CN111773390B

CN111773390B - Application of medicine in preparing medicine for treating brain metastasis tumor and related diseases

Info

Publication number: CN111773390B
Application number: CN202010622510.8A
Authority: CN
Inventors: 闫超; 黄腾飞; 徐天琦
Original assignee: Nanjing University
Current assignee: Nanjing University
Priority date: 2020-07-01
Filing date: 2020-07-01
Publication date: 2021-08-20
Anticipated expiration: 2040-07-01
Also published as: CN111773390A; WO2022001082A1

Abstract

The application provides an application of a medicament in preparing a medicament for treating brain metastasis related diseases, wherein the medicament comprises at least one TRPV4 agonist capable of promoting calcium ion influx of a TRPV4 signal channel, and the brain metastasis and the related diseases comprise brain metastasis, diseases generated in the process of forming the brain metastasis and complications, sequelae and diseases related to the brain metastasis caused by the brain metastasis. The medicine is applied to preparing medicines for treating brain metastasis related diseases, can play a remarkable anti-tumor role through a clear action mechanism, and has good treatment effect and good application prospect.

Description

Application of medicine in preparing medicine for treating brain metastasis tumor and related diseases

Technical Field

The application relates to the technical field of medicines, in particular to application of a medicine in preparing a medicine for treating brain metastasis tumor and related diseases thereof.

Background

Brain tumor is a new organism growing in cranial cavity, also called intracranial tumor and brain cancer, and can originate from brain, meninges, nerves, blood vessels and brain attachments, or be formed by transferring other tissues or organs of a body to invade into cranium, and can generate headache, intracranial hypertension and focal symptoms, including primary brain tumor and brain metastatic tumor.

Brain metastasis is a secondary malignant tumor, is the most common adult intracranial tumor, mainly comes from lung, breast cancer; in addition, malignant tumors such as digestive tract, liver, pancreas, uterus, ovary, thyroid gland, adrenal gland, prostate, kidney, bone, etc., and sarcoma, etc., can be transferred to brain to form brain metastasis, which often occurs in the apical occipital lobe region of the hemisphere.

For a long time, the medical community has taken brain metastasis of malignant tumors as one of the criteria for judging the advanced stage of tumors. Once a patient is found to have a brain metastasis, it is predicted that the patient will enter the terminal stage of the disease. Generally, after tumor brain metastasis, it is found that good treatment effect cannot be obtained by conventional means such as surgery, radiotherapy and chemotherapy, and the like, and the method has large side effect, non-ideal prognosis effect and great risk.

The brain metastasis is different from the primary brain tumor, for example, if the brain metastasis of a patient is formed by lung cancer brain metastasis, the brain metastasis cell of the patient is a lung cancer cell, and if the brain metastasis of the patient is formed by breast cancer brain metastasis, the brain metastasis cell of the patient is a breast cancer cell, so that the medicine for treating the primary brain tumor cannot be applied to the treatment of the brain metastasis. Due to the existence of the blood-brain barrier, most of the drugs for treating lung cancer, breast cancer and the like can not enter the brain through the blood-brain barrier to exert the due drug effect, so how to treat the brain metastasis tumor becomes a problem to be solved urgently.

Disclosure of Invention

In view of this, the embodiments of the present application provide an application of a drug in preparing a drug for treating brain metastasis and related diseases, so as to solve the technical defects in the prior art.

The technical purpose of the application is realized by the following technical scheme:

an object of the present application is to provide a medicament for inhibiting brain metastases and related diseases thereof, comprising at least one TRPV4 agonist capable of promoting calcium influx of the TRPV4 signal channel, the TRPV4 agonist being present in a concentration of 0.01 μ M to 30 μ M, the TRPV4 agonist being preferably cannabidiol.

Meanwhile, the TRPV4 agonist can also be other TRPV4 agonist types or cannabidiol and other types of TRPV4 agonists.

On the basis, the medicine can also comprise a tumor inhibitor with antitumor activity, namely a TRPV4 agonist (such as cannabidiol) can be combined with the tumor inhibitor (such as temozolomide), the TRPV4 agonist and the tumor inhibitor can synergistically enhance the antitumor effect, and the toxic and side effects and/or drug resistance of the tumor inhibitor can be reduced to a great extent. The concentration ratio of the tumor suppressor and the TRPV4 agonist is (10-500): (10-30), the concentration ratio of temozolomide to cannabidiol is (10-500): (10-30), and the concentration of the tumor suppressor can be 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 40, 50, 60, 80, 100, 200, 300, 400 or 500 muM when in use.

Further, the above tumor suppressor includes at least one of a drug that interferes with nucleic acid biosynthesis, a drug that directly affects DNA, a drug that interferes with a transcription process, and a drug that prevents RNA synthesis.

The tumor suppressor can also be at least one of methotrexate, fluorouracil, mercaptopurine, hydroxyurea, cytarabine, an alkylating agent, doxorubicin, actinomycin D, daunorubicin, amrubicin, erlotinib hydrochloride tablets, lenatinib, and exemestane. These components may be used either together with temozolomide or alone.

In addition, the medicament can also comprise a synergistic substance, and the synergistic substance comprises borneol and/or menthol. The concentration ratio of the tumor suppressor, TRPV4 agonist and the synergistic substance is (10-500): 10-30): 10-80, and the concentration of the synergistic substance can be 0.01-80 μ M, such as 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80 μ M and the like. The synergistic substance can be used together with TRPV4 agonist, or in combination with at least one TRPV4 agonist and at least one tumor suppressor, such as a synergistic substance used together with cannabidiol and temozolomide as a medicine. The synergistic material can improve the overall drug effect of the drug; and the absorption rate of the medicine can be increased, so that the utilization rate of the medicine is improved, and the use amount of the medicine is reduced, so that the cost is reduced.

Still further, the medicament may further include at least one of an excipient, an adjuvant, an additive, a surfactant, a desiccant, and a diluent.

Another invention of the present application is to provide an application of a drug in preparing a drug for treating brain metastasis and related diseases thereof, wherein the drug is the drug described in any one of the above paragraphs, and the brain metastasis and related diseases thereof include brain metastasis, diseases generated in a process of forming the brain metastasis, and complications, sequelae and diseases related to the brain metastasis caused by the brain metastasis.

The medicine for treating the brain metastasis tumor and the related diseases thereof is a medicine which is synergistic in anti-tumor effect by promoting and inducing autophagy of tumor cells, inhibiting proliferation of the tumor cells and inhibiting activity of tumor stem cells. Therefore, the combined tumor inhibition is realized through the anti-tumor mechanisms in various ways, and the curative effect is good.

