CN117982660A - Combined pharmaceutical composition for resisting acute myelogenous leukemia and application thereof - Google Patents
Combined pharmaceutical composition for resisting acute myelogenous leukemia and application thereof Download PDFInfo
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a combined pharmaceutical composition for resisting acute myeloid leukemia and application thereof, wherein medicinal active components in the combined pharmaceutical composition consist of a Bcl-2 inhibitor, a PPAR agonist and a histone deacetylase inhibitor. The invention develops a brand-new medicine combination mode, the three medicines are combined to be used as medicines for resisting acute myeloid leukemia, and the AML cell strain proves that the combined medicine composition can synergistically inhibit the proliferation of AML cells, induce the apoptosis of the AML cells and inhibit the clone formation of the AML cells, and has more remarkable technical effects than the single therapy or the combined use of the two medicines. In animal experiments, the combination of three drugs has also been demonstrated to synergistically inhibit the tumorigenic progression of mouse AML. The invention provides an effective drug combination strategy for preventing, relieving or treating acute myeloid leukemia, and has very remarkable significance.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to a novel prevention, alleviation or treatment mode of acute myeloid leukemia, and in particular relates to a combined medicine composition for resisting acute myeloid leukemia and application thereof.
Background
Acute Myeloid Leukemia (AML) is a heterogeneous hematological malignancy that is manifested by rapid proliferation of abnormal myeloid cells in the bone marrow and blood and interference with normal blood cell growth. Although current first-line treatment regimens of cytarabine in combination with anthracycline chemotherapy can result in remission in a large proportion of patients, most AML patients relapse and prognosis remains uneconomical. The main reason for chemotherapy failure is that AML patients develop resistance to chemotherapy. Therefore, there is an urgent need to find new AML treatment regimens, to extend patient survival time and to increase patient cure rate.
Bcl-2 inhibitors can specifically target Bcl-2 and inhibit the anti-apoptosis function of Bcl-2, thereby mediating apoptosis of tumor cells to perform the tumor cell killing function. The results of prior studies show that overexpression of anti-apoptotic Bcl-2 family proteins has a close correlation with AML developing chemotherapy resistance and prognosis defects. Thus, lowering the threshold of apoptosis occurrence by targeted inhibition of anti-apoptotic Bcl-2 family proteins is a potential approach to the treatment of AML. Valnemulin (Venetoclax, ABT-199), the first small molecule inhibitor of protein-protein interactions (PPI) worldwide, is a highly potent, selective and orally active small molecule Bcl-2 inhibitor that binds to the hydrophobic groove of Bcl-2, disrupting Bcl-2 molecule interactions with pro-apoptotic proteins (e.g. Bax). However, the monotherapy of ABT-199 has poor results and is prone to drug resistance. Thus, there is a need for rational combination therapies to improve the therapeutic efficacy of ABT-199 in AML.
The sodium cilaglita (Chiglitazar) is a diabetes treatment drug which is independently designed and synthesized by Shenzhen micro-core biotechnology, inc. of China, has a brand new chemical structure and global intellectual property protection, has the full activation of PPARalpha, PPARdelta and PPARgamma, belongs to a new generation of insulin sensitizer, and is mainly used for treating type 2 diabetes. Sodium cilagliptin has been shown to inhibit the progression of AML by inhibiting the glycolytic level of AML cells.
Inhibitors of Histone Deacetylase (HDACs) can increase tumor cell sensitivity, with ciladalimine (CS 055) approved by the FDA in 2015 for the treatment of relapsed/refractory peripheral T-cell lymphomas.
The effective drug combination strategies for treating the acute myeloid leukemia disclosed in the prior art are relatively few, and the development of more novel acute myeloid leukemia treatment strategies is very significant.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel prevention, alleviation or treatment mode of acute myeloid leukemia, in particular to a combined drug combination for resisting acute myeloid leukemia and application thereof.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
In a first aspect, the present invention provides a combination pharmaceutical composition for the treatment of acute myeloid leukemia, wherein the pharmaceutically active ingredients of the combination pharmaceutical composition consist of a Bcl-2 inhibitor, a PPAR agonist and a histone deacetylase inhibitor.
