Combined pharmaceutical composition for improving or treating acute myelogenous leukemia and application thereof

Abstract

The invention relates to a combined pharmaceutical composition for improving or treating acute myelogenous leukemia and application of the combined pharmaceutical composition. Active components of the combined pharmaceutical composition comprise 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 MI-3, pharmaceutically acceptable salts, isomers, solvates and metabolites thereof; the second active component is selected from any one or a combination of at least two of sitagliptin sodium, pharmaceutically acceptable salts, isomers, solvates and metabolites of the sitagliptin sodium. According to the present invention, the research results show that the MI-3 and the sitagliptin sodium not only can reduce the dosage of the MI-3 or the sitagliptin sodium and improve the medication safety, but also can significantly inhibit the acute myelogenous leukemia compared to the single MI-3 or the single sitagliptin sodium so as to achieve the synergistic promotion effect;

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and relates to a new combined drug intervention method for acute myeloid leukemia, and specifically to a combined drug composition for improving or treating acute myeloid leukemia and its application. Background Art

[0002] Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive malignant blood tumor and the most common subtype of adult leukemia. With the continuous deepening of aging, the incidence of AML is on the rise, posing more challenges to clinical diagnosis and treatment. In recent years, although there has been an increase in treatments for AML, such as chemotherapy, targeted therapy, and hematopoietic stem cell transplantation, the overall prognosis of patients is still not ideal, especially in elderly patients and those with other health problems. Therefore, there is an urgent need to develop new treatment options to provide effective solutions to the complex pathological characteristics and drug resistance problems of AML.

[0003] MI-3 is a classic menin inhibitor that can prevent the interaction between menin and MLL, thereby killing AML. However, in clinical trials, researchers have found that menin mutations can cause patients to develop resistance to menin inhibitors. Therefore, MI-3-based combination regimens are an effective strategy for the widespread use of MI-3 in clinical treatment in the future.

[0004] Chiglitazar is a non-thiazolidinedione small molecule agonist. It is the world's first oral peroxisome proliferator-activated receptor (PPARs) agonist independently developed by my country. It is mainly used to treat type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NAFLD).

[0005] In clinical practice, it is found that Siglitstat has the characteristics of few side effects, no bone marrow suppression, low price, and oral administration. It is still unclear whether MI-3 combined with Siglitstat can be used to treat AML and its mechanism of action on AML-related cell lines. Summary of the invention

[0006] In view of the deficiencies of the prior art, the purpose of the present invention is to provide a new combined drug intervention method for acute myeloid leukemia, specifically to provide a combined drug composition for improving or treating acute myeloid leukemia and its application.

[0007] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a combined pharmaceutical composition for improving or treating acute myeloid leukemia, wherein the active component of the combined pharmaceutical composition consists of a first active component and a second active component;

[0009] The first active ingredient is selected from MI-3, any one of its pharmaceutically acceptable salts, isomers, solvates, metabolites, or a combination of at least two thereof;

[0010] The second active ingredient is selected from sitagliptin sodium, any one of its pharmaceutically acceptable salts, isomers, solvates, metabolites, or a combination of at least two thereof.

[0011] The combined pharmaceutical composition involved in the present invention creatively combines MI-3 and Siglitstat sodium as a drug for improving or treating acute myeloid leukemia. The present invention has found that MI-3 and Siglitstat sodium can not only reduce the dosage of MI-3 or Siglitstat sodium, improve the safety of medication, but also have a more significant effect of inhibiting acute myeloid leukemia than single MI-3 or Siglitstat sodium, and play a synergistic promotion effect. The present invention first uses acute myeloid leukemia cell lines to prove that it can significantly inhibit the proliferation of acute myeloid leukemia cells, induce apoptosis, and block the cell cycle process; through mitochondrial membrane potential detection, it is proved that it can induce mitochondrial membrane potential increase to cause apoptosis of acute myeloid leukemia cells; through CDX mouse model, it is proved that the combined pharmaceutical composition can inhibit the tumor formation process of mice; finally, through Western blot experiments, it is proved that it can inhibit the expression of cell cycle-related proteins in acute myeloid leukemia cells. The present invention provides an effective drug combination strategy for the improvement or treatment of acute myeloid leukemia, which is of great significance.

[0012] Preferably, the combined pharmaceutical composition further contains a pharmaceutically acceptable excipient.