Further, the related diseases of brain metastasis include malignant tumors of lung, breast, digestive tract, liver, pancreas, uterus, ovary, thyroid, adrenal gland, prostate, kidney, skeleton and brain tumors formed by metastasis of sarcoma to brain and related diseases caused by the malignant tumors.

The beneficial effect of this application does:

the inventor of the invention clearly researches the action mechanism of cannabidiol for the first time, namely, the anti-tumor action mechanism of cannabidiol as a TRPV4 agonist is clearly understood, and cannabidiol can promote the calcium ion inflow of a TRPV4 signal channel, so that the mitochondrial autophagy of tumor cells is promoted, and a stronger anti-tumor effect is realized. Therefore, it is clearly known that cannabidiol, a TRPV4 agonist, has an anti-tumor effect, and the effect is also confirmed by experiments. And by the mechanism and the application and research of the cannabidiol in other fields in the prior art, the cannabidiol is basically predicted to have no toxic or side effect or have extremely small toxic or side effect. Therefore, the method has excellent value and significance in clinical research and application.

Through clear research and cognition of cannabidiol as a TRPV4 agonist, the effect is greatly improved by combining the TRPV4 agonist with a tumor inhibitor. If the cannabidiol and the temozolomide are used together and act in a complementary way, the effect is greatly improved, the toxic and side effects of nausea, vomiting and lassitude of the temozolomide are remarkably reduced, the drug resistance of the existing temozolomide when used alone is eliminated, and the effect is very surprising.

On the basis of TRPV4 agonist cannabidiol and tumor inhibitor, synergistic substances are added, so that the drug effect can be further improved, the absorption rate and the utilization rate are increased, and the toxic and side effects of temozolomide are synergistically improved.

Moreover, the proportion of each component can be better and more reasonably adjusted by clearly understanding the mechanism of each component, the optimal treatment effect can be realized under the concentration ratio condition given by the application, and the drug effect can be greatly reduced when the proportion is higher or lower.

The medicine provided by the scheme is applied to preparation of medicines for treating brain metastasis tumor and related diseases thereof, preferably, cannabidiol is used as a TRPV4 agonist, temozolomide is used as a tumor inhibitor, cannabidiol and temozolomide can interact with each other to induce tumor cells to generate autophagy, so that the remarkable inhibition effect on the brain metastasis tumor is achieved, the cannabidiol and the temozolomide have extremely high bioavailability and antitumor activity when being used in a compatible mode, the remarkable antitumor effect can be achieved, the drug resistance of the temozolomide can be remarkably reduced, and the treatment effect is improved.

In addition, the medicine that this application provided can also include synergistic material, and synergistic material can strengthen blood brain barrier permeability, improves the effect concentration of medicine at brain focal zone, promotes the organism to the absorption of medicine, improves the treatment of medicine.

Cannabidiol, temozolomide and synergistic substances can form a complex whole, so that the cannabidiol, the temozolomide and the synergistic substances interact with each other, the antitumor effect can be enhanced from multiple angles, the toxic and side effects can be remarkably reduced, and the medicament has a good treatment effect on side effects such as vomiting, dizziness and hypodynamia generated by the traditional temozolomide.

Drawings

FIG. 1 is a bar graph illustrating the relative viability of various groups of breast cancer cells according to an experimental example of the present application;

FIG. 2 is a graph of the distribution of breast cancer cells in various groups of mice according to an experimental example of the present application;

FIG. 3 is a line graph showing survival time of each group of mice according to an experimental example of the present application;

FIG. 4 is a bar graph illustrating the relative viability of various groups of lung cancer cells according to an experimental example of the present application;

FIG. 5 is a bar graph illustrating the relative viability of various groups of breast cancer cells according to an experimental example of the present application;

FIG. 6 is a schematic representation of apoptosis of various groups of breast cancer cells according to an experimental example of the present application;

FIG. 7 is a graph comparing the growth of tumors in various groups of mice as described in an experimental example of the present application;

FIG. 8 is a graph showing the relative cell viability of the drug-resistant cell lines of each group according to an experimental example of the present application.

Detailed Description

The following description of specific embodiments of the present application refers to the accompanying drawings.

In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. Also, the reagents, materials and procedures used herein are those that are widely used in the corresponding fields. Meanwhile, in order to better understand the present invention, the definitions and explanations of related terms are provided below.

MTT method: also known as MTT colorimetric method, is a method for detecting cell survival and growth. The detection principle is that succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT into water-insoluble blue-violet crystalline Formazan (Formazan) and deposit the Formazan in the cells, and dead cells do not have the function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and an enzyme linked immunosorbent assay detector is used for measuring the light absorption value of the formazan at the wavelength of 570nm, so that the quantity of living cells can be indirectly reflected. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number. The method is widely used for activity detection of some bioactive factors, large-scale antitumor drug screening, cytotoxicity test, tumor radiosensitivity determination and the like, and has high sensitivity.

The detection steps of the MTT method are as follows:

(1) collecting cells to be detected, adjusting the concentration of cell suspension, adding 100ul of cell suspension into each hole, paving the plate to adjust the density of the cells to be detected to 3000 holes, and filling the marginal holes with sterile PBS;

(2)5％CO₂incubating at 37 ℃ until the cell monolayer is fully plated on the bottom of the well (96-well flat bottom plate), and adding the drug with a concentration gradient;

(3)5％CO₂incubation at 37 ℃ for 72 hours;

(4) adding 20ul MTT solution (5mg/ml, namely 0.5% MTT) into each well, and continuing culturing for 4 h;

(5) terminating the culture and sucking out the culture solution in the hole;

(6) adding 100ul dimethyl sulfoxide into each well, placing on a shaking table, oscillating at low speed for 10min to fully dissolve the crystal, and measuring the light absorption value of each well at an enzyme-linked immunosorbent assay (ELISA) OD550 nm;

(7) and setting a zero setting hole (culture medium, MTT and dimethyl sulfoxide) and a control hole (cells, a drug dissolving medium with the same concentration, a culture solution, MTT and dimethyl sulfoxide).

Example 1

The present example provides a drug that inhibits brain metastases, which is a TRPV4 agonist. The TRPV4 agonist can promote calcium ion inflow of a TRPV4 signal channel, so that autophagy of brain tumor cells is promoted to be induced, and a stronger brain tumor resisting effect is realized. The TRPV4 agonist is used in amounts of: the concentration is 0.01. mu.M-30. mu.M, such as 0.01. mu.M, 0.05. mu.M, 0.1. mu.M, 0.5. mu.M, 1. mu.M, 5. mu.M, 10. mu.M, 15. mu.M, 20. mu.M, 25. mu.M, 30. mu.M, etc.

