Application of bedaquiline in preparation of medicine for preventing and / or treating leukemia

Abstract

The invention provides application of bedaquiline in preparation of a medicine for preventing and / or treating leukemia, and belongs to the technical field of medicines. The invention provides an application of bedaquiline in preparation of a medicine for preventing and / or treating leukemia. In-vitro leukemia cell experiments show that the bedaquiline has an obvious inhibition effect on the proliferation of leukemia cells, the EC50 of the bedaquiline to human chronic myelogenous leukemia cells is 10.06 mu M, and the EC50 of the bedaquiline to human acute lymphoblastic leukemia cells is 11.15 mu M. Besides, the BDQ has no obvious influence on the survival rate of normal cells, and the BDQ is a marketed medicine and can be quickly applied to a clinical stage, so that unnecessary time waste is reduced, and a patient can be treated in time. The invention provides a new scheme for treatment of leukemia.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to the application of bedaquiline in the preparation of drugs for preventing and / or treating leukemia. Background Art

[0002] Leukemia is a common malignant tumor of the hematopoietic system, which is caused by gene aberrations of hematopoietic stem cells and progenitor cells. According to the location where it occurs, it is divided into lymphocytic leukemia and myeloid leukemia. According to the differences in symptoms at the onset, leukemia is divided into acute and chronic.

[0003] Currently, the main clinical treatment methods for leukemia are chimeric antigen receptor T cell therapy (CAR-T) and targeted drugs. Although both of these treatment methods can improve the treatment effect and quality of life of patients, there are problems with poor treatment effects for both. For example, CAR-T therapy will cause loss of target antigen during treatment, and side effects such as cytokine release syndrome (CRS) and neurotoxicity will also occur. Therefore, there is an urgent need to develop new drugs that can effectively treat leukemia. Summary of the Invention

[0004] In view of this, the present invention provides an application of bedaquiline (BDQ) in the preparation of drugs for preventing and / or treating leukemia. BDQ prevents and / or treats leukemia by inhibiting the proliferation and activity of a variety of leukemia cells, and has no toxic side effects.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] The present invention provides an application of bedaquiline in the preparation of drugs for preventing and / or treating leukemia.

[0007] In the present invention, the leukemia includes myeloid leukemia and / or lymphocytic leukemia.

[0008] In the present invention, the leukemia includes the proliferation of leukemia cells.

[0009] In the present invention, the leukemia cells include myeloid leukemia cells and / or lymphocytic leukemia cells.

[0010] In the present invention, the myeloid leukemia cells include chronic myeloid leukemia cells and / or acute myeloid leukemia cells;

[0011] The lymphocytic leukemia cells include chronic lymphocytic leukemia cells and / or acute lymphocytic leukemia cells.

[0012] In the present invention, the dosage form of the drug includes oral preparations and / or injections.

[0013] In the present invention, the concentration of bedaquiline in the drug is above 8 μM.

[0014] The present invention provides a method for inhibiting the proliferation and / or activity of leukemia cells in vitro, which is characterized in that bedaquiline is used to inhibit the proliferation and / or activity of leukemia cells.

[0015] In the present invention, the leukemia cells include myeloid leukemia cells and / or lymphoid leukemia cells.

[0016] In the present invention, the working concentration of bedaquiline is 8 - 30 μM.

[0017] The present invention has the following advantages compared with the prior art:

[0018] The present invention provides an application of bedaquiline in the preparation of a drug for preventing and / or treating leukemia. Through in vitro leukemia cell proliferation experiments, the present invention shows that BDQ has an obvious inhibitory effect on the proliferation of leukemia cells and can be used for the treatment of leukemia. The prior art also shows that BDQ has no obvious effect on the survival rate of normal cells and has almost no cytotoxicity. In addition, BDQ is an already marketed drug, which can be quickly applied to the clinical stage, reducing unnecessary time waste and enabling patients to receive treatment in a timely manner. The present invention provides a new treatment plan for leukemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is a result diagram of BDQ inhibiting the proliferation of leukemia cells, where a is human chronic myeloid leukemia cells (K562), and b is human acute lymphoblastic leukemia cells (MOLT4). DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention provides an application of bedaquiline in the preparation of a drug for preventing and / or treating leukemia.