[0013] Preferably, the combination pharmaceutical composition of the present invention can be administered alone or in combination with excipients to make an appropriate dosage form for administration. 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.

[0014] Preferably, the combination pharmaceutical composition is a single compound preparation or a combination of two separate preparations.

[0015] Preferably, the combined pharmaceutical composition is a combination of two separate preparations, and the two separate preparations are administered simultaneously or sequentially.

[0016] The combination pharmaceutical composition may 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 may be simultaneous administration, cross administration or sequential administration.

[0017] Preferably, the preparation is any pharmaceutically acceptable dosage form, such as tablets, powders, suspensions, granules, capsules, solutions, enemas, emulsions, etc.

[0018] In a second aspect, the present invention provides use of the combined pharmaceutical composition according to the first aspect in the preparation of a drug for improving or treating acute myeloid leukemia.

[0019] In a third aspect, the present invention provides use of the combined pharmaceutical composition according to the first aspect in the preparation of an acute myeloid leukemia cell proliferation inhibitor.

[0020] In a fourth aspect, the present invention provides use of the combined pharmaceutical composition according to the first aspect in the preparation of an acute myeloid leukemia cell proliferation inhibitor for non-therapeutic purposes.

[0021] In a fifth aspect, the present invention provides use of the combined pharmaceutical composition according to the first aspect in the preparation of an acute myeloid leukemia cell apoptosis promoter.

[0022] In a sixth aspect, the present invention provides use of the combined pharmaceutical composition according to the first aspect in the preparation of an acute myeloid leukemia cell apoptosis promoter for non-therapeutic purposes.

[0023] In a seventh aspect, the present invention provides use of the combined pharmaceutical composition according to the first aspect in the preparation of an acute myeloid leukemia cell cycle inhibitor.

[0024] In an eighth aspect, the present invention provides use of the combined pharmaceutical composition according to the first aspect in the preparation of an acute myeloid leukemia cell cycle inhibitor for non-therapeutic purposes.

[0025] In the present invention, the above-mentioned acute myeloid leukemia cells include MV-4-11 cells and / or MOLM-13 cells.

[0026] According to the research results of the present invention, the combined pharmaceutical composition has the effects of significantly inhibiting the proliferation of acute myeloid leukemia cells, promoting the apoptosis of acute myeloid leukemia cells and blocking the cell cycle process of acute myeloid leukemia cells. Therefore, the results indicate that the combined pharmaceutical composition can be used as an in vitro experimental reagent in the field of scientific research, such as studying the growth, apoptosis, cell cycle and metabolic mechanism or behavior of acute myeloid leukemia cells, screening drugs for treating acute myeloid leukemia, etc.

[0027] In a ninth aspect, the present invention provides use of the combined pharmaceutical composition according to the first aspect in the preparation of an inhibitor of expression of cell cycle-related proteins in acute myeloid leukemia cells.

[0028] In a tenth aspect, the present invention provides use of the combination pharmaceutical composition according to the first aspect for non-therapeutic purposes in the preparation of an inhibitor of expression of cell cycle-related proteins in acute myeloid leukemia cells.

[0029] According to the research results of the present invention, the combined pharmaceutical composition has the effect of significantly inhibiting the expression of key cell cycle proteins (CDK1, CDK2, Cyclin A2, Cyclin B1) of acute myeloid leukemia cells. Therefore, the results indicate that the combined pharmaceutical composition can be used as an in vitro experimental reagent in the field of scientific research, such as studying the physiological metabolic mechanisms related to key cell cycle proteins (CDK1, CDK2, Cyclin A2, Cyclin B1) of leukemia cells.

[0030] In the present invention, the cell cycle-related proteins include CDK1, CDK2, Cyclin A2 and Cyclin B1.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The combined pharmaceutical composition involved in the present invention creatively combines MI-3 and Siglitstat sodium as a drug for improving or treating acute myeloid leukemia. The present invention has found that MI-3 and Siglitstat sodium can not only reduce the dosage of MI-3 or Siglitstat sodium, improve the safety of medication, but also have a more significant effect of inhibiting acute myeloid leukemia than single MI-3 or Siglitstat sodium, and play a synergistic promotion effect. The present invention first uses acute myeloid leukemia cell lines to prove that it can significantly inhibit the proliferation of acute myeloid leukemia cells, induce apoptosis, and block the cell cycle process; through mitochondrial membrane potential detection, it is proved that it can induce mitochondrial membrane potential increase to cause apoptosis of acute myeloid leukemia cells; through CDX mouse model, it is proved that the combined pharmaceutical composition can inhibit the tumor formation process of mice; finally, through Western blot experiments, it is proved that it can inhibit the expression of cell cycle-related proteins in acute myeloid leukemia cells. The present invention provides an effective drug combination strategy for the improvement or treatment of acute myeloid leukemia, which is of great significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1A This is the result graph of cell proliferation inhibition rate of MV-4-11 cells after MI-3 combined with sitagliptin for 24 hours;