The invention develops a brand-new medicine combination mode, namely three medicines of a Bcl-2 inhibitor, a PPAR agonist and a histone deacetylase inhibitor are combined to be used as medicines for resisting acute myeloid leukemia, and the combined use of the Bcl-2 inhibitor, the PPAR agonist and the histone deacetylase inhibitor in an AML cell strain proves that the combined use of the Bcl-2 inhibitor, the PPAR agonist and the histone deacetylase inhibitor can synergistically inhibit the proliferation of AML cells, induce the apoptosis of the AML cells and inhibit the clone formation of the AML cells, and has the functions of obviously inhibiting the proliferation of the AML cells, inducing the apoptosis of the AML cells and inhibiting the clone formation of the AML cells compared with the single therapy or the combined use of the two medicines. In animal experiments, the combination of three drugs has also been demonstrated to synergistically inhibit the tumorigenic progression of mouse AML. The invention provides an effective drug combination strategy for preventing, relieving or treating acute myeloid leukemia, and has very remarkable significance.
In terms of mechanism, the three drug combinations related to the invention can synergistically target and inhibit the expression level of BCL-2 family proteins (BCL-2, BCL-XL, MCL 1) and HDACs (HDAC 1, HDAC2, HDAC3 and HDAC 10) in AML cells, up-regulate the protein expression level of PPARα and finally inhibit the occurrence and development processes of AML. The action mechanism of the compound for inhibiting the occurrence and development progress of AML is shown in figure 1.
Preferably, the Bcl-2 inhibitor is selected from any one or a combination of at least two of valnemulin or a pharmaceutically acceptable salt, isomer, solvate, metabolite, crystalline form or amorphous form thereof.
Preferably, the PPAR agonist is selected from any one or a combination of at least two of the group consisting of sitagliptin or a pharmaceutically acceptable salt, isomer, solvate, metabolite, crystalline form or amorphous form thereof.
Preferably, the pharmaceutically acceptable salt of the sitagliptin is selected from any one of alkali metal salt, alkaline earth metal salt, ammonium salt or quaternary ammonium salt.
Preferably, the isomer of ciglibenclamide is selected from the group consisting of the levorotatory forms.
Preferably, the PPAR agonist is selected from sodium, potassium or the levorotatory form thereof.
Preferably, the histone deacetylase inhibitor is selected from any one or a combination of at least two of cetadamine or pharmaceutically acceptable salts, isomers, solvates, metabolites, crystalline forms or amorphous forms thereof.
Preferably, the pharmaceutical combination further comprises pharmaceutically acceptable excipients.
Preferably, the pharmaceutical composition for combined use of the present invention may be administered alone or in combination with an auxiliary material to prepare a suitable dosage form, and the pharmaceutically acceptable auxiliary material includes any one or a combination of at least two of diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, bacteriostats or buffers.
In the invention, the combined pharmaceutical composition is a single compound preparation or a combination of three independent single preparations.
Preferably, the combination pharmaceutical composition is a combination of three separate single formulations, which are administered simultaneously, sequentially or cross-administered.
In the invention, the preparation is any pharmaceutically acceptable dosage form.
In a second aspect, the invention provides the use of a combination pharmaceutical composition according to the first aspect for the preparation of a medicament for the prevention, alleviation or treatment of acute myeloid leukemia.
In a third aspect, the present invention provides the use of a combination pharmaceutical composition according to the first aspect for the preparation of an inhibitor of proliferation of acute myeloid leukemia cells.
Preferably, the acute myeloid leukemia cells comprise KG-1 alpha cells and/or Kasumi cells.
According to the research result of the invention, the combined pharmaceutical composition has the effect of obviously inhibiting the proliferation of the acute myeloid leukemia cells, so the result shows that the combined pharmaceutical composition can be used as an in vitro experimental reagent in the scientific research field, for example, the research on the growth, apoptosis and metabolic mechanism or behavior of the acute myeloid leukemia cells, the screening of therapeutic drugs and the like. The proliferation inhibitor disclosed by the invention is not used for eliminating the etiology or the focus, namely, the application of the proliferation inhibitor in preparing the acute myeloid leukemia cell proliferation inhibitor with the non-therapeutic purpose.
In a fourth aspect, the invention provides the use of a combination pharmaceutical composition according to the first aspect for the preparation of an apoptosis promoter for acute myeloid leukemia cells.
Preferably, the acute myeloid leukemia cells comprise KG-1 alpha cells and/or Kasumi cells.