[0021] In the present invention, the bedaquiline is a clinical anti-tuberculosis drug, with the molecular formula: C 32 H 31 BrN2O2, molecular weight: 555.5 g / mol, CAS number: 843663-66-1, and the structural formula is shown in Formula I:

[0022]

[0023] The present invention does not have special limitations on the source of the bedaquiline, and it can be purchased through conventional commercial channels. In the examples of the present invention, the bedaquiline was purchased from MCE Company.

[0024] In the present invention, the leukemia preferably includes the proliferation of leukemia cells. The leukemia preferably includes myeloid leukemia and / or lymphocytic leukemia. The leukemia cells preferably include myeloid leukemia cells and / or lymphocytic leukemia cells. The myeloid leukemia cells preferably include chronic myeloid leukemia cells and / or acute myeloid leukemia cells; the lymphocytic leukemia cells preferably include chronic lymphocytic leukemia cells and / or acute lymphocytic leukemia cells.

[0025] In the present invention, the dosage form of the drug preferably includes oral dosage forms and / or injections. The drug preferably further contains pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients are conventionally selected according to the dosage form of the drug. The excipients for oral dosage forms can be selected from, but are not limited to, diluents, binders, and disintegrants. The diluent can be one or more of sucrose, maltodextrin, and modified starch. The binder can be one or more of povidone, methylcellulose, and ethylcellulose. The disintegrant can be one or more of crospovidone, croscarmellose sodium, and hydroxypropylcellulose. The excipients for injections include at least one of water, propylene glycol, polyethylene glycol, organic acid salts, hydrochloric acid, sodium hydroxide, sodium chloride, and glucose.

[0026] In the present invention, the concentration of bedaquiline in the drug is preferably 8 μM or more, can be 8 - 30 μM, can be 10 - 25 μM, can also be 10.06 - 25 μM, can further be 11 - 20 μM, and further is 11.15 μM.

[0027] In the present invention, the CCK8 assay kit can evaluate the proliferation ability and cell activity of cells by detecting the dehydrogenase activity in the cells. In the examples of the present invention, the CCK8 assay kit was used to detect the toxicity of BDQ to leukemia cells. The results showed that when the working concentration of BDQ was 8 μM, it could inhibit the dehydrogenase activity in K562 (human chronic myeloid leukemia cells) and MOLT4 (human acute lymphoblastic leukemia cells), and had an obvious inhibitory effect on the proliferation and activity of leukemia cells. Moreover, as the concentration increased, the inhibitory effect gradually enhanced. The EC 50 of BDQ for K562 was 10.06 μM. The EC 50 of BDQ for MOLT4 was 11.15 μM. Existing technologies show that BDQ has no obvious effect on the survival rate of normal cells and has almost no cytotoxicity. In addition, BDQ is an already marketed drug and can be quickly applied to the clinical stage. The present invention provides a new solution for the treatment of leukemia.

[0028] The present invention provides a method for inhibiting the proliferation and / or activity of leukemia cells in vitro, using bedaquiline to inhibit the proliferation and / or activity of leukemia cells.

[0029] In the present invention, the type of the leukemia cells is preferably the same as that of the leukemia cells in the application, which will not be elaborated herein. The present invention does not specifically limit the growth stage of the leukemia cells, and leukemia cells at any growth stage can be used. In the embodiments of the present invention, leukemia cells in the logarithmic growth phase are taken as an example to illustrate the efficacy of bedaquiline. The present invention does not specifically limit the solvent of bedaquiline, and a solvent commonly used in the art to dissolve bedaquiline can be used. In the embodiments of the present invention, dimethyl sulfoxide is used as the solvent of bedaquiline.

[0030] In the present invention, the use of bedaquiline to inhibit the proliferation and / or activity of leukemia cells is preferably culturing leukemia cells with a solution containing bedaquiline. The working concentration of bedaquiline is preferably 8 - 30 μM, which can be 10 - 25 μM, can also be 10.06 - 25 μM, and can further be 11 - 20 μM, and more preferably 11.15 μM. The solution preferably includes a leukemia cell culture medium, more preferably RPMI 1640 medium containing serum and antibiotics. The volume fraction of fetal bovine serum in the cell culture medium is preferably 10%, and the antibiotic preferably includes penicillin, and the concentration of penicillin in the cell culture medium is preferably 100 U / mL. The culture time is preferably 24 - 72 h, more preferably 36 - 60 h, and most preferably 48 h. The culture method of the present invention is beneficial to bedaquiline in inhibiting the proliferation and / or activity of leukemia cells.

