Double-active-ingredient acute myelogenous leukemia resisting medicine and application thereof

Abstract

The invention relates to a double-active-component acute myelogenous leukemia resisting drug and application thereof. The active components of the double-active-component acute myelogenous leukemia resisting drug are composed of a first active component and a second active component, the first active component is selected from any one or a combination of at least two of simvastatin, pharmaceutically acceptable salt, isomer, solvate and metabolite of simvastatin; and the second active component is selected from any one or a combination of at least two of Selanisole, pharmaceutically acceptable salts, isomers, solvates and metabolites of the Selanisole. Research finds that combination of simvastatin and Senanisole not only can reduce the dosage of simvastatin or Senanisole and improve the medication safety, but also has the effect of improving or treating acute myelogenous leukemia more remarkably compared with single simvastatin or Senanisole, and plays a synergistic promotion effect.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and relates to a new drug strategy for acute myeloid leukemia, specifically to a dual-active ingredient anti-acute myeloid leukemia drug and its application. Background Art

[0002] Acute myeloid leukemia (AML) is the most common acute myeloid leukemia in adults. Although new chemotherapy drugs are constantly emerging and chemotherapy regimens are continuously optimized and improved, the remission rate after induction therapy and the long-term disease-free survival rate after induction therapy are relatively low. Most patients will develop drug resistance to chemotherapy drugs during the treatment process. Therefore, the treatment of AML still faces huge challenges at present. At present, it is very difficult for chemotherapy to significantly improve the prognosis of AML, and new treatment strategies are urgently needed.

[0003] Simvastatin is a statin drug mainly used to lower cholesterol and prevent cardiovascular diseases. Selinexor is a selective nuclear export inhibitor that exerts antitumor effects by targeting the nuclear export protein Exportin 1 (XPO1) and interfering with the nuclear export of tumor suppressor proteins. Although the therapeutic effect of selinexor is expected, its adverse reactions also need attention, including nausea, vomiting, diarrhea, fatigue, myelosuppression, and electrolyte disorders (such as hyponatremia). These adverse reactions can be alleviated to a certain extent through appropriate dose adjustment. At the same time, the emergence of drug resistance is still a major challenge, and future research needs to explore strategies to overcome drug resistance, such as developing a new generation of XPO1 inhibitors or optimizing combination treatment regimens. Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a new drug strategy for acute myeloid leukemia, specifically to provide a dual-active ingredient anti-acute myeloid leukemia drug and its application.

[0005] To achieve the purpose of the present invention, the following technical solutions are adopted:

[0006] In the first aspect, the present invention provides a dual-active ingredient anti-acute myeloid leukemia drug, and the active ingredients of the dual-active ingredient anti-acute myeloid leukemia drug are composed of a first active ingredient and a second active ingredient;

[0007] The first active ingredient is selected from any one or a combination of at least two of simvastatin, its pharmaceutically acceptable salts, isomers, solvates, and metabolites;

[0008] The second active ingredient is selected from any one or a combination of at least two of selinexor, its pharmaceutically acceptable salts, isomers, solvates, and metabolites.

[0009] The present invention explores the synergistic killing effect and mechanism of action of low-dose selinexor combined with simvastatin on acute myeloid leukemia cells, and finds that the combination of simvastatin and selinexor can not only reduce the dosage of simvastatin or selinexor, improve the drug safety, but also has a more significant effect on improving or treating acute myeloid leukemia than single simvastatin or selinexor, achieving a synergistic promotion effect. The present invention first proves through acute myeloid leukemia cell lines that it can significantly inhibit the proliferation of acute myeloid leukemia cells and induce their apoptosis; it proves through mitochondrial membrane potential detection that it can induce an increase in mitochondrial membrane potential and cause apoptosis of acute myeloid leukemia cells; it proves through cell WB experiments that it can activate the expression of genes and proteins related to the P53 pathway of acute myeloid leukemia cells; finally, it proves through the CDX mouse model that it can inhibit the tumorigenesis process in mice. The present invention provides an effective drug combination strategy for the improvement or treatment of acute myeloid leukemia, which has very significant significance.