Example 2

Based on example 1, the TRPV4 agonist is cannabidiol at a concentration of 0.01 μ M to 30 μ M, such as 0.01 μ M, 0.05 μ M, 0.1 μ M, 0.5 μ M, 1 μ M, 5 μ M, 10 μ M, 15 μ M, 20 μ M, 25 μ M, 30 μ M, and the like. The cannabidiol promotes the calcium ion inflow of a TRPV4 signal channel, thereby promoting and inducing the tumor cells to generate mitochondrion autophagy and finally realizing stronger anti-tumor effect.

Wherein, TRPV4 (transient receptor potential channel 4) is a transient calcium ion channel, the action of cannabidiol on TRPV4 can cause calcium ion influx, the calcium ion influx is a main cause for activating endoplasmic reticulum stress, and the action of the cannabidiol can be reversed under the condition of using TRPV4 antagonist, so TRPV4 can be used as a potential target for the action of cannabidiol in brain tumor.

Cannabidiol can also significantly induce the morphological change of mitochondria, and the number of mitochondria is significantly reduced along with the increase of the concentration of cannabidiol, so the TRPV4 agonist provided by the embodiment can significantly induce tumor cells to undergo mitochondrial autophagy, further cause the death of the tumor cells, and inhibit the further development and spread of tumors.

The drug provided by the embodiment has good treatment effect and application prospect for brain metastasis tumor and related diseases thereof, wherein the TRPV4 channel is a potential target of action of cannabidiol after entering a human body, and the TRPV4 agonist can promote calcium ion inflow of the TRPV4 channel after entering the human body, activate endoplasmic reticulum stress, further induce mitochondrial damage, cause autophagy of mitochondria, further cause death of tumor cells, and have good treatment effect for the brain metastasis tumor and the related diseases thereof.

Example 3

This example provides a medicament for inhibiting brain metastasis, comprising a TRPV4 agonist and a tumor suppressor having anti-tumor activity. The concentration ratio of TRPV4 agonist to tumor suppressor was (i.e. the same concentration units in the same solution): (10-30):(10-500). The action mechanism of the TRPV4 agonist is matched with the inhibition mechanism of the tumor inhibitor, and the TRPV4 agonist and the tumor inhibitor are combined to realize the anti-tumor effect of synergism and reduction of toxic and side effects.

In this embodiment, any one or more TRPV4 agonists may be used in combination with any one or more tumor suppressors.

Preferably, the tumor suppressor comprises temozolomide. The temozolomide may be used in combination with at least one TRPV4 agonist.

Preferably, the TRPV4 agonist comprises cannabidiol. Cannabidiol, a TRPV4 agonist, may be used in combination with at least one tumor suppressor.

Preferably, if the tumor suppressor is temozolomide, the TRPV4 agonist is cannabidiol, and the ratio of the amounts of cannabidiol and temozolomide is: the concentration ratio is preferably (10-20) to (10-300).

Example 4

The present embodiment provides a drug for inhibiting brain metastasis, comprising: cannabidiol and temozolomide.

The concentration of cannabidiol is 0.01 μ M to 30 μ M, and in practical applications, the concentration of cannabidiol may be 0.01 μ M, 0.05 μ M, 0.1 μ M, 0.5 μ M, 1 μ M, 5 μ M, 10 μ M, 15 μ M, 20 μ M, 25 μ M, 30 μ M, or the like, preferably 10 μ M or 20 μ M, as the case may be, and the present application is not limited thereto.

Cannabidiol is added into the medicine, so that on one hand, the medicine can permeate a blood brain barrier and act on a brain focus area; on the other hand, the medicine added with cannabidiol takes TRPV4 as a target, and acts TRPV4 to induce tumor cells to generate mitochondrion autophagy, so that the tumor cells die, the effect of inhibiting the proliferation of tumors is achieved, and the effect of preventing or treating diseases related to brain tumors is achieved.

It should be noted that, in the case of using other cannabinoids such as Tetrahydrocannabinol (THC) alone, it usually affects memory, attention and judgment of a human, and causes confusion, sleepiness, confusion, hallucinations, and the like, and it has addiction, but cannabidiol is a non-addictive substance among cannabinoids, and not only does not cause the above symptoms and addiction, but also can significantly improve mental state of a patient in the case of using cannabidiol in combination with temozolomide.

Temozolomide is an active substance which can be rapidly absorbed and transformed by a human body, and the temozolomide is added into the medicine disclosed by the embodiment, so that the bioavailability and the antitumor activity of the medicine are improved. Specifically, the medicament added with temozolomide can be rapidly and spontaneously degraded in vivo after entering the body, so that the proliferation of tumors is inhibited, and an anti-tumor effect is generated.

In the medicine described in this embodiment, cannabidiol and temozolomide are used in a compatible manner, cannabidiol contributes to improving the tumor inhibition effect of temozolomide, temozolomide contributes to improving the bioavailability of cannabidiol, and the combined use of the two can play a significant synergistic effect, significantly improve the clonal proliferation ability of the medicine to inhibit tumor cells, and significantly improve the activity ability of the medicine to inhibit tumor cells, thereby achieving the effect of treating diseases related to brain tumor, improving the survival rate of patients, prolonging the life cycle of patients, improving the life quality of patients, and improving the treatment effect of brain metastasis tumor and related diseases.

In addition, the drug resistance of the patient is usually generated under the condition of taking temozolomide for a long time, and the combination use of the cannabidiol and the temozolomide is beneficial to improving the permeability of cell membranes and promoting the drug to better permeate the cell membranes to enter tumor cells to play an inhibiting role, so that the generation of the drug resistance can be effectively avoided, and the treatment effect is improved.

In practical applications, the temozolomide is present in a concentration of 0.01-500 μ M, such as 0.01 μ M, 0.05 μ M, 0.1 μ M, 0.5 μ M, 1 μ M, 5 μ M, 10 μ M, 15 μ M, 30 μ M, 50 μ M, 80 μ M, 90 μ M, 100 μ M, 150 μ M, 200 μ M, 250 μ M, 300 μ M, 350 μ M, 400 μ M, 450 μ M, 500 μ M, preferably 10-300 μ M, more preferably 10-200 μ M, and the cannabidiol is preferably present in a concentration of 10 μ M or 20 μ M, in which case, i.e. when the drug has only these two components, the ratio is optimal, because, at this ratio, temozolomide is the least, its toxic side effects are improved or eliminated, and the overall effect of the drug is the most, or if the ratio is changed, the effect is best affected, the toxic and side effects of the temozolomide are improved slightly or the drug resistance of the temozolomide is not improved, so all factors of the two components are balanced comprehensively, the whole treatment effect is optimal when the ratio is the ratio, and the cannabidiol is more obvious in improving the tumor inhibition effect of the temozolomide, reducing the toxic and side effects of the temozolomide and improving or eliminating the drug resistance of the temozolomide. In addition, the effect was also significant in the case of temozolomide at a concentration of 500. mu.M.