According to the research result of the invention, the combined pharmaceutical composition has the effect of obviously inducing the apoptosis of the acute myeloid leukemia cells, so the result shows that the combined pharmaceutical composition can be used as an in vitro experimental reagent in the scientific research field, such as research on the growth, apoptosis and metabolic mechanism or behavior of the acute myeloid leukemia cells, screening of therapeutic drugs and the like. The apoptosis promoter claimed in the invention is not used for eliminating etiology or focus, namely, the application of the apoptosis promoter in preparing acute myeloid leukemia cell apoptosis promoter by taking non-treatment as a destination.
In a fifth aspect, the present invention provides the use of a combination pharmaceutical composition according to the first aspect for the preparation of an inhibitor of cell clone formation of acute myeloid leukemia cells.
Preferably, the acute myeloid leukemia cells comprise KG-1 alpha cells and/or Kasumi cells.
According to the research result of the invention, the combined pharmaceutical composition has the effect of obviously inhibiting the clone formation of the acute myeloid leukemia cells, so the result shows that the combined pharmaceutical composition can be used as an in vitro experimental reagent in the scientific research field, for example, the metabolic mechanism or behavior of the acute myeloid leukemia cells is researched, and the therapeutic drugs are screened. The clonogenic inhibitor claimed in the present invention is not used for eliminating the cause or the focus, i.e. it is a non-therapeutic use for the preparation of an acute myeloid leukemia cell clonogenic inhibitor.
In a sixth aspect, the present invention provides a method of preventing, alleviating or treating acute myeloid leukemia, said method comprising administering to a patient in need thereof an effective amount of a combination pharmaceutical composition according to the first aspect.
In the present invention, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated step or component or group of steps or components but not the exclusion of any other step or component or group of steps or components.
The term "treatment" refers to the administration or application of a therapeutic agent to a subject, or the administration of a step or pattern to a subject, with the aim of obtaining therapeutic benefit for a disease or health-related condition, such as effective in improving the underlying pathological conditions and clinical manifestations of acute myeloid leukemia herein.
The term "prevent" means to reduce or completely inhibit to any extent to achieve the desired result. For example, the degree of activity or symptom may be reduced by 5%, 10%, 20%, 30%, 50%, 75%, 90%, 99% or more, or any range encompassed herein, as compared to normal.
The term "effective amount" means an amount of a compound effective to produce the desired prophylactic, palliative or therapeutic effect. The amount of the combination pharmaceutical composition according to the invention that is "effective" will vary depending on the compound, the symptoms and severity thereof, the age of the mammal being treated, but can be routinely determined by one of ordinary skill in the art based on their knowledge in conjunction with the present disclosure.
The term "compound formulation" refers to a formulation having two or more active pharmaceutical ingredients, for example, when the combination of the present invention is a compound formulation, it may represent that it comprises the Bcl-2 inhibitor vitamin e-troke, the PPAR agonist cilaglipta sodium and the histone deacetylase inhibitor cidamine.
The term "single formulation" refers to a formulation having a single active pharmaceutical ingredient, e.g., when the combination of the present invention is a single formulation, it may represent a combination of three separate formulations each containing the Bcl-2 inhibitor vitamin e toltrak, the PPAR agonist cilaglitanium and the histone deacetylase inhibitor ciladalim.
Compared with the prior art, the invention has the following beneficial effects:
The invention develops a brand-new medicine combination mode, namely three medicines of a Bcl-2 inhibitor, a PPAR agonist and a histone deacetylase inhibitor are combined to be used as medicines for resisting acute myeloid leukemia, and the combined use of the Bcl-2 inhibitor, the PPAR agonist and the histone deacetylase inhibitor in an AML cell strain proves that the combined use of the Bcl-2 inhibitor, the PPAR agonist and the histone deacetylase inhibitor can synergistically inhibit the proliferation of AML cells, induce the apoptosis of the AML cells and inhibit the clone formation of the AML cells, and has the functions of obviously inhibiting the proliferation of the AML cells, inducing the apoptosis of the AML cells and inhibiting the clone formation of the AML cells compared with the single therapy or the combined use of the two medicines. In animal experiments, the combination of three drugs has also been demonstrated to synergistically inhibit the tumorigenic progression of mouse AML. The invention provides an effective drug combination strategy for preventing, relieving or treating acute myeloid leukemia, and has very remarkable significance.