[0010] Preferably, the dual-active ingredient anti-acute myeloid leukemia drug further contains pharmaceutically acceptable excipients. The dual-active ingredient anti-acute myeloid leukemia drug involved in the present invention can be used alone or in combination with excipients to form an appropriate dosage form for use.

[0011] Preferably, the pharmaceutically acceptable excipients include any one or a combination of at least two of carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, solubilizing agents, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, bacteriostatic agents or buffers.

[0012] Preferably, the dual-active ingredient anti-acute myeloid leukemia drug is a single compound preparation or a combination of two separate preparations.

[0013] Preferably, the dual-active ingredient anti-acute myeloid leukemia drug is a combination of two separate preparations, and the two separate preparations are administered simultaneously or sequentially.

[0014] The dual-active ingredient anti-acute myeloid leukemia drug can be in the form of a single compound preparation or a combination of two separate preparations; when it is a combination of two separate preparations, the administration method can be simultaneous administration, or cross-administration or sequential administration.

[0015] Preferably, the preparation is any pharmaceutically acceptable dosage form, such as tablets, powders, suspensions, granules, capsules, solutions, enemas, emulsions, etc.

[0016] Second aspect, the present invention provides the use of the dual-active ingredient anti-acute myeloid leukemia drug according to the first aspect in the preparation of a medicament for improving or treating acute myeloid leukemia.

[0017] Third aspect, the present invention provides the use of the dual-active ingredient anti-acute myeloid leukemia drug according to the first aspect in the preparation of an acute myeloid leukemia cell proliferation inhibitor.

[0018] Alternatively, the present invention provides the use of the dual-active ingredient anti-acute myeloid leukemia drug according to the first aspect in the preparation of an acute myeloid leukemia cell proliferation inhibitor for non-therapeutic purposes.

[0019] Fourth aspect, the present invention provides the use of the dual-active ingredient anti-acute myeloid leukemia drug according to the first aspect in the preparation of an acute myeloid leukemia cell apoptosis promoter.

[0020] Alternatively, the present invention provides the use of the dual-active ingredient anti-acute myeloid leukemia drug according to the first aspect in the preparation of an acute myeloid leukemia cell apoptosis promoter for non-therapeutic purposes.

[0021] Fifth aspect, the present invention provides the use of the dual-active ingredient anti-acute myeloid leukemia drug according to the first aspect in the preparation of an acute myeloid leukemia cell mitochondrial membrane potential disruptor.

[0022] Alternatively, the present invention provides the use of the dual-active ingredient anti-acute myeloid leukemia drug according to the first aspect in the preparation of an acute myeloid leukemia cell mitochondrial membrane potential disruptor for non-therapeutic purposes.

[0023] Preferably, the acute myeloid leukemia cells include Molm-13 cells and / or MV-4-11 cells.

[0024] Sixth aspect, the present invention provides the use of the dual-active ingredient anti-acute myeloid leukemia drug according to the first aspect in the preparation of a P53 signaling pathway activator.

[0025] Alternatively, the present invention provides the use of the dual-active ingredient anti-acute myeloid leukemia drug according to the first aspect in the preparation of a P53 signaling pathway activator for non-therapeutic purposes.

[0026] According to the research results of the present invention, the dual-active ingredient anti-acute myeloid leukemia drug significantly inhibits the proliferation of acute myeloid leukemia cells, promotes the apoptosis of acute myeloid leukemia cells, interferes with the mitochondrial membrane potential of acute myeloid leukemia cells, and activates the P53 signaling pathway of acute myeloid leukemia cells. Therefore, these results indicate that the drug can be used as a reagent for in vitro experiments in the scientific research field, such as studying the metabolic mechanisms or behaviors of acute myeloid leukemia cells, such as growth and apoptosis, and screening drugs for the treatment of acute myeloid leukemia.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The present invention explored the synergistic killing effect and mechanism of action of low-dose selinexor combined with simvastatin on acute myeloid leukemia cells, and found that the combination of simvastatin and selinexor can not only reduce the dosage of simvastatin or selinexor, improve the drug safety, but also has a more significant effect on improving or treating acute myeloid leukemia than single simvastatin or selinexor, showing a synergistic promoting effect. The present invention first demonstrated through acute myeloid leukemia cell lines that it can significantly inhibit the proliferation of acute myeloid leukemia cells and induce their apoptosis; through mitochondrial membrane potential detection, it was proved that it can induce an increase in mitochondrial membrane potential and cause apoptosis of acute myeloid leukemia cells; through cell WB experiments, it was proved that it can activate the expression of P53 pathway-related genes and proteins in acute myeloid leukemia cells; finally, through the CDX mouse model, it was proved that it can inhibit the tumorigenesis process in mice. The present invention provides an effective drug combination strategy for the improvement or treatment of acute myeloid leukemia, which has very significant significance. Description of the Drawings