In this embodiment, the TRPV4 agonist cannabidiol is used in combination with a tumor suppressor temozolomide, and the two can exert significant synergistic effects, and even may form an organic whole, the composition not only can enhance the promotion effect on TRPV4 channel calcium ion influx, but also can improve the bioavailability and antitumor activity of the whole drug in a human body, inhibit the activity of tumor cells, inhibit the clonal proliferation capacity of tumor cells, improve the therapeutic effect of brain metastasis and related diseases, improve the survival rate of patients, prolong the survival period of patients, and improve the survival quality of patients on the basis of promoting TRPV4 channel calcium ion influx, activating endoplasmic reticulum stress, inducing mitochondrial damage and autophagy, and inducing tumor cells.

Example 5

The present embodiment provides a drug for inhibiting brain metastasis, comprising: a TRPV4 agonist and a synergistic agent.

Preferably, the TRPV4 agonist is cannabidiol and the synergistic agent is borneol and/or menthol.

In this embodiment, cannabidiol can promote calcium ion inflow of a TRPV4 signal channel as a TRPV4 agonist, thereby promoting mitochondrial autophagy of induced tumor cells, achieving a stronger anti-brain tumor effect, enhancing blood brain barrier permeability by a synergistic substance, increasing the action concentration of the drug in a brain focal region, promoting absorption of the drug, improving the therapeutic effect of the drug, and interacting between the two, so that the anti-tumor effect can be enhanced from multiple angles, toxic and side effects can be remarkably reduced, and the therapeutic effect can be provided.

Example 6

On the basis of example 3 or 4, the medicament for inhibiting brain metastasis can also comprise a synergistic substance, the synergistic substance comprises borneol and/or menthol, for example, borneol, menthol, a combination of borneol and menthol and the like can be added.

Borneolum is prepared from stem and leaf of blumea balsamifera of Compositae or branch and leaf of Cinnamomum camphora of Lauraceae by steam distillation and recrystallization. Menthol is a chemical agent extracted from the leaves and stems of peppermint and is in the form of white crystals.

In the medicine of the embodiment, borneol, menthol and other synergistic substances are added, so that the borneol and the menthol can generate the function of inducing resuscitation, can increase the content of 5-hydroxytryptamine in hypothalamus, promote the generation of nitric oxide by brain microvascular endothelial cells under physiological and pathological conditions, further enhance the permeability of blood brain barrier, help cannabidiol and temozolomide in the medicine to quickly and efficiently reach a focal region of the brain through the blood brain barrier to play a role in inhibiting tumor, and borneol and menthol can also inhibit the activity of P-glycoprotein on cell membranes, thereby greatly reducing the probability of eliminating the cannabidiol and the temozolomide entering the blood brain barrier, promoting the absorption of the effective components of the cannabidiol and the temozolomide in the medicine in the focal region of the brain, promoting the exertion of the medicine effect of the medicine and improving the treatment effect of the medicine on diseases related to brain tumor.

The borneol and the menthol promote the opening of a blood brain barrier to be physiological opening, have certain protection effect on the blood brain barrier while promoting the opening of the blood brain barrier, and cannot cause pathological damage to the brain.

The concentration ratio of the TRPV4 agonist cannabidiol, temozolomide and the synergistic substance is (10-30): (10-500): (10-80). The preferred concentration ratio is (10-20): (10-300): (20-50) or (10-20):500 (30-60), namely when the medicament contains the three components, the ratio is the best, because the toxic and side effect of the temozolomide is the smallest at the ratio, the improvement or elimination effect of the drug resistance is the best, and the effect of the whole medicament is the best, if the ratio is changed, either the effect is influenced, the toxic and side effect of the temozolomide is little improved, or the drug resistance is not improved, or the auxiliary synergy effect of the synergistic materials on the other two components is not significant, the toxic and side effect reduction effect and the drug resistance reduction effect are not significant, so all the factors of the three components are comprehensively balanced, and the whole treatment effect is the best when the ratio is obtained.

In practical applications, the concentration of cannabidiol may be 10 μ M, 20 μ M, etc., the concentration of temozolomide may be 10 μ M, 50 μ M, 100 μ M, 150 μ M, 200 μ M, etc., and the concentration of synergistic substance may be 0.01 μ M, 0.05 μ M, 0.1 μ M, 0.5 μ M, 1 μ M, 5 μ M, 10 μ M, 15 μ M, 20 μ M, 30 μ M, 40 μ M, 50 μ M, 60 μ M, 70 μ M, 80 μ M, etc., which is not limited in this application.

In addition, under the condition of single use of temozolomide, obvious toxic and side effects such as vomiting, dizziness, hypodynamia and the like exist, in the medicament disclosed by the embodiment, cannabidiol, a synergistic substance and the like are used together with the temozolomide, so that symptoms such as vomiting, dizziness, hypodynamia and the like caused by the temozolomide can be obviously reduced, and the side effect is obviously relieved.

In this embodiment, a complex may be formed between cannabidiol, temozolomide and the synergistic substance, so that the cannabidiol, temozolomide and the synergistic substance interact with each other, thereby not only enhancing the anti-tumor effect from multiple angles, but also significantly reducing the toxic and side effects, and particularly having a good therapeutic effect on side effects such as vomiting, vertigo and hypodynamia caused by the conventional temozolomide.

Example 7

The agent for inhibiting brain metastasis, based on any of examples 1 to 6, may further include: at least one of excipient, adjuvant, additive, surfactant, desiccant, and diluent.

The excipient is an additive in the pharmaceutical preparation except the main drug, and can also be called as an auxiliary material. In the present embodiment, in the case where the drug is made into a tablet, the excipient may be a binder, a filler, a disintegrant, a lubricant, or the like; in the case of preparing the drug into a liquid formulation, the excipient may be a preservative, an antioxidant, a flavoring agent, an aromatic, a solubilizing agent, an emulsifier, a solubilizer, an osmotic pressure regulator, a colorant, etc., as the case may be, and the present application is not limited thereto. The excipient is added into the medicine, so that the preparation flexibility of the medicine can be improved, the medicine can be prepared into different dosage forms according to different actual requirements, the applicable population of the medicine is enlarged, and the treatment effect of the medicine on different types of patients is improved.

