Application of aureomycin A in aspects of inducing cell differentiation to prevent and treat leukemia

Abstract

The invention belongs to the technical field of medicines, discloses application of a compound aureomycin A for preventing and treating leukemia by inducing differentiation of leukemia HL-60, and particularly discloses application of the compound aureomycin A shown in a formula (I) in inducing expression of mature macrophage markers CD11b, CD14 and CSF1R of leukemia HL-60 cells to induce cell differentiation for preventing and treating leukemia. Pharmacological experiments prove that the aureomycin A can be used for remarkably inducing the expression of CD11b, CD14 and CSF1R in leukemia HL-60 cells. Experimental results show that the aureomycin A has the effect of inducing leukemia cell differentiation to prevent and treat leukemia.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to the use of chlortetracycline A in inducing cell differentiation and preventing leukemia. Background Technology

[0002] Leukemia is a malignant disease originating from hematopoietic stem cells. Its pathogenesis is complex, involving uncontrolled proliferation of leukemia cells in the bone marrow and other hematopoietic tissues, leading to suppression of normal hematopoiesis and leakage into other organs. Acute myeloid leukemia (AML) is the most common type of leukemia. AML is a highly heterogeneous group of hematologic malignancies characterized by uncontrolled proliferation of hematopoietic cells. Currently, AML treatment mainly involves anthracyclines (such as daunorubicin, nordaunorubicin, doxorubicin, etc.) or chemotherapy using all-trans retinoic acid combined with cytarabine. However, the toxic side effects and drug resistance of current drug treatments remain significant challenges for differentiation-inducing therapy. Therefore, finding new, highly effective, and low-toxicity differentiation-inducing agents is crucial.

[0003] The acute myeloid leukemia cell line HL-60 can be used to study pathological mechanisms and develop related therapeutic drugs. Cell surface antigens are closely related to the differentiation and developmental stages of cells, and changes in leukemia antigen expression can be used to examine the differentiation direction of leukemia. HL-60 acute promyelocytic leukemia cells differentiate into monocytes, progressing from monocytes and premonocytes to mature monocytes. During this process, the surface antigens CD11b, CD14, and CSF1R are highly expressed.

[0004] Compounds and their metabolites derived from marine microorganisms possess complex and varied structures, representing an endless diversity of structures. Obtaining compounds for treating glioma from marine natural products is a crucial approach in drug development in this field. Aureomycin A, derived from Streptomyces in marine sediments, has been reported to possess bioactivities against melanoma, lymphoma, cervical cancer, lung cancer, glioma, and leukemia. In 1989, James A. Matson et al. observed that aureomycin A could prolong median survival time (MST) to some extent in mouse tumor models transplanted with P388 and L1210 leukemia cells. In 2013, Shreyans K. Jain et al. reported that aureomycin A caused DNA damage and apoptosis in HL-60 cells. Induction of differentiation is an important mechanism in leukemia treatment; however, there are currently no reports on the use of aureomycin A to induce leukemia cell differentiation for leukemia prevention and treatment. Summary of the Invention

[0005] The technical problem solved by this invention is to provide a compound with the structural formula shown in Formula (I), chlortetracycline A, and its pharmaceutical composition for inducing the expression of mature macrophage markers CD11b, CD14, and CSF1R in human acute promyelocytic leukemia cells HL-60, thereby inducing cell differentiation and preventing leukemia.

[0006]

[0007] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0008] The first aspect of the present invention is to provide the use of the compound aureomycin A, as shown in formula (I), in inducing cell differentiation and preventing leukemia by increasing the expression of CD11b in HL-60 leukemia cells.

[0009]

[0010] The second aspect of the present invention provides the use of the compound aureomycin A, as shown in formula (I), in inducing cell differentiation and preventing leukemia by increasing the expression of CD14 in HL-60 leukemia cells.

[0011]

[0012] The third aspect of the present invention is to provide the use of the compound aureomycin A, as shown in formula (I), in inducing cell differentiation and preventing leukemia by increasing the expression of CSF1R in HL-60 leukemia cells.

[0013] The fourth aspect of the present invention is to provide the use of a pharmaceutical composition in inducing cell differentiation and preventing leukemia, wherein the pharmaceutical composition comprises the compound aureomycin A of formula (I) and a pharmaceutically acceptable carrier or excipient.

[0014]

[0015] This invention also relates to pharmaceutical compositions of the compounds of this invention and conventional pharmaceutical excipients or adjuvants.

[0016] Pharmaceutical compositions of the compounds of the present invention can be prepared according to methods known in the art. For this purpose, if desired, the compounds of the present invention can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to formulate suitable administration or dosage forms for use as human or veterinary medicine.

[0017] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum, or rectum.

[0018] The compounds of this invention or pharmaceutical compositions containing them can be administered via injection. Injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, and acupoint injection, etc.

[0019] Dosage forms can be liquid or solid. Liquid dosage forms include true solutions, colloids, microparticles, emulsions, and suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and lyophilized powder injections.

[0020] The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0021] Beneficial technical effects: There are currently no reports of the use of aureomycin A for the proliferation of glioma cells and related treatment of glioma. Attached Figure Description

[0022] Figure 1 Effect of aureomycin A on CD11b expression in HL-60 leukemia cells. Values ​​are expressed as mean ± SEM (n=3); compared with the control group, ***P<0.001.