[0029] Figure 1A It is a statistical result chart of the cell proliferation inhibition rate after treating Molm-13 cells with simvastatin combined with selinexor for 24 h;

[0030] Figure 1B It is a statistical result chart of the cell proliferation inhibition rate after treating MV-4-11 cells with simvastatin combined with selinexor for 24 h;

[0031] Figure 2A It is a statistical result chart of the flow cytometry detection of the cell apoptosis level after treating Molm-13 cells with simvastatin combined with selinexor for 24 h;

[0032] Figure 2B It is a statistical result chart of the flow cytometry detection of the cell apoptosis level after treating MV-4-11 cells with simvastatin combined with selinexor for 24 h;

[0033] Figure 3A It is a detection result chart of the cell mitochondrial membrane potential after treating Molm-13 cells with simvastatin combined with selinexor for 24 h;

[0034] Figure 3B It is a statistical chart of the mitochondrial membrane potential detection results after treating Molm-13 cells with simvastatin combined with selinexor for 24 hours;

[0035] Figure 4A It is a diagram of the detection results of the mitochondrial membrane potential of cells after treating MV-4-11 cells with simvastatin combined with selinexor for 24 hours;

[0036] Figure 4B It is a statistical chart of the mitochondrial membrane potential detection results after treating MV-4-11 cells with simvastatin combined with selinexor for 24 hours;

[0037] Figure 5 It is a Western blot result diagram of the protein expression level of the P53 signaling pathway after treating Molm-13 / MV-4-11 cells with simvastatin combined with selinexor for 24 hours;

[0038] Figure 6A It is a diagram of the anatomical appearance of the spleens of mice in each group after treating CDX mouse models with simvastatin combined with selinexor;

[0039] Figure 6B It is a statistical chart of the spleen weight of mice in each group after treating CDX mouse models with simvastatin combined with selinexor;

[0040] Figure 6C It is simvastatin combined with selinexor treating hCD45 in CDX mouse models + A statistical chart of the proportion of cells in the mouse spleen;

[0041] Figure 6D It is simvastatin combined with selinexor treating hCD45 in CDX mouse models + A statistical chart of the proportion of cells in the mouse bone marrow;

[0042] Figure 6E It is a statistical chart of the weight change of mice in each group after treating CDX mouse models with simvastatin combined with selinexor;

[0043] Figure 6F It is an in vivo imaging diagram of mice in each group after treating CDX mouse models with simvastatin combined with selinexor;

[0044] Among them, Simvastatin in the attached figures refers to simvastatin, Selinexor refers to selinexor, and Combo refers to the combination of simvastatin and selinexor. Detailed implementation methods

[0045] The technical solution of the present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only for helping to understand the present invention and should not be regarded as specific limitations on the present invention.

[0046] In the process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the specifically mentioned content below, are all common knowledge and well-known common sense in the art, and the present invention has no particularly restricted content. For the experimental methods without specific conditions noted in each embodiment, they are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0047] Unless otherwise specified, the meanings of all professional terms and scientific terms used in this specification are the same as those generally understood by those skilled in the technical field to which the present invention belongs. However, in case of conflict, this specification including the definitions shall prevail.

[0048] The drug Simvastatin involved in the following embodiments was purchased from Selleck.

[0049] The drug Selinexor involved in the following embodiments was purchased from Selleck.

[0050] The AML cell lines (including Molm-13 cells and MV-4-11 cells) were provided by the Institute of Hematology, School of Medicine, Xiamen University.