The adjuvant is a non-specific immunopotentiator. In this embodiment, the adjuvant added to the drug may be any one of aluminum hydroxide adjuvant, corynebacterium parvum, lipopolysaccharide, cytokine, alum, and the like, which is not limited in this application, and the drug described in this embodiment may be added with different adjuvants according to actual requirements, so as to improve the immune response capability of the patient body and correspondingly improve the therapeutic effect of the drug.

The additive is a substance for improving the treatment quality and curative effect of the medicament. In this embodiment, the additive added to the medicine may be a macrolide additive, a polypeptide additive, a tetracycline additive, a chemical synthesis additive, and the like, as the case may be, and the present application is not limited thereto. Different additives are added into the medicine according to actual requirements, so that the quality and the safety of the medicine can be improved, and the treatment effect of the medicine is further improved.

The surfactant is a substance which can obviously change the interface state of a solution system when being added in a small amount. In this embodiment, the surfactant may be a cationic surfactant, an anionic surfactant, a nonionic surfactant, an amphoteric surfactant, a complex surfactant, other surfactants, etc., as the case may be, and the present application is not limited thereto. Different types of surfactants are added into the medicine according to actual requirements, so that the solubility of the medicine in the solution can be increased under the condition that the medicine is prepared into a solution, the medicine can be effectively sterilized and disinfected, and the safety of the medicine is improved.

A desiccant is a substance that removes moisture from a moist substance. In this embodiment, the drying agent may be a chemical drying agent such as calcium carbonate and calcium chloride, a physical drying agent such as silica gel and activated alumina, or other types of drying agents, which is not limited in this application. Different types of drying agents are added into the medicine according to actual requirements, so that the drying property of the medicine can be improved, and the storage time of the medicine can be prolonged.

A diluent, also known as a bulking agent, is a substance that can increase the weight or volume of a tablet. In this embodiment, when the drug is made into a tablet, the diluent may be a starch-based diluent such as starch and dextrin, a sugar-based diluent such as powdered sugar, lactose and mannitol, or another type of diluent such as microcrystalline cellulose, which is not limited in the present application. In the case that the medicament described in this embodiment is made into a tablet, different types of diluents are added according to actual requirements, so that the tabletting quality of the medicament can be effectively improved, and the storage of the medicament is facilitated.

In addition, the medicament of this embodiment may further include other components, such as a binder, a wetting agent, a disintegrant, a lubricant, etc., which may depend on the specific dosage form of the medicament, and the present application is not limited thereto.

The dosage form of the drug described in this embodiment may be prepared into dosage forms such as tablets, capsules, powders, granules, pills, suppositories, ointments, solutions, suspensions, lotions, gels, pastes, and the like, which may be determined according to specific situations, and the present application is not limited thereto.

Therefore, the drug provided by the embodiment can be added with excipients, diluents and other substances according to actual requirements, so that the drug can be prepared into different dosage forms, the requirements of different patient groups can be flexibly met, the application range of the drug is greatly increased, and the drug has a good treatment effect and a good application prospect on brain metastasis related diseases.

Example 8

This example provides the use of a medicament as described in any one of examples 1 to 7 in the preparation of a medicament for the treatment of brain metastases and related diseases thereof.

In practical application, the medicament can be a TRPV4 agonist, so that the medicament can realize stronger antitumor effect by promoting calcium ion inflow of a TRPV4 signal channel; the medicine can also be a combination of TRPV4 agonist and tumor suppressor, a combination of TRPV4 agonist and synergistic substance, and a combination of TRPV4, tumor suppressor and synergistic substance.

Specifically, the TRPV4 agonist is at least one of a calcium channel agonist, an endoplasmic reticulum activator and a mitophagy inducer.

Wherein the TRPV4 agonist is an agent capable of promoting calcium ion influx in a TRPV4 channel, the calcium channel agonist is an agent capable of promoting calcium ion influx in a body, the endoplasmic reticulum activator is an agent capable of promoting endoplasmic reticulum stress activation, and the mitophagy inducer is an agent capable of promoting mitophagy in tumor cells.

More specifically, TRPV4 (transient receptor potential channel 4) is a transient calcium ion channel, and because the action of a drug causes calcium ion influx in the body, which is a major cause of endoplasmic reticulum activation stress, and in the case of using a TRPV4 antagonist, the action of the drug is reversed, TRPV4 can be used as a potential target of the drug for the action in brain tumors, and the drug provided in this example can inhibit tumor cells by promoting calcium ion influx, activating endoplasmic reticulum stress, and inducing mitochondrial autophagy.

The drug provided by the embodiment can also obviously induce the form change of mitochondria, and the number of mitochondria is obviously reduced along with the increase of the drug concentration, so that the drug provided by the embodiment can obviously induce tumor cells to generate mitochondrial autophagy, further cause the death of the tumor cells and inhibit the further development and diffusion of brain tumors, and meanwhile, the synergistic substance in the drug can also reduce the toxic and side effects of temozolomide and improve the treatment effect of diseases related to the brain tumors.

In practical applications, the drug may be at least one of a drug for inducing autophagy of tumor cells, a drug for inhibiting proliferation of tumor cells, and a drug for inhibiting activity of tumor cells.

Specifically, the brain metastasis related diseases comprise malignant tumors of lung, breast, digestive tract, liver, pancreas, uterus, ovary, thyroid, adrenal gland, prostate, kidney and skeleton, and brain tumors formed by metastasis of sarcoma to the brain and related diseases caused by the malignant tumors.

In practical application, the medicament is combined with other medicaments for preventing or treating the brain metastasis related diseases in the medicament for treating the brain metastasis related diseases.

In this embodiment, the other drugs for preventing or treating the brain metastasis related diseases can be drugs interfering with nucleic acid biosynthesis, such as Methotrexate (MTX), fluorouracil (5-FU), mercaptopurine, hydroxyurea, cytarabine, etc., or drugs directly affecting DNA, such as alkylating agents, etc., or drugs interfering with transcription process and preventing RNA synthesis, such as doxorubicin, actinomycin D, daunorubicin, etc., or drugs preventing or treating lung cancer, breast cancer, etc., such as amrubicin, erlotinib hydrochloride tablet, neratinib, exemestane, etc., or other drugs having related preventing or treating effects, which is not limited in this application.