[0034] Figure 1BThis is the result graph of cell proliferation inhibition rate of MOLM-13 cells after MI-3 combined with Siglitstat treatment for 24 hours;

[0035] Figure 1C This is the result of synergy index analysis of MV-4-11 cells treated with MI-3 combined with sitagliptin for 24 hours;

[0036] Figure 1D This is the result of synergy index analysis of MOLM-13 cells treated with MI-3 and sitagliptin for 24 hours;

[0037] Figure 2A This is the result of flow cytometry detection of apoptosis level in MV-4-11 cells treated with MI-3 and Siglitstat for 24 hours;

[0038] Figure 2B This is the statistical result of apoptosis rate of MV-4-11 cells;

[0039] Figure 2C This is the result of flow cytometry detection of apoptosis level in MOLM-13 cells treated with MI-3 and Siglitstat for 24 hours;

[0040] Figure 2D This is the statistical result of apoptosis rate of MOLM-13 cells;

[0041] Figure 3A This is the result of the cell mitochondrial membrane potential detection of MV-4-11 cells after MI-3 combined with Siglitstat treatment for 24 hours;

[0042] Figure 3B This is a statistical graph of the mitochondrial membrane potential detection results of MV-4-11 cells;

[0043] Figure 3C This is the result of the cell mitochondrial membrane potential detection of MOLM-13 cells after MI-3 combined with Siglitstat sodium treatment for 24 hours;

[0044] Figure 3D This is a statistical chart of the mitochondrial membrane potential detection results of MOLM-13 cells;

[0045] Figure 4A This is the result of cell cycle detection of MV-4-11 cells after MI-3 combined with sitagliptin for 24 hours;

[0046] Figure 4B This is a statistical graph of the cell cycle results of MV-4-11 cells;

[0047] Figure 4C This is the result of cell cycle detection of MOLM-13 cells after MI-3 combined with Siglitstat treatment for 24 hours;

[0048] Figure 4D This is a statistical graph of the cell cycle detection results of MOLM-13 cells;

[0049] Figure 5A This is a comparison of the weight changes of each group of mice after the MOLM-13-CDX mouse model was treated with each group of drugs;

[0050] Figure 5B This is a comparison of the tumor volumes of each group of mice after the CDX mouse model was treated with each drug;

[0051] Figure 5C This is the result of the analysis of the difference in subcutaneous tumor volume of each group of mice after the CDX mouse model was treated with each drug;

[0052] Figure 5D These are the anatomical appearances of subcutaneous tumors in each group of mice after the CDX mouse model was treated with drugs in each group;

[0053] Figure 6 This is the Western blot result of the expression level of key cell cycle proteins in MV-4-11 / MOLM-13 cells treated with MI-3 combined with sitagliptin for 24 hours;

[0054] Wherein, Chiglitazar or Chi marked in the accompanying drawings refers to sitagliptin; Combo refers to the combination of MI-3 and sitagliptin. DETAILED DESCRIPTION

[0055] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0056] The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention has no particular restrictions. The experimental methods without specifying specific conditions in the embodiments are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0057] Unless otherwise specified, all technical terms and scientific terms used in this specification have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. However, in case of any conflict, the present specification including the definitions shall prevail.

[0058] The drug MI-3 involved in the following examples was provided by Jiangsu Nanjing Taoshu Biological Company.

[0059] The drug sitagliptin sodium involved in the following examples was provided by Shenzhen Chipscreen Biotech Co., Ltd.

[0060] Acute myeloid leukemia cell lines (including MV-4-11 cells and MOLM-13 cells) were provided by the Institute of Hematology, Xiamen University School of Medicine.