[0031] In the embodiments of the present invention, after culturing logarithmic-phase leukemia cells and bedaquiline solutions with different concentrations in RPMI 1640 medium containing 10% (volume fraction) fetal bovine serum and 100 U / mL penicillin for 48 h, the effects of bedaquiline on leukemia cells were detected. The results showed that bedaquiline could effectively inhibit the proliferation and / or activity of leukemia cells.

[0032] To further illustrate the present invention, the solutions provided by the present invention will be described in detail below in conjunction with the drawings and embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0033] Experimental materials:

[0034] Human chronic myeloid leukemia cells (K562) and human acute lymphoblastic leukemia cells (MOLT4) were purchased from ATCC, and BDQ was purchased from MCE. The solvent of the BDQ solution is DMSO.

[0035] The cell culture medium is RPMI 1640 medium containing 10% (volume fraction) fetal bovine serum and 100 U / mL penicillin. RPMI 1640 medium was purchased from Gibco, and the product name is RPMI Medium 1640 basic (1x).

[0036] Example 1

[0037] Experiment on the inhibition of the proliferation of leukemia cells K562 and MOLT4 by BDQ

[0038] 1. After culturing K562 or MOLT4 to the logarithmic phase respectively, the cultured cells were centrifuged, resuspended with fresh cell culture medium, and the cell concentration was adjusted to 2×10 5 cells / mL. 100 μL was added to each well of a 96-well plate, and the total number of cells in each well was 2×10 4 cells;

[0039] 2. BDQ was first prepared into a 20 mM stock solution with DMSO as the solvent, and then diluted to BDQ solutions with different concentrations. There were 3 parallels for each concentration.

[0040] 3. BDQ solutions with different concentrations were taken and added to the 96-well plate and mixed with K562 or MOLT4, so that the final concentrations of BDQ in the 96-well plate included 8 concentration gradients from high to low: 20 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, and 0.3125 μM. Another control group was set, and the final concentration of BDQ in the control group was 0 μM. The volume percentage of DMSO in each well was 0.1%. After mixing, the cells were incubated in an incubator at 37 °C and 5% CO2 for 48 h.

[0041] 4. After incubation for 48 h, the OD 450 value was measured using a CCK8 detection kit (purchased from MCE Company), and then plotted with GraphPad and the cell proliferation was analyzed. The results of the in vitro anti-leukemia cell proliferation experiment are as Figure 1 shown.

[0042] From Figure 1 the results, it can be seen that BDQ can effectively inhibit the proliferation of K562 and MOLT4. When the working concentration of BDQ is 8 μM, it can inhibit the dehydrogenase activity in K562 and MOLT 4, and has an obvious inhibitory effect on the proliferation and activity of leukemia cells. Moreover, as the concentration increases, the inhibitory effect gradually enhances. The method of the present invention provides a new scheme for the treatment of leukemia. In addition, as a drug that has been on the market, BDQ can be quickly applied to the clinical stage, reducing unnecessary time waste and enabling patients to receive treatment in a timely manner.

[0043] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. Other embodiments can also be obtained based on this embodiment without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. Use of bedaquiline in the preparation of a drug for preventing and / or treating leukemia.

2. The use according to claim 1, characterized in that: The leukemia includes myeloid leukemia and / or lymphoid leukemia.

3. The application according to claim 1, characterized in that: The leukemia involves the proliferation of leukemic cells.

4. The use according to claim 3, characterized in that: The leukemia cells include myeloid leukemia cells and / or lymphoid leukemia cells.

5. The application according to claim 4, characterized in that: The myeloid leukemia cells include chronic myeloid leukemia cells and / or acute myeloid leukemia cells; The lymphoid leukemia cells include chronic lymphoid leukemia cells and / or acute lymphoid leukemia cells.

6. The use according to claim 1, characterized in that: The dosage form of the drug includes oral preparation and / or injection.

7. The use according to any one of claims 1 to 6, characterized in that: The concentration of bedaquiline in the drug is above 8 μM.

8. A method for inhibiting the proliferation of leukemia cells and / or inhibiting the activity of leukemia cells in vitro, characterized in that: Bedaquiline is used to inhibit the proliferation and / or activity of leukemia cells.

9. The method according to claim 9, characterized in that: The leukemia cells include myeloid leukemia cells and / or lymphoid leukemia cells.

10. The method according to claim 8 or 9, characterized in that: The working concentration of bedaquiline is 8-30 μM.

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