[0051] Example 1

[0052] Inhibitory effect of the dual-active ingredient anti-acute myeloid leukemia drug on the proliferation of AML cell lines:

[0053] The operation method was as follows: Take 2×10 4 AML cell lines in the logarithmic growth phase (including Molm-13 and MV-4-11 cell lines) were inoculated into 96-well plates, and a simvastatin single-drug group, a selinexor single-drug group, a combination group of simvastatin and selinexor, and a control group were set up;

[0054] For Molm-13 cells or MV-4-11 cells, the concentrations of simvastatin monotherapy in the experimental groups were 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, and 6 μM respectively, and the concentrations of selinexor monotherapy in the experimental group cells were 0.05 μM, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, and 0.3 μM respectively. The concentrations of the combination group of simvastatin and selinexor were 1 μM + 0.05 μM, 2 μM + 0.1 μM, 3 μM + 0.15 μM, 4 μM + 0.2 μM, 5 μM + 0.25 μM, 6 μM + 0.3 μM (the former is simvastatin and the latter is selinexor). Among them, the control group cells were treated with the same volume of DMSO; after gently oscillating and mixing the corresponding volume of the drug or DMSO with the cells in the above 96-well cell culture plate, the cells were cultured in a cell culture incubator (Thermo) for 24 h, and then the cell proliferation level was detected using a CCK8 kit (MCE, Shanghai).

[0055] The results of the cell proliferation levels of each group are as Figure 1A (Molm-13) and Figure 1B (MV-4-11) shown;

[0056] From Figure 1A the results shown, compared with higher concentrations of simvastatin monotherapy and higher concentrations of selinexor monotherapy, the combination of simvastatin and selinexor can significantly reduce the usage amounts of the two drugs on the basis of improving the inhibition level, that is, it can ensure both low drug toxicity and side effects and excellent therapeutic effects against acute myeloid leukemia.

[0057] Example 2

[0058] Inductive effect of the anti-acute myeloid leukemia drug with dual active ingredients on the apoptosis of AML cell lines:

[0059] The operation method was as follows: Take 2 × 10 5 AML cell lines (including Molm-13 and MV-4-11 cell lines) in the logarithmic growth phase and inoculate them into 24-well plates. Set up the simvastatin monotherapy group, selinexor monotherapy group, combination group of simvastatin and selinexor, and control group;

[0060] For Molm-13 cells or MV-4-11 cells, the single-agent concentrations of simvastatin in the experimental group cells were 1 μM, 2 μM, 3 μM, and 4 μM respectively, and the single-agent concentrations of selinexor in the experimental group cells were 0.05 μM, 0.1 μM, 0.15 μM, and 0.2 μM respectively. The combined concentrations of simvastatin and selinexor were 1 μM + 0.05 μM, 2 μM + 0.1 μM, 3 μM + 0.15 μM, and 4 μM + 0.2 μM (the former is simvastatin and the latter is selinexor). Among them, the control group cells were treated with the same volume of DMSO; after gently oscillating and mixing the corresponding volume of the drug or DMSO with the cells in the above 24-well cell culture plate, the cells were cultured in a cell incubator for 24 h, then centrifuged at 4 °C and 300 g for 5 min to collect the cells, washed once with PBS, and then the apoptosis level of the cells was detected by Annexin V / PI (Thermofisher, USA) flow cytometry staining method and the apoptosis rate of the cells was statistically analyzed.

[0061] Figure 2A and Figure 2B are respectively the statistical results of the apoptosis rate of Molm-13 cells ( Figure 2A ) or MV-4-11 cells ( Figure 2B ) after being treated with simvastatin combined with selinexor for 24 h.

[0062] It can be seen from the results shown in the above figure that compared with higher concentrations of simvastatin alone or higher concentrations of selinexor alone, the combination of simvastatin and selinexor can significantly reduce the usage amounts of the two drugs on the basis of improving the level of promoting cell apoptosis, that is, it can ensure both low drug toxicity and side effects and excellent therapeutic effects against acute myeloid leukemia.