[0061] Example 1

[0062] Inhibitory effect of combined drug composition on proliferation of AML cell lines

[0063] The operation method is: take the quantity as 1×10 5 AML cell lines (including MV-4-11 and MOLM-13 cell lines) in the logarithmic growth phase were inoculated in 96-well plates, and MI-3 monotherapy group, sitagliptin monotherapy group, MI-3 and sitagliptin combination group, and control group were set up;

[0064] The single drug concentration of MI-3 in the experimental group cells was 5μM, 10μM, 15μM and 20μM, respectively; the single drug concentration of sitagliptin in the experimental group cells was 5μM, 10μM, 15μM and 20μM, respectively; the concentrations of MI-3 and sitagliptin combination group (Combo) were 5μM+5μM, 10μM+10μM, 15μM+15μM, 20μM+20μM, respectively; the control group cells were treated with the same volume of DMSO; the corresponding volume of drug or DMSO was gently shaken and mixed with the cells in the above 96-well cell culture plate, and then cultured in a cell culture incubator (Thermo) for 24 hours, and the cell proliferation level was detected using a CCK-8 kit (MCE, Shanghai).

[0065] The results of cell proliferation levels in each group are shown in Figure 1A (MV-4-11) and Figure 1B (MOLM-13) shows that the synergy index analysis results of each group are as follows Figure 1C (MV-4-11) and Figure 1D (MOLM-13) shown;

[0066] pass Figure 1A and Figure 1B The results show that compared with a higher concentration of MI-3 alone or a higher concentration of sitagliptin alone, the combination of MI-3 and sitagliptin can significantly reduce the dosage of both drugs while improving the inhibition level; Figure 1C and Figure 1D The results show that the combination of the two drugs can play a synergistic role in killing AML cells, that is, it can simultaneously ensure low drug toxicity and side effects and excellent therapeutic effects against acute myeloid leukemia.

[0067] Example 2

[0068] Effect of combined drug combination on inducing apoptosis of AML cell lines

[0069] The operation method is: take the quantity as 1×10 5 AML cell lines in the logarithmic growth phase (including MV-4-11 cell line and MOLM-13 cell line) were inoculated in 24-well plates, and MI-3 monotherapy group, sitagliptin monotherapy group, MI-3 and sitagliptin combination group, and control group were set up;

[0070] The single drug concentration of MI-3 in the experimental group cells was 5μM, 10μM, 15μM and 20μM, respectively; the single drug concentration of sitagliptin in the experimental group cells was 5μM, 10μM, 15μM and 20μM, respectively; the concentrations of MI-3 and sitagliptin combination group (Combo) were 5μM+5μM, 10μM+10μM, 15μM+15μM, 20μM+20μM, respectively; the cells in the control group were treated with the same volume of DMSO; the corresponding volume of drug or DMSO was gently shaken and mixed with the cells in the above 24-well cell culture plate, and then cultured in a cell culture incubator for 24h, and then centrifuged at 4°C, 300g for 5min to collect the cells, washed once with PBS, and then Annexin V / PI (Thermofisher, USA) flow staining was used to detect the cell apoptosis level and calculate the cell apoptosis rate.

[0071] Figure 2A and Figure 2B They are the flow cytometry results of apoptosis level and apoptosis rate statistics of MV-4-11 cells treated with MI-3 combined with Siglitstat for 24 hours; Figure 2C and Figure 2D They are flow cytometry results of apoptosis level and statistical results of apoptosis rate of MOLM-13 cells treated with MI-3 and sitagliptin for 24 hours.

[0072] From the results shown in the above figure, it can be seen that compared with a higher concentration of MI-3 alone or a higher concentration of sitagliptin alone, the combination of MI-3 and sitagliptin can significantly reduce the dosage of the two drugs while improving the level of apoptosis in MV-4-11 and MOLM-13 cell lines, that is, it can simultaneously ensure low drug toxicity and side effects and excellent therapeutic effects against acute myeloid leukemia.