In addition, the medicine for treating the diseases related to the brain metastasis tumor can be used for treating patients by other treatment means, such as chemotherapy, radiotherapy, surgical treatment and the like, so that the treatment effect is improved.

Optionally, the medicament prevents or treats brain metastasis and related diseases by inhibiting the proliferation and dryness of tumor cells.

Furthermore, the drug takes TRPV4 as a target to induce tumor cells to generate mitophagy so as to cause tumor cell death, thereby preventing or treating brain metastasis and related diseases.

Specifically, the drug provided by the embodiment can induce the tumor cells to generate mitophagy by acting on the potential target TRPV4, so that the tumor cells die, and further play a role in preventing or treating primary brain tumors and related diseases thereof.

Wherein, TRPV4 (transient receptor potential channel 4) is a transient calcium ion channel, which can cause calcium ion influx after drug action, and the calcium ion influx is the main cause of endoplasmic reticulum activation stress, and in case of antagonist, TRPV4 can reverse the drug action, so TRPV4 can be used as a potential target of drug action in brain metastasis.

The drug provided by the embodiment can also obviously induce the form change of mitochondria, and the number of mitochondria is obviously reduced along with the increase of the drug concentration, so that the drug provided by the embodiment can obviously induce tumor cells to generate mitochondrial autophagy, further cause the death of the tumor cells, and inhibit the further development and diffusion of brain metastasis tumor, and meanwhile, the synergistic substance in the drug can also reduce the toxic and side effects of temozolomide, and improve the treatment effect of primary brain tumor and related diseases thereof.

Therefore, the medicine provided by the embodiment is applied to preparing medicines for preventing or treating the brain metastasis and the related diseases thereof, can reduce toxic and side effects generated in the clinical treatment process of the brain metastasis and the related diseases thereof, and improves the treatment effect of the brain metastasis and the related diseases thereof.

Test example 1

The test example is provided with a control group 1 and test groups 1-3, each group selects the same number of in vitro breast cancer cell lines, the in vitro breast cancer cell lines comprise MCF-7 cells, MDA-MB-453 cells and MDA-MB-231 cells, wherein the control group 1 does not perform any treatment on the in vitro breast cancer cell lines, the test group 1 uses 10 mu M cannabidiol to treat the in vitro breast cancer cell lines for 48 hours, the test group 2 uses 15 mu M temozolomide to treat the in vitro breast cancer cell lines for 48 hours, the test group 3 uses 10 mu M cannabidiol and 15 mu M temozolomide to treat the in vitro breast cancer cell lines for 48 hours, and after 48 hours, the activity conditions of the breast cancer cells MCF-7, MDA-MB-453 and MDA-MB-231 in each group are respectively detected by an MTT method.

The results are shown in fig. 1, and it can be seen from fig. 1 that when cannabidiol or temozolomide is used alone to treat mice with breast cancer, the activity of breast cancer cells is reduced to a certain extent, that is, breast cancer cells are inhibited to a certain extent, but when cannabidiol and temozolomide are used in combination to treat mice with breast cancer, the activity of breast cancer cells is significantly reduced, that is, breast cancer cells are significantly inhibited, so that the inhibition effect on breast cancer cells can be greatly improved by the combined use of cannabidiol and temozolomide, and the treatment effect on breast cancer is greatly improved.

Test example 2

In this test example, control group 1 and test groups 1 to 3 were set, 6 female NOD-SCID mice of 6 to 8 weeks old were selected for each group, the mice were anesthetized with isoflurane/O, and 1X10 was added⁵The breast cancer cells of (a) were injected into the left ventricle of each mouse in 100. mu.l of PBS, wherein 10 days later, the mice of the test groups 1-3 were treated in the manner described in Table 1, and the mice of the control group 1 were not treated at all.

TABLE 1 test group 1-3 mice treatment mode control table

Noninvasive bioluminescence imaging was performed on each group of mice using the IVIS in vivo imaging system, and the results are shown in fig. 2.

As can be seen from fig. 2, in the case of the mice of the control group 1 without any treatment, the breast cancer rapidly develops and rapidly metastasizes to the brain, in the case of the mice of the

test groups

1 and 2 treated with cannabidiol or temozolomide alone, the breast cancer is partially inhibited, the metastasis to the brain is improved to some extent, and in the case of the mice of the test group 3 treated with cannabidiol and temozolomide in combination, the breast cancer is significantly inhibited and the diffusion of the breast cancer to the brain is effectively prevented.

The survival time of each group of mice was counted, and the results are shown in fig. 3. The horizontal axis represents days, and the vertical axis represents the percentage of survival number of the mice, so that the survival time of the mice which do not receive any treatment in the control group 1 is shortest along with the passage of time, the survival time of the mice can be temporarily prolonged by singly using the cannabidiol or the temozolomide in the test group 1 and the test group 2, and the survival time of the mice can be prolonged by about one time by jointly using the cannabidiol and the temozolomide in the test group 3, so that the treatment effect is greatly improved.

Therefore, the medicine can obviously inhibit the proliferation of breast cancer cells, inhibit the growth of breast cancer and the metastasis to the brain, inhibit the growth of brain metastasis tumor, prolong the life cycle and have good treatment effect on the breast cancer brain metastasis tumor.

Test example 3

In the experimental example, a control group 1 and test groups 1 to 3 were set, each group selected the same number of in vitro lung cancer cell lines including a549 cells and NCI-H446 cells, wherein the control group 1 did not treat the in vitro lung cancer cell lines, the test group 1 treated the in vitro lung cancer cell lines with 10 μ M cannabidiol for 48 hours, the test group 2 treated the in vitro lung cancer cell lines with 15 μ M temozolomide for 48 hours, the test group 3 treated the in vitro lung cancer cell lines with 10 μ M cannabidiol and 15 μ M temozolomide for 48 hours, and after 48 hours, the activity of the lung cancer cells a549 and NCI-H446 in each group of mice was respectively detected by MTT method.

As shown in fig. 4, it can be seen from fig. 4 that, when cannabidiol or temozolomide is used alone to treat an in vitro lung cancer cell line, the activity of the lung cancer cell is reduced to a certain extent, that is, the lung cancer cell is inhibited to a certain extent, but when cannabidiol and temozolomide are used in combination to treat an in vitro lung cancer cell line with lung cancer, the activity of the lung cancer cell is significantly reduced, that is, the lung cancer cell is significantly inhibited, so that the inhibition effect on the lung cancer cell can be greatly improved by the combined use of cannabidiol and temozolomide, and the treatment effect on the lung cancer is greatly improved.