[0023] Figure 2 Effect of aureomycin A on CD14 expression in HL-60 leukemia cells. Values ​​are expressed as mean ± SEM (n=3); compared with the control group, ***P<0.001.

[0024] Figure 3 Effect of aureomycin A on CSF1R expression in HL-60 leukemia cells. Values ​​are expressed as mean ± SEM (n=3); compared with the control group, *P<0.05, **P<0.01. Detailed Implementation

[0025] Example 1: Effect of Chloramphenicol A on the Differentiation of HL-60 Leukemia Cells

[0026] 1. Experimental Methods

[0027] HL-60 cells were cultured in 1640 medium containing 20% ​​domestic fetal bovine serum, and passaged every 1-2 days at a rate of 1.3 × 10⁻⁶ cells / day. 6Cells were seeded at a density of 6-well plates, and different concentrations of chlortetracycline A were prepared using complete culture medium and added to the plates. Incubation was continued for 48 hours. After cell collection, the expression levels of CD11b, CD14, and CSF1R in cells were detected by flow cytometry using FITC-labeled mouse anti-human CD11b monoclonal antibody, FITC-labeled mouse anti-human CD14 monoclonal antibody, and PE-labeled macrophage colony-stimulating factor receptor (CSF1R) antibody (purchased from Beijing Bio-Sens Biotechnology Co., Ltd.). The average fluorescence intensity of the corresponding fluorescent labels was calculated.

[0028] 2. Experimental Results

[0029] 2.1 Effect of Chloramphenicol A on CD11b expression in HL-60 cells

[0030] Compared with the control group, CD11b expression was significantly increased in the 0.1 μM, 0.3 μM and 1 μM groups of chlortetracycline A (Table 1). Figure 1 The results showed that chlortetracycline A significantly induced the differentiation of HL-60 cells.

[0031] Table 1. Effects of chlortetracycline A on CD11b expression in HL-60 cells.

[0032] Group CD11b-FITC mean fluorescence intensity control group 4063.67±1076.9692 Chloramphenicol A 0.01 μM 5553.33±808.71 Chloramphenicol A 0.03 μM 5202.33±660.43 Chloramphenicol A 0.1 μM 11707±764.57*** Chloramphenicol A 0.3 μM 11543.67±191.54*** Chloramphenicol A 1μM 12903.67±592.70*** all-trans retinoic acid 1μM 30435.33±1236.31***

[0033] Numerical values ​​are expressed as mean ± SEM (n = 3); compared with the control group, ***P < 0.001.

[0034] 2.2 Effect of Chloramphenicol A on CD14 expression in HL-60 cells

[0035] Compared with the control group, CD14 expression was significantly increased in the 0.03 μM, 0.1 μM, 0.3 μM and 1 μM chlortetracycline A groups (Table 2). Figure 2 The results showed that aureomycin A significantly induced the differentiation of HL-60 cells.

[0036] Table 2. Effects of chlortetracycline A on CD14 expression in HL-60 cells.

[0037]

[0038]

[0039] Numerical values ​​are expressed as mean ± SEM (n = 3); compared with the control group, ***P < 0.001.

[0040] 2.3 Effect of Chloramphenicol A on CSF1R Expression in HL-60 Cells

[0041] Compared with the control group, CSF1R expression was significantly increased in the 0.3 μM and 1 μM chlortetracycline A groups (Table 1). Figure 1 The results showed that aureomycin A significantly induced the differentiation of HL-60 cells.

[0042] Table 3 Effects of chlortetracycline A on CSF1R expression in HL-60 cells

[0043] Group Average fluorescence intensity of CSF1R-PE control group 817.67±15.11 Chloramphenicol A 0.01 μM 1315.33±351.72 Chloramphenicol A 0.03 μM 1217±244.24 Chloramphenicol A 0.1 μM 984.33±80.38 Chloramphenicol A 0.3 μM 1462.33±214.79* Chloramphenicol A 1μM 1675.33±242.99** all-trans retinoic acid 1μM 509.33±37.87

[0044] Numerical values ​​are expressed as mean ± SEM (n = 3); compared with the control group, *P < 0.05, **P < 0.01.

Claims

1. Use of a compound of Formula (I) aurodyamycin A for the preparation of a medicament for the prevention and treatment of leukemia by inducing cell differentiation through increasing the expression of CD11b in leukemia HL-60 cells, 2. Use of a compound of Formula (I) aurodyamycin A for the preparation of a medicament for the prevention and treatment of leukemia by inducing cell differentiation through increasing the expression of CD14 in leukemia HL-60 cells, 3. Use of a compound of Formula (I) aurodyamycin A for the preparation of a medicament for the prevention and treatment of leukemia by inducing cell differentiation through increasing the expression of CSF1R in leukemia HL-60 cells, 4. Use of a pharmaceutical composition for the preparation of a medicament for the prevention and treatment of leukemia, said pharmaceutical composition comprising a compound of Formula (I) aurodyamycin A and a pharmaceutically acceptable carrier or excipient, 5. Use of a compound of Formula (I) aurodyamycin A for the preparation of a medicament for the prevention and treatment of leukemia.

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