[0073] Example 3

[0074] Effect of combined drug composition on mitochondrial membrane potential of AML cell line

[0075] The operation method is: take the quantity as 1×10 5 AML cell lines in the logarithmic growth phase (including MV-4-11 cell line and MOLM-13 cell line) were inoculated in 24-well plates, and MI-3 monotherapy group, sitagliptin monotherapy group, MI-3 and sitagliptin combination group, and control group were set up;

[0076] The MI-3 single drug concentration of the experimental group cells was 20 μM, the sitagliptin sodium single drug concentration of the experimental group cells was 20 μM, and the concentration of the MI-3 and sitagliptin sodium combination group was 20 μM + 20 μM, wherein the control group cells were treated with the same volume of DMSO; the corresponding volume of drug or DMSO was gently shaken and mixed with the cells in the above-mentioned 24-well cell culture plate, and then cultured in a cell culture incubator for 24 hours, and then centrifuged at 4°C, 300g for 5 minutes to collect the cells, washed once with PBS, and then the intracellular mitochondrial membrane potential was detected by JC-1 flow staining and the positive rate was counted.

[0077] Figure 3A and Figure 3B They are the intracellular mitochondrial membrane potential result graph and statistical result graph after MV-4-11 cells were treated with MI-3 combined with Siglitstat for 24 hours; Figure 3C and Figure 3D They are the intracellular mitochondrial membrane potential result graph and statistical result graph after MOLM-13 cells were treated with MI-3 combined with sitagliptin for 24 hours.

[0078] From the results shown in the above figure, it can be seen that compared with 20μM MI-3 alone or 20μM sitagliptin sodium alone, the combination of MI-3 and sitagliptin sodium (20μM+20μM) can further increase the cell mitochondrial membrane potential, that is, the two drugs can synergistically enhance this effect.

[0079] Example 4

[0080] Effect of combined drug composition on blocking cell cycle progression of AML cell line

[0081] The operation method is: take the quantity as 1×10 6 AML cell lines in the logarithmic growth phase (including MV-4-11 cell line and MOLM-13 cell line) were inoculated in 12-well plates, and MI-3 monotherapy group, sitagliptin monotherapy group, MI-3 and sitagliptin combination group, and control group were set up;

[0082] The single drug concentration of MI-3 in the experimental group cells was 20 μM, the single drug concentration of sitagliptin in the experimental group cells was 20 μM, and the concentration of MI-3 and sitagliptin combined group was 20 μM+20 μM, wherein the cells in the control group were treated with the same volume of DMSO; after the corresponding volume of drug or DMSO was slightly shaken and mixed with the cells in the above-mentioned 12-well cell culture plate, after culturing in a cell culture incubator for 24 hours, 2 μL of 10 mM Edu solution was added to each well; after blowing and mixing, 200 μL was transferred to a 96-well U-type flow cytometer plate, and the well plate was placed in a cell culture incubator at 37°C for incubation for 60-90 minutes; after collecting and washing the cells, 200 μL of 4% paraformaldehyde was added to each well and fixed at room temperature for 15 minutes; after collecting and washing the cells, 100 μL of 0.3% Trinton was added to each well X-100, incubate at room temperature for 10 min; collect and wash the cells, add the reaction solution, and react in the dark for 30 min; collect and wash the cells, add 200 μL DAPI working solution (10 μg / mL) to each well, and incubate in the dark for 10 min at room temperature; collect and wash the cells, add 200 μL FACS to each well and resuspend for flow cytometry detection.

[0083] Figure 4A and Figure 4B They are the cell cycle result diagram and statistical result diagram of MV-4-11 cells treated with MI-3 combined with sitagliptin for 24 hours; Figure 4C and Figure 4D They are the cell cycle result graph and statistical result graph of MOLM-13 cells after MI-3 combined with sitagliptin treatment for 24 hours.

[0084] From the results shown in the above figure, it can be seen that compared with 20μM MI-3 alone or 20μM sitagliptin sodium alone, the combination of MI-3 and sitagliptin sodium (20μM+20μM) can further block the late stage of cell progression, that is, the two drugs synergistically enhance the above effects.

[0085] Example 5

[0086] Effect of combined drug combination on AML progression

[0087] The specific operation method is as follows:

[0088] (1) A control group, an MI-3 monotherapy group, a sitagliptin sodium monotherapy group, and an MI-3 and sitagliptin sodium combination group were set up, wherein MI-3 was prepared into a suspension using 0.5% sodium carboxymethyl cellulose, and sitagliptin sodium was prepared into a suspension using 0.5% sodium carboxymethyl cellulose.

[0089] (2) Construction of CDX mouse model

[0090] Take 1×107 MOLM-13 cells in the logarithmic growth phase were subcutaneously injected into nude mice (BALB / c-nu) to form tumors and establish the CDX mouse model.