Drawings
FIG. 1 is a schematic diagram of the mechanism of action of the combination pharmaceutical composition of the invention in inhibiting the progression of AML;
FIG. 2A is a graph showing the results of inhibition of cell proliferation after 24h of KG-1. Alpha. Cells treated with different drug groups according to example 1;
FIG. 2B is a graph showing the results of inhibition of cell proliferation after 24h of Kasumi-1 cells treated with different drug groups in example 1;
FIG. 3A is a graph showing the results of horizontal flow assays of apoptosis after KG-1. Alpha. Cells were treated for 24h in the different drug groups of example 2;
FIG. 3B is a graph showing the statistics of apoptosis rate of KG-1. Alpha. Cells treated with different drug groups of example 2 for 24 h;
FIG. 3C is a graph showing the results of a horizontal flow assay for apoptosis after Kasumi-1 cells were treated for 24h with different drug groups as described in example 2;
FIG. 3D is a graph showing the statistics of apoptosis rate of Kasumi-1 cells treated with different drug groups of example 2 for 24 hours;
FIG. 4A is a graph showing the results of the test for the clonogenic potential of KG-1. Alpha. Cells treated with different drug groups for 24 hours in example 3;
FIG. 4B is a statistical chart showing the results of the test for the clonality of cells 24h after treatment of KG-1. Alpha. Cells with different drug groups in example 3;
FIG. 4C is a graph showing the results of the test for the clonogenic potential of Kasumi-1 cells treated with the different drug groups of example 3 for 24 hours;
FIG. 4D is a statistical chart showing the results of the cell clonality assay after 24h of Kasumi-1 cells treated with different drug groups in example 3;
FIG. 5A is a graph showing Western blot analysis of protein levels of PPARα, HDACs and BCL2 family after 24h treatment of KG-1 α cells with different drug groups of example 4;
FIG. 5B is a graph showing Western blot analysis of PPARα, HDACs and BCL2 family protein levels after 24h treatment of Kasumi-1 cells with different drug groups of example 4;
FIG. 6A is a statistical plot of survival of KG-1. Alpha. Cell CDX mice in example 5;
FIG. 6B is a statistical plot of Kasumi-1 cell CDX mouse survival in example 5;
fig. 6C is a statistical plot of PDX mouse survival in example 5.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
The procedures, conditions, reagents, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited. The experimental methods in each example, in which specific conditions are not noted, are generally performed under conventional conditions or under conditions recommended by the manufacturer.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. However, in case of conflict, the present specification, including definitions, will control.
The drug vinatoka referred to in the following examples is a product available from MedChemExpress LLC company under the model number HY-15531; both sodium ciliata and cidamine are available from Shenzhen micro-core biotechnology Co., ltd.
AML cell lines (including KG 1a, kasumi) were supplied by the university of mansion medical college hematology institute.
Example 1
Inhibition of proliferation of AML cell lines by combination pharmaceutical compositions
The operation method comprises the following steps: 1X 10 4 log phase AML cell lines KG-1 alpha and Kasumi-1 were inoculated into 96-well cell culture plates, respectively, control groups were treated with DMSO, and experimental groups were treated with 3 drugs alone or in combination: the valnemulin concentration was set at 40nM; the sodium concentration of sitagliptin was set to 8 μm; the concentration of cetadamine was set to 2 μm. After 24h of treatment of each group, the level of cell proliferation was detected using CCK8 kit (MCE, shanghai). The statistical results of the obtained cell proliferation levels are shown in FIG. 2A (KG 1. Alpha.) and FIG. 2B (Kasumi).
As can be seen from fig. 2A and 2B, compared with the control group, the inhibition effect of the combination of three drugs, namely, sitagliptin and valnemulin, on the proliferation of AML cells in either the AML cell line KG-1a or Kasumi-1 was significantly better than that of the combination of two drugs or the single drug.
Example 2
Apoptosis inducing effect of combination pharmaceutical composition on AML cell line
The operation method comprises the following steps: 1X 10 5 log phase AML cell lines KG-1 alpha and Kasumi-1 were inoculated into 24-well cell culture plates, respectively, control groups were treated with DMSO, and experimental groups were treated with 3 drugs alone or in combination: the valnemulin concentration was set at 40nM; the sodium concentration of sitagliptin was set to 8 μm; the concentration of cetadamine was set to 2 μm. After 24h treatment, the level of apoptosis was detected by Annexin V/PI flow staining and the rate of apoptosis was counted. The results are shown in FIGS. 3A-3D.