[0063] Example 3

[0064] Effect of the dual-active ingredient anti-acute myeloid leukemia drug on the mitochondrial membrane potential of AML cell lines:

[0065] The operation method is as follows: Take 2 × 10 5 AML cell lines (including Molm-13 and MV-4-11 cell lines) in the logarithmic growth phase and inoculate them in a 24-well plate. Set up a simvastatin single-agent group, a selinexor single-agent group, a combination group of simvastatin and selinexor, and a control group;

[0066] For Molm-13 cells or MV-4-11 cells, the concentration of simvastatin alone in the experimental group cells was 2 μM, the concentration of selinexor alone in the experimental group cells was 0.1 μM, and the concentration in the simvastatin and selinexor combination group was 2 μM + 0.1 μM (the former was simvastatin and the latter was selinexor). Among them, the control group cells were treated with the same volume of DMSO; after gently oscillating and mixing the corresponding volume of the drug or DMSO with the cells in the above 24-well cell culture plate, the cells were cultured in a cell incubator for 24 h, then centrifuged at 4 °C and 300 g for 5 min to collect the cells, washed once with PBS, and then the mitochondrial membrane potential in the cells was detected by JC-1 flow cytometry staining method and the positive rate was counted.

[0067] Figure 3A , Figure 3B They are respectively the result graph and statistical graph of the mitochondrial membrane potential in Molm-13 cells after treatment with simvastatin combined with selinexor for 24 h.

[0068] Figure 4A , Figure 4B They are respectively the result graph and statistical graph of the mitochondrial membrane potential in MV-4-11 cells after treatment with simvastatin combined with selinexor for 24 h.

[0069] From the results shown in the above figures, it can be seen that compared with higher concentrations of simvastatin alone or higher concentrations of selinexor alone, the combination of simvastatin and selinexor can significantly reduce the usage amounts of the two drugs on the basis of increasing the mitochondrial membrane potential of cells, that is, it can simultaneously ensure low drug toxicity and side effects and excellent therapeutic effects against acute myeloid leukemia.

[0070] Example 4

[0071] Activation effect of the dual-active ingredient anti-acute myeloid leukemia drug on the P53 pathway expression of AML cell lines:

[0072] The operation method was as follows: Take 1×10 6 AML cell lines in the logarithmic growth phase (including Molm-13 and MV-4-11 cell lines) were inoculated into 12-well plates, and a simvastatin alone group, a selinexor alone group, a simvastatin and selinexor combination group, and a control group were set up;

[0073] The single - drug concentrations of simvastatin in the experimental group cells were 2 μM respectively, and the single - drug concentrations of selinexor in the experimental group cells were 0.1 μM respectively. The concentrations in the combination group of simvastatin and selinexor were 2 μM + 0.1 μM (the former was simvastatin and the latter was selinexor). Among them, the control group cells were treated with the same volume of DMSO. After gently oscillating and mixing the corresponding volume of the drug or DMSO with the cells in the above 12 - well cell culture plate, they were cultured in a cell incubator for 24 h. Then, the cells were collected by centrifugation at 4 °C and 300 g for 5 min, washed once with PBS, lysed on ice for 1 h with 200 μL of RIPA lysis buffer (Thermo, USA), and the total protein was extracted for Western blot to detect the expression level of the P53 pathway.

[0074] Figure 5 As shown in the Western blot results, compared with the use of simvastatin or selinexor alone, the combination of simvastatin and selinexor promoted the expression of proteins related to the P53 signaling pathway in the AML cell line more significantly.

[0075] Example 5

[0076] Effect of the dual - active - ingredient anti - acute myeloid leukemia drug on the tumorigenic process of AML:

[0077] The specific operation method is as follows:

[0078] (1) Set up a control group, a simvastatin single - drug group, a selinexor single - drug group, and a combination group of simvastatin and selinexor. Among them, simvastatin was prepared as a suspension with 0.5% sodium carboxymethylcellulose for use, and selinexor was prepared as a suspension with 0.5% sodium carboxymethylcellulose for use.

[0079] (2) Establish a CDX mouse model

[0080] Take 1×10 6 The GFP - Luc - MV - 4 - 11 cell line has been successfully constructed and injected into NOD - Prkdc - / - IL2rg - / - (NSG) mice through the tail vein for tumorigenesis to establish a CDX mouse model.