[0091] (3) The drug was administered from the next day after injection, with a MI-3 dose of 50 mg / kg / day and a sitagliptin sodium dose of 15 mg / kg / day for 9 consecutive days. The tumor progression of mice was detected by measuring the size of subcutaneous tumors, and the day of drug administration was defined as day 0 for statistical analysis of the experimental results. Nude mice were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. and were raised by the Experimental Animal Center of Xiamen University.

[0092] The weight changes of mice in each group are shown in 5A, and the tumor volume changes are shown in Figure 5B The results of tumor volume difference analysis are shown in Figure 5C The anatomical appearance of the tumor is shown in Figure 5D As shown. This indicates that MI-3 combined with sitagliptin has synergistic effect in inhibiting the tumor progression of the CDX model.

[0093] Example 6

[0094] Inhibitory effect of combined drug composition on expression of key cell cycle proteins

[0095] The operation method is: take the quantity as 1×10 6 AML cell lines (including MV-4-11 and MOLM-13 cell lines) in the logarithmic growth phase were inoculated in 12-well plates, and MI-3 monotherapy group, sitagliptin monotherapy group, MI-3 and sitagliptin combination group, and control group were set up;

[0096] The single drug concentration of MI-3 in the experimental group cells was 20 μM, the single drug concentration of sitagliptin in the experimental group cells was 20 μM, and the concentration of MI-3 and sitagliptin combination group was 20 μM+20 μM, wherein the cells in the control group were treated with the same volume of DMSO; the corresponding volume of drug or DMSO was gently shaken and mixed with the cells in the above 12-well cell culture plate, and then cultured in a cell culture incubator for 24 h, and then centrifuged at 4°C, 300g for 5 min to collect the cells, washed once with PBS, and lysed on ice for 1 h with 200 μL RIPA lysis buffer (Thermo, USA), and the total protein was extracted for Western blot to detect the expression level of key cell cycle proteins.

[0097] Figure 6 The results of Western blot test show that MI-3 or sitagliptin can inhibit the expression of key cell cycle proteins in AML cell lines, and the two drugs have synergistic effects in the above effects.

[0098] The applicant declares that the present invention illustrates a combined pharmaceutical composition for preventing or treating acute myeloid leukemia and its application 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.

[0099] 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.

[0100] 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 combined pharmaceutical composition for improving or treating acute myeloid leukemia, characterized in that: The active component of the combined pharmaceutical composition consists of a first active component and a second active component; The first active ingredient is selected from MI-3, 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 sitagliptin sodium, any one of its pharmaceutically acceptable salts, isomers, solvates, metabolites, or a combination of at least two thereof.

2. The combined pharmaceutical composition according to claim 1, characterized in that: The combined pharmaceutical composition further contains pharmaceutically acceptable excipients; Preferably, the pharmaceutically acceptable excipients include any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an emulsifier, a solubilizer, a solubilizing agent, an osmotic pressure regulator, a surfactant, a coating material, a colorant, a pH regulator, an antioxidant, an antibacterial agent or a buffer.

3. The combined pharmaceutical composition according to claim 1, characterized in that: The combination pharmaceutical composition is a single compound preparation or a combination of two separate preparations; Preferably, the combination pharmaceutical composition 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.

4. Use of the combined pharmaceutical composition according to any one of claims 1 to 3 in the preparation of a medicament for improving or treating acute myeloid leukemia.

5. Use of the combined pharmaceutical composition according to any one of claims 1 to 3 in the preparation of an acute myeloid leukemia cell proliferation inhibitor.

6. Use of the combined pharmaceutical composition according to any one of claims 1 to 3 in the preparation of an acute myeloid leukemia cell apoptosis promoter.

7. Use of the combined pharmaceutical composition according to any one of claims 1 to 3 in the preparation of an acute myeloid leukemia cell cycle inhibitor.

8. The use according to any one of claims 5 to 7, characterized in that: The acute myeloid leukemia cells include MV-4-11 cells and / or MOLM-13 cells.

9. Use of the combined pharmaceutical composition according to any one of claims 1 to 3 in the preparation of an inhibitor of expression of cell cycle-related proteins in acute myeloid leukemia cells.

10. The use according to claim 9, characterized in that: The cell cycle-related proteins include CDK1, CDK2, Cyclin A2 and Cyclin B1.

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