As can be seen from fig. 3A-3D, the combined use of three drugs, cilaglipta sodium, cildamine and valnemtock, in either the AML cell line KG-1a or Kasumi-1, significantly improved the promotion of AML apoptosis compared to the control group.
Example 3
Inhibition of cell clone formation by AML cell lines by combination pharmaceutical compositions
The operation method comprises the following steps: 1X 10 5 log phase AML cell lines KG-1 alpha and Kasumi-1 were inoculated into 24-well cell culture plates, respectively, control groups were treated with DMSO, and experimental groups were treated with 3 drugs alone or in combination: the valnemulin concentration was set at 40nM; the sodium concentration of sitagliptin was set to 8 μm; the concentration of cetadamine was set to 2 μm. After 24h of treatment, 2000 treated KG-1 alpha and Kasumi-1 cells were taken, respectively, and their clonogenic potential was examined by soft agar experiments. The results are shown in FIGS. 4A-4D.
As can be seen from fig. 4A-4D, compared with the control group, the inhibition effect of the combination of three drugs, namely, cilaglipta sodium, cildaben amine and valnemtock, on the clone formation of AML cells in either the AML cell line KG-1a or Kasumi-1 was significantly better than that of the combination of two drugs or the single drug.
Example 4
Effect of combination pharmaceutical compositions on AML cell line protein expression
The operation method comprises the following steps: 1X 10 6 log phase AML cell lines KG-1 alpha and Kasumi-1 were inoculated into 6cm cell culture dishes, control groups were treated with DMSO, and experimental groups were treated with 3 drugs alone or in combination: the valnemulin concentration was set at 40nM; the sodium concentration of sitagliptin was set to 8 μm; the concentration of cetadamine was set to 2 μm. After 24h treatment, cells were collected by centrifugation at 300g for 5min, lysed with 400. Mu. LRIPA lysate for 1h, western blot was performed to extract total protein, and PPARα, HDACs (HDAC 1, HDAC2, HDAC3 and HDAC 10) expression levels of BCL-2 family proteins (BCL-2, BCL-XL, MCL 1) were detected. The results are shown in FIGS. 5A-5B.
As can be seen from fig. 5A-5B, the pharmaceutical combination composition according to the present invention synergistically up-regulates the protein expression level of pparα of AML cell lines, down-regulates the expression levels of pparα, HDACs (HDAC 1, HDAC2, HDAC3 and HDAC 10) and BCL-2 family proteins (BCL-2, BCL-XL, MCL 1) of AML cell lines, and has a remarkable technical effect compared with the control group, the single drug, and the combination of both drugs. The combined pharmaceutical composition can synergistically target various paths including activating PPARalpha, inhibiting HDACs and inhibiting BCL-2 family proteins, and further synergistically inhibit the disease progression of AML groups.
Example 5
Evaluation of the killing of AML cells by combination pharmaceutical compositions from animal level
The operation method comprises the following steps:
(1) Construction of a PDX (human tissue xenograft) mouse model:
Primary AML cells were collected, and the primary AML cells were then tumor-established by injecting into NOD-SCID IL-2rγnull (NSG) mice at a dose of 1.5Gy via the tail vein, and AML humanized mice were constructed, and human AML cells were sorted from the spleen of the humanized mice, and a mouse PDX model was established by injecting 1×10 5 human AML cells via the tail vein for each NSG mouse. Wherein NSG mice were purchased from and bred by the university of Xiamen laboratory animal center.
(2) The killing effect of various drugs and combinations thereof on AML cells was examined:
A control group, a two-drug combination group and a three-drug combination group are respectively arranged. About 14 days after injection of human AML cells, valnemulin was administered at a dose of 40mg/kg/day, cilagliptin was administered at a dose of 7.5mg/kg/day, and cilobromide was administered at a dose of 7.5 mg/kg/day. The administration was once on day 0 and 3 with the administration start diary for 14 days. There were 5 mice in each group.