Test example 4

In the experimental example, test groups 1 to 6 were set up, and each of the control group 1 and the test groups 1 to 6 selected the same number of in vitro breast cancer cell lines including MBA-MB-453 cells and MD-MB-231 cells, wherein the control group 1 did not treat the in vitro breast cancer cell lines, the test group 1 treated the in vitro breast cancer cell lines with 15 μ M cannabidiol and 5 μ M tetrahydrocannabinol for 48 hours, the test group 2 treated the in vitro breast cancer cell lines with 10 μ M temozolomide and 15 μ M menthol for 48 hours, the test group 3 treated the in vitro breast cancer cell lines with 10 μ M temozolomide and 15 μ M borneol for 48 hours, the test group 4 treated the in vitro breast cancer cell lines with 10 μ M temozolomide, 15 μ M cannabidiol and 15 μ M menthol for 48 hours, and the test group 5 treated the in vitro breast cancer cell lines with 10 μ M temozolomide, 15 μ M menthol for 5, 15 mu M cannabidiol and 15 mu M borneol are used for treating the in vitro breast cancer cell lines for 48 hours, the test group 6 adopts 10 mu M temozolomide, 15 mu M cannabidiol, 15 mu M menthol and 15 mu M borneol to treat the in vitro breast cancer cell lines for 48 hours, and the relative activity of the in vitro breast cancer cell lines of each group is detected by an MTT method after 48 hours.

The results are shown in fig. 5, fig. 5 is a schematic diagram of relative cell viability of in vitro breast cancer cell lines, wherein the horizontal axis represents group, and the vertical axis represents cell viability levels of MBA-MB-453 and MD-MB-231 cells with reference to control group 1, it can be seen that test group 1 treated with cannabidiol and tetrahydrocannabinoid to inhibit breast cancer cells in vitro, test group 2 treated with temozolomide and menthol to inhibit breast cancer cells in vitro, the inhibition effect of breast cancer cells is slightly improved but not significantly improved compared with test group 1, test group 3 treated with temozolomide and borneol to inhibit breast cancer cells in vitro, the inhibition effect of breast cancer cells is substantially equal to that of test group 1, and test group 4 treated with cannabidiol, temozolomide and menthol to inhibit breast cancer cells in vitro, the inhibition effect on the breast cancer cells is remarkably improved, the vitality of the breast cancer cells is remarkably reduced, the experiment group 5 adopts cannabidiol, temozolomide and menthol to treat the breast cancer cells in vitro, the inhibition effect on the breast cancer cells is further improved, the experiment group 6 adopts cannabidiol, temozolomide, menthol and borneol to treat the breast cancer cells in vitro, the inhibition capability on the breast cancer cells in vitro is strongest, and the cell vitality of the breast cancer cells in vitro is lowest. The medicine provided by the application can generate good inhibition effect and treatment effect on breast cancer cells.

The apoptosis of breast cancer cell lines in vitro of each group was examined, and the results are shown in FIG. 6, in which the horizontal axis represents the group and the vertical axis represents the ratio of the number of live cells, early apoptotic cells, late apoptotic cells and necrotic cells, and FIG. 6 is a schematic view of MDA-MB-231 apoptosis. As can be seen from FIG. 6, when temozolomide, cannabidiol, menthol and borneol are used for treating MDA-MB-231 cells, the proportion of MDA-MB-231 living cells is the minimum, and the apoptosis quantity of MDA-MB-231 cells is the maximum.

Test example 5

This test example was provided with control group 1 and test groups 1 to 5. Control group 1 and test groups 1 to 5 60 mice each having breast cancer and having tumors spread to the brain were selected, and the mice of each group were kept in the same keeping environment and keeping conditions for four weeks, wherein the mice of control group 1 were not administered any drug, and the administration conditions of the mice of test groups 1 to 5 were as shown in table 2:

table 2 schematic table of administration of each group of mice

The growth of tumors was examined in each group of mice on the seventh and twenty-eighth days of feeding, respectively, and the results are shown in FIG. 7, in which FIG. 7 is a comparison of the growth of tumors in mice, it can be seen that in the case of the

test groups

1 and 2, when the mice were treated with tetrahydrocannabinol and cannabidiol, or temozolomide and menthol, the breast cancer of the mice was not improved, and does not inhibit the diffusion of breast cancer to the brain, and in the case of using temozolomide and borneol to treat mice in the test group 3, the development condition of breast cancer and the brain metastasis condition of the mice are slightly improved, and the test group 4 and the test group 5 adopt temozolomide, cannabidiol and borneol, or when the mouse is treated by temozolomide, cannabidiol and menthol, the development of breast cancer and brain metastasis of the mouse are obviously inhibited, and the treatment effect is obvious. Therefore, the medicine provided by the application can be used for treating breast cancer and breast cancer brain metastasis tumor, and has a good treatment effect.

Test example 6

In this test example, control group 1 and test groups 1 to 6 were set. 50 male nude mice of BALB/c-nu/nu7-8 weeks old, which had breast cancer and had spread to the brain, were selected per each of the control group 1 and the test groups 1 to 6, and the mice of each group were kept in the same keeping environment and keeping conditions for four weeks, wherein the administration of the mice of the control group 1 and the test groups 1 to 6 is shown in Table 3:

TABLE 3 schematic table of administration of each group of mice

Adverse reactions were observed and counted in each group of mice during the feeding period, and the results are shown in table 4.

TABLE 4 adverse reaction conditions of mice in each group

Currently, temozolomide is generally used for treating primary brain tumor related diseases, and a plurality of adverse reactions are often caused when temozolomide is used for treating the primary brain tumor related diseases. The experimental example proves that when mice with breast cancer brain metastasis are treated by temozolomide alone, serious adverse reactions such as gastrointestinal reaction, thrombocytopenia and the like can be caused, and the results of the control group 1 are shown; as shown in the results of test groups 1-2, when temozolomide and borneol or temozolomide and menthol are simultaneously used for mice with breast cancer brain metastasis tumor, the adverse reaction of the mice is slightly improved; as shown in the results of test group 3, in the case of treating mice with temozolomide in combination with cannabidiol, the adverse reactions of the mice were significantly improved; as shown in the results of test group 3, in the case of treating mice with temozolomide in combination with cannabidiol and a synergistic substance, adverse reactions were further inhibited.

Therefore, the medicament provided by the application combines temozolomide, cannabidiol and synergistic substances for use, so that adverse reactions such as vomiting, nausea and thrombocytopenia caused by temozolomide can be obviously reduced, and the use feeling of patients is improved.