[0081] (3) Start drug administration 7 days after injection. The dose of simvastatin is 10 mg / kg / day, and the dose of selinexor is 5 mg / kg / day. Administer the drugs continuously for 14 days. Detect the tumorigenic progress of the mice by collecting peripheral blood of the mice. Fourteen days after drug administration, detect the proportion of AML cells in the spleen and bone marrow of the mice by flow cytometry, and comprehensively analyze the efficacy and toxicity of the combination treatment plan for the AML mouse model. And take the start date of drug administration as day 0, and count the experimental results and the survival rate of the mice. Among them, NSG mice were purchased from the Experimental Animal Center of Xiamen University and raised by the Experimental Animal Center.

[0082] After the treatment, the mice in each group were dissected and tested. The anatomical appearance of the spleen of each group of mice was as follows: Figure 6A The spleen weights of mice in each group are shown in Figure 6B As shown, flow cytometry was used to detect hCD45 + The results of the proportion of cells in the spleen of each group of mice are shown in Figure 6C As shown, flow cytometry was used to detect hCD45 + The ratio of cells in the bone marrow of each group of mice was as follows Figure 6D The body weight changes of mice in each group are shown in 6E, and the in vivo imaging images of mice in each group are shown in 6F.

[0083] As can be seen from the above figure, the dual-active ingredient anti-acute myeloid leukemia drug involved in the present invention has an excellent effect of inhibiting the tumor formation process of the CDX model, and simvastatin and selinexor have synergistic effects in inhibiting the tumor formation process of the CDX model.

[0084] The applicant declares that the present invention illustrates the technical solution of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0085] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0086] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A dual-active ingredient anti-acute myeloid leukemia drug, characterized in that: The active ingredients of the dual-active ingredient anti-acute myeloid leukemia drug consist of a first active ingredient and a second active ingredient; The first active ingredient is selected from simvastatin, any one of its pharmaceutically acceptable salts, isomers, solvates, metabolites, or a combination of at least two thereof; The second active ingredient is selected from selinexor, any one of its pharmaceutically acceptable salts, isomers, solvates, metabolites, or a combination of at least two thereof.

2. The dual-active ingredient anti-acute myeloid leukemia drug according to claim 1, characterized in that: The dual-active ingredient anti-acute myeloid leukemia drug also contains pharmaceutically acceptable excipients.

3. The dual-active ingredient anti-acute myeloid leukemia drug according to claim 2, characterized in that: The pharmaceutically acceptable excipients include any one or a combination of at least two of carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, antibacterial agents or buffers.

4. The dual-active ingredient anti-acute myeloid leukemia drug according to claim 1, characterized in that: The dual-active ingredient anti-acute myeloid leukemia drug is a single compound preparation or a combination of two separate preparations; Preferably, the dual-active ingredient anti-acute myeloid leukemia drug is a combination of two separate preparations, and the two separate preparations are administered simultaneously or sequentially; Preferably, the preparation is in any pharmaceutically acceptable dosage form.

5. Use of the dual-active ingredient anti-acute myeloid leukemia drug according to any one of claims 1 to 4 in the preparation of a drug for improving or treating acute myeloid leukemia.

6. Use of the dual-active ingredient anti-acute myeloid leukemia drug according to any one of claims 1 to 4 in the preparation of an acute myeloid leukemia cell proliferation inhibitor.

7. Use of the dual-active ingredient anti-acute myeloid leukemia drug according to any one of claims 1 to 4 in the preparation of an acute myeloid leukemia cell apoptosis promoter.

8. Use of the dual-active ingredient anti-acute myeloid leukemia drug according to any one of claims 1 to 4 in the preparation of an acute myeloid leukemia cell mitochondrial membrane potential disruptor.

9. The use according to any one of claims 6 to 8, characterized in that: The acute myeloid leukemia cells include Molm-13 cells and / or MV-4-11 cells.

10. Use of the dual-active ingredient anti-acute myeloid leukemia drug according to any one of claims 1 to 4 in the preparation of a P53 signaling pathway activator.

Images