(3) Construction of a CDX (cell lines KG-1. Alpha. And Kasumi-1) mouse model:
1X 10 6 KG-1 alpha cells and Kasumi-1 cells were collected and injected into NOD-SCID IL-2Rγnull (NSG) mice purchased from and fed to the university of Xiamen laboratory animal center via the tail vein at a dose of 1.5Gy for oncologic and thus AML CDX mice were constructed.
(4) The killing effect of various drugs and combinations thereof on AML cells was examined:
A control group, a two-drug combination group and a three-drug combination group are respectively arranged. About 14 days after injection of AML cells, valnemulin was administered at a dose of 40mg/kg/day, cilagliptin was administered at a dose of 7.5mg/kg/day, and cilobromide was administered at a dose of 7.5 mg/kg/day. The administration was once on day 0 and 3 with the administration start diary for 14 days. There were 5 mice in each group.
The survival rate and survival curve of each group of mice are shown in fig. 6A, 6B and 6C, respectively, and it can be seen that the survival rate of the mice in the three-drug combination group is significantly higher than that of the mice in the control group and the two-drug combination group. The results show that the three-drug combination significantly reduces the tumor burden in the bone marrow and spleen of the mice and inhibits the in vivo AML (tumor formation) progression of CDX and PDX mouse models.
The applicant states that the technical solution of the present invention is illustrated by the above embodiments, but the present invention is not limited to the above embodiments, i.e. it does not mean that the present invention must be implemented by the above embodiments. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (10)
1. A pharmaceutical combination for resisting acute myeloid leukemia is characterized in that the pharmaceutical active components in the pharmaceutical combination consist of a Bcl-2 inhibitor, a PPAR agonist and a histone deacetylase inhibitor.
2. The pharmaceutical combination of claim 1, wherein the Bcl-2 inhibitor is selected from any one or a combination of at least two of valnemulin or a pharmaceutically acceptable salt, isomer, solvate, metabolite, crystalline form or amorphous form thereof.
3. The pharmaceutical combination according to claim 1, wherein the PPAR agonist is selected from the group consisting of any one or a combination of at least two of the pharmaceutically acceptable salts, isomers, solvates, metabolites, crystalline forms or amorphous forms thereof;
preferably, the pharmaceutically acceptable salt of the sitagliptin is selected from any one of alkali metal salt, alkaline earth metal salt, ammonium salt or quaternary ammonium salt;
Preferably, the isomer of ciglibenclamide is selected from the group consisting of the levorotatory forms;
preferably, the PPAR agonist is selected from sodium, potassium or the levorotatory form thereof.
4. The pharmaceutical combination of claim 1, wherein the histone deacetylase inhibitor is selected from the group consisting of cetosteanamine or a pharmaceutically acceptable salt, isomer, solvate, metabolite, crystalline form or amorphous form thereof.
5. The combination pharmaceutical composition against acute myeloid leukemia according to any one of claims 1-4, wherein the combination pharmaceutical composition further comprises pharmaceutically acceptable excipients;
Preferably, the pharmaceutically acceptable auxiliary materials comprise any one or a combination of at least two of diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, bacteriostats or buffers.
6. The combination pharmaceutical composition of any one of claims 1-5, wherein the combination pharmaceutical composition is a single compound formulation or a combination of three separate single formulations;
Preferably, the combination pharmaceutical composition is a combination of three separate single formulations, which are administered simultaneously, sequentially or cross-administered;
preferably, the preparation is any one of pharmaceutically acceptable dosage forms.
7. Use of a combination pharmaceutical composition according to any one of claims 1-6 for the preparation of a medicament for the prevention, alleviation or treatment of acute myeloid leukemia.
8. Use of a combination pharmaceutical composition according to any one of claims 1-6 for the preparation of an inhibitor of proliferation of acute myeloid leukemia cells;
preferably, the acute myeloid leukemia cells comprise KG-1 alpha cells and/or Kasumi cells.
9. Use of a combination pharmaceutical composition according to any one of claims 1-6 for the preparation of an apoptosis promoter for acute myeloid leukemia cells;
preferably, the acute myeloid leukemia cells comprise KG-1 alpha cells and/or Kasumi cells.
10. Use of a combination pharmaceutical composition according to any one of claims 1-6 for the preparation of an inhibitor of cell clone formation of acute myeloid leukemia cells;
preferably, the acute myeloid leukemia cells comprise KG-1 alpha cells and/or Kasumi cells.
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