Test example 7

In the test example, test groups 1 to 7 were set, wherein each of the test groups 1 to 7 selected the same number of drug-resistant in vitro breast cancer cell lines including MCF-7-resistant cells and MD-MB-231-resistant cells, and both the MCF-7-resistant cells and the MD-MB-231-resistant cells were treated with temozolomide to develop drug resistance. Wherein, the test group 1 adopts 10 MuM temozolomide to treat the in vitro breast cancer cells for 48 hours, the test group 2 adopts 10 MuM temozolomide and 15 MuM cannabidiol to treat the in vitro breast cancer cells for 48 hours, the test group 3 adopts 10 MuM temozolomide and 15 MuM menthol to treat the in vitro breast cancer cells for 48 hours, the test group 4 adopts 10 MuM temozolomide and 15 MuM borneol to treat the in vitro breast cancer cells for 48 hours, the test group 5 adopts 10 MuM temozolomide, 15 MuM cannabidiol and 15 MuM borneol to treat the in vitro breast cancer cells for 48 hours, the test group 6 adopts 10 MuM temozolomide, 15 MuM cannabidiol and 15 MuM menthol to treat the in vitro breast cancer cells for 48 hours, the test group 7 adopts 10 MuM temozolomide, 15 MuM cannabidiol, 15 MuM menthol and 15 MuM borneol to treat the in vitro breast cancer cells for 48 hours, after 48 hours, each group of in vitro breast cancer cell lines was treated using the MTT method.

As shown in fig. 8, fig. 8 is a schematic diagram of the relative cell viability of the drug-resistant cell line, wherein the horizontal axis represents the group, and the vertical axis represents the cell viability level of the MCF-7 and MD-MB-231 drug-resistant cell lines, and it can be seen that the inhibition ability of the cell line against MBA-MB-453 and MD-MB-231 drug-resistant cells is very weak when the cell line is treated with temozolomide, and the inhibition ability of the cell line against MBA-MB-453 and MD-MB-231 drug-resistant cells is greatly improved when the cell line is treated with temozolomide in combination with any one or more of cannabidiol, menthol and borneol, and particularly, the inhibition ability of the cell line against MBA-MB-453 and MD-MB-231 drug-resistant cells is very significant when the cell line is treated with temozolomide in combination with cannabidiol, menthol and borneol. Therefore, the medicament provided by the application can effectively improve the drug resistance of temozolomide and improve the treatment effect of brain metastasis related diseases.

In addition, through a large number of mouse experiments, the observation is made that most of mice are poor in mental state, often lack of mental state, and have repeated disease after being stopped for a period of time when the mice with brain metastasis are treated by using cannabinoids such as tetrahydrocannabinol, which indicates that cannabinoids such as tetrahydrocannabinol have adverse effects on the mental state of the mice and are easy to generate dependence and addiction; when cannabidiol is used for treating mice with brain metastasis, the mental state of most of the mice is good, the tumor condition is remarkably inhibited, and the symptoms of repeated disease condition and mental state change do not appear after the mice are stopped for a period of time, so that the cannabidiol can be used for treating the brain metastasis and related diseases without generating adverse effect on the mental state of patients, generating no dependence and addiction and having good treatment effect.

In conclusion, the medicine provided by the invention can be applied to preparation of medicines for treating brain metastasis tumor and related diseases thereof, cannabidiol serving as a TRPV4 agonist can promote calcium ion inflow of a TRPV4 signal channel, so that mitochondrial autophagy of tumor cells is promoted to be induced, and a stronger anti-tumor effect is realized. The borneol and/or menthol can enhance the permeability of blood brain barrier, improve the action concentration of the medicine in the focal region of the brain, promote the absorption of the medicine by the body and improve the treatment effect of the medicine as a synergistic substance. The above three components may form a complex whole body to make them interact with each other, not only can enhance the anti-tumor effect from a plurality of angles, but also can obviously reduce the toxic and side effects, and especially has good treatment effect on the side effects of vomiting, dizziness, hypodynamia and the like generated by the traditional temozolomide.

In this document, "upper", "lower", "front", "rear", "left", "right", and the like are used only to indicate relative positional relationships between relevant portions, and do not limit absolute positions of the relevant portions.

In this document, "first", "second", and the like are used only for distinguishing one from another, and do not indicate the degree and order of importance, the premise that each other exists, and the like.

In this context, "equal", "same", etc. are not strictly mathematical and/or geometric limitations, but also include tolerances as would be understood by a person skilled in the art and allowed for manufacturing or use, etc.

Unless otherwise indicated, numerical ranges herein include not only the entire range within its two endpoints, but also several sub-ranges subsumed therein.

The preferred embodiments and examples of the present application have been described in detail with reference to the accompanying drawings, but the present application is not limited to the embodiments and examples described above, and various changes can be made within the knowledge of those skilled in the art without departing from the concept of the present application.

Claims

1. The application of a medicine in preparing a medicine for treating brain metastasis, wherein the medicine comprises at least one TRPV4 agonist capable of promoting calcium ion influx of a TRPV4 signal channel, the TRPV4 agonist comprises cannabidiol, the medicine further comprises at least one tumor inhibitor with antitumor activity and at least one synergistic substance, the tumor inhibitor comprises temozolomide, the synergistic substance comprises borneol and/or menthol, the concentration ratio of the tumor inhibitor to the TRPV4 agonist is (10-500): (10-30), and the brain metastasis is brain tumor formed by metastasis of malignant tumor of a breast to a brain.

2. The use as claimed in claim 1, wherein the TRPV4 agonist is at a concentration of 0.01 μ Μ to 30 μ Μ.

3. The use of claim 2, wherein the tumor suppressor further comprises at least one of an inhibitor that interferes with nucleic acid biosynthesis, an inhibitor that directly affects DNA, and an inhibitor that interferes with transcription processes and prevents RNA synthesis.

4. The use according to claim 3, wherein the tumor suppressor further comprises at least one of methotrexate, fluorouracil, mercaptopurine, hydroxyurea, cytarabine, alkylating agents, doxorubicin, actinomycin D, daunorubicin, amrubicin, erlotinib hydrochloride tablets, lenatinib, exemestane.

5. The use according to claim 1, wherein the concentration ratio of the tumor suppressor, TRPV4 agonist and the synergistic agent is (10-500): (10-30): (10-80).

6. The use of claim 1, wherein the medicament further comprises: at least one of excipient, adjuvant, additive, surfactant, desiccant, and diluent.

7. The use of claim 1, wherein the medicament is a medicament that synergistically antagonizes the tumor by promoting the induction of autophagy in the tumor cell, by inhibiting the proliferation of the tumor cell, and by inhibiting the activity of the tumor cell.