg twice daily administration group (15 mg / kgb.id), a trimetazidine hydrochloride 30 mg / kg daily single administration group (30 mg / kgq.d.), and a trimetazidine hydrochloride 60 mg / kg daily single administration group (60 mg / kgq.d.), with 6 animals in each group, wherein the model group was given an equal volume of solvent control-0.5% sodium carboxymethyl cellulose, and the temozolomide group was given an oral administration of 50 mg / kg for five consecutive days and then stopped. The experiment was terminated on the 12th day after modeling, and the weight of the mice was evaluated according to methods known in the art, and the changes in the five classifications of the peripheral blood of the mice were detected using a five-classifier, and the size of the intracranial tumor of the mice was detected by a nuclear magnetic imaging instrument.

[0033] Experimental results: During the experiment, trimetazidine hydrochloride can maintain the body weight of mice inoculated with G422 in situ (see Figure 3) At the end of the experiment 12 days after modeling, the results of nuclear magnetic resonance imaging showed that trimetazidine hydrochloride could significantly inhibit the growth of tumors in situ, and the tumor inhibition effect of twice-daily administration was better than that of daily single administration. The tumor treatment effect of the 15 mg / kg b.id group was equivalent to that of temozolomide (see Figure 4) In the peripheral blood, the leukocytes, lymphocytes and neutrophils in the 15mg / kgb.id group increased significantly. The above research results suggest that trimetazidine hydrochloride can penetrate the blood-brain barrier and inhibit the growth of in situ gliomas, and it is expected to become a drug for the clinical treatment of gliomas.

[0034] Experimental Example 3: Pharmacodynamic study of trimetazidine hydrochloride on ectopic inoculation of B16F10

[0035] Experimental method: The pharmacodynamic effect of trimetazidine hydrochloride on melanoma was evaluated in an animal model of ectopic inoculation of B16F10 melanoma in C57 mice. 1.5×10 6B16F10 tumor cells were grouped and administered on the first day after modeling, and were divided into a control group (model), a temozolomide group (TMZ), a trimetazidine hydrochloride 7.5 mg / kg twice daily administration group (7.5 mg / kg b.id), a trimetazidine hydrochloride 15 mg / kg twice daily administration group (15 mg / kg b.id), a trimetazidine hydrochloride 30 mg / kg daily single administration group (30 mg / kg q.d.), and a trimetazidine hydrochloride 60 mg / kg daily single administration group (60 mg / kg q.d.), with 7 animals in each group, wherein the model group was given an equal volume of solvent control-0.5% sodium carboxymethyl cellulose, and the temozolomide group was given 50 mg / kg by gavage for five consecutive days and then stopped. The experiment was terminated on the 18th day after modeling, and the mouse body weight, tumor volume, and tumor weight were evaluated according to methods known in the art, and flow cytometry was performed to detect changes in immune cells in tumor tissues.

[0036] Experimental results: During the experiment, trimetazidine hydrochloride can maintain the body weight of ectopically inoculated B16F10 mice (see Figure 6) At the end of the experiment 18 days after modeling, trimetazidine was able to significantly inhibit the growth of melanoma tumors. With the increase of the dosage, the tumor growth slowed down and the weight decreased. The tumor inhibition effect of twice-daily administration was better than that of daily single administration. The tumor inhibition effect of the 7.5 mg / kg b.id group was better than that of the 30 mg / kg q.d. group (see Figure 7) The 15mg / kgb.id group had the best tumor treatment effect, with a tumor inhibition rate of 65.3%. The above research results suggest that trimetazidine hydrochloride can treat ectopically inoculated B16F10 tumors, and has a short half-life, rapid drug metabolism, and good safety, and can be expected to be used as a clinical drug for the treatment of melanoma.

[0037] The results of flow cytometry detection of tumor tissue immune cells showed that after treatment with trimetazidine, there was no significant statistical change in lymphocytes and B cells in the tumor tissue, while NK cells, T cells and their subtypes in the 7.5 mg / kg b.id group increased significantly. In addition, in the tumor tissue, granuloid myeloid suppressor cells and monocytic myeloid suppressor cells increased significantly. Tumor-associated macrophages also increased significantly after treatment with trimetazidine (see Figure 8) Therefore, it is suggested that trimetazidine hydrochloride may not regulate tumor immunity in the treatment of melanoma, but regulate other more important pathways to exert such a significant therapeutic effect.

[0038] Table 2 The inhibitory effect of trimetazidine hydrochloride on the growth of subcutaneous tumors of mouse skin melanoma cells B16F10

[0039]

[0040] Statistics:

[0041] The mean, standard deviation and standard error of each item were calculated, and the data of each group were compared between groups using T.TEST. P < 0.05 was considered to be significantly different.

Claims

1. Use of trimetazidine hydrochloride or a pharmaceutically acceptable salt thereof represented by formula (I) in the preparation of a drug for preventing and treating brain glioma, melanoma and various solid tumors, 2. Use of a pharmaceutical composition in the preparation of a drug for preventing and treating brain glioma, melanoma and other solid tumors, characterized in that: The pharmaceutical composition contains a therapeutically effective amount of trimetazidine hydrochloride or a pharmaceutically acceptable salt thereof represented by formula (I), and a pharmaceutically acceptable carrier.

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