Use of YW2301 in the preparation of a medicine for resisting Burkitt lymphoma

Abstract

The application discloses application of YW2301 in preparation of a medicine for resisting Burkitt lymphoma, utilizes CCK8 cell activity experiment to detect the inhibition ability of YW2301 on Raji and CA46 cell proliferation, constructs a NON / SCID subcutaneous transplantation tumor model by using a Raji cell line, evaluates the therapeutic significance of YW2301 on Burkitt lymphoma, YW2301 can effectively inhibit the tumorigenicity of Burkitt lymphoma cells and the growth speed of the transplantation tumor, and adopts immunohistochemical staining to detect the ALDH18A1 and c-Myc protein expression in a Burkitt lymphoma transplantation tumor tissue section, YW2301 can effectively down-regulate the ALDH18A1 and c-Myc protein expression in a Burkitt lymphoma tissue, and further proves that YW2301 can be used as a candidate small molecule for targeted treatment of Burkitt lymphoma.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of biopharmaceuticals, in particular to application of YW2301 in preparation of a medicine for resisting Burkitt lymphoma. BACKGROUND

[0002] Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma originating from follicular germinal centers. Due to its high malignancy and short tumor cell doubling time, if not treated in time, patients often die within a few months. About 50% of BL patients are in the progressive stage when they are found. Therefore, finding new therapeutic targets and related strategies has important clinical significance. Mutant-induced c-Myc disorder is one of the characteristics of BL, and its therapeutic significance is particularly prominent. However, c-Myc is considered to be an "undruggable" target for therapeutic intervention. Therefore, targeting the expression of c-Myc protein by targeting the upstream regulatory proteins of c-Myc has great prospects.

[0003] As an important subtype in the acetaldehyde dehydrogenase family, ALDH18A1 plays an important role in metabolic reprogramming and epigenetic regulation of tumors. Studies have shown that ALDH18A1 is highly expressed in Luminal B (ER + HER2 - ) breast cancer, is closely related to poor prognosis of patients, and is significantly positively correlated with expression of MYC gene. In addition, MYC can regulate the expression of ALDH18A1 in prostate cancer and Burkitt lymphoma. In our previous studies, it was also found that ALDH18A1 is highly expressed in N-MYC amplified neuroblastoma cells and regulates the self-renewal of neuroblastoma.

[0004] It has been shown in literature that there are two c-Myc binding sites in the gene promoter region of ALDH18A1, suggesting that ALDH18A1 gene may be a target gene of c-Myc. Therefore, the small molecule inhibitor YW2301 of ALDH18A1 can effectively inhibit the proliferation of Burkitt lymphoma cells and the tumorigenic ability in vivo, and may become a potential target therapy candidate small molecule. The application has potential clinical value for finding new Burkitt lymphoma treatment targets and improving the treatment effect of Burkitt lymphoma patients. SUMMARY

[0005] In view of this, the application aims to provide application of YW2301 in preparation of a medicine for resisting Burkitt lymphoma.

[0006] To achieve the above-mentioned purpose, the application provides the following technical scheme:

[0007] 1. Use of YW2301 in the preparation of a medicament for treating Burkitt lymphoma, wherein the YW2301 has a molecular formula of C 32 H 55 BrN4O, and a molecular structure of:

[0008] .

[0009] In some embodiments of the present application, the use of YW2301 in the preparation of a medicament for inhibiting the proliferation of Burkitt lymphoma cells.

[0010] In some embodiments of the present application, the use of YW2301 in the preparation of a medicament for inhibiting the tumorigenicity of Burkitt lymphoma cells.

[0011] In some embodiments of the present application, the use of YW2301 in the preparation of a medicament for inhibiting the expression of ALDH18A1 and c-Myc proteins in Burkitt lymphoma cell xenografts.

[0012] The present application has the beneficial effects that the present application discloses the use of YW2301 in the preparation of a medicament for treating Burkitt lymphoma, CCK8 cell activity experiment is used to detect the inhibitory effect of YW2301 on the proliferation of Raji and CA46 cells; a NON / SCID subcutaneous tumor model is constructed using Raji cell line to evaluate the therapeutic significance of YW2301 on Burkitt lymphoma, YW2301 can effectively inhibit the tumorigenicity of Burkitt lymphoma cells and the growth rate of tumor xenografts; immunohistochemical staining is used to detect the expression of ALDH18A1 and c-Myc proteins in Burkitt lymphoma tumor xenograft tissue sections, YW2301 can effectively down-regulate the expression of ALDH18A1 and c-Myc proteins in Burkitt lymphoma tissue, which further proves that it can be used as a candidate small molecule for targeted therapy of Burkitt lymphoma. BRIEF DESCRIPTION OF DRAWINGS

[0013] In order to make the purpose, technical scheme and beneficial effects of the present application clearer, the present application provides the following drawings for illustration:

[0014] Figure 1 YW2301 on the proliferation of Burkitt lymphoma cells.

[0015] Figure 2 YW2301 on the tumorigenicity of Burkitt lymphoma in vivo.

[0016] Figure 3Effects of YW2301 on ALDH18A1 and c-Myc protein expression in Burkitt lymphoma cell xenografts. DETAILED DESCRIPTION

[0017] The present application will be further described with reference to the following drawings and specific examples, so that those skilled in the art can better understand the present application and implement it. The examples are not intended to limit the present application.

[0018] Chinese name of YW2301: Yiben 16 ammonium, molecular formula: C 32 H 55 BrN4O, manufacturer: Taosu, product number: T2188, CAS number: 553-08-2, molecular structure formula:

[0019]

[0020] Example 1, YW2301 inhibits the cell proliferation ability of Burkitt lymphoma cells

[0021] The CCK8 cell activity experiment was used to detect the inhibitory ability of YW2301 on the proliferation of Raji and CA46 cells. The results showed that, compared with the control group, the absorbance value of Raji and CA46 cells treated with YW2301 was significantly decreased (P<0.05, A-B). The above results showed that the ALDH18A1 inhibitor YW2301 could significantly reduce the in vitro proliferation ability of Burkitt lymphoma cells. Figure 1

[0022] Example 2, YW2301 inhibits the in vivo tumorigenic ability of Burkitt lymphoma cells

[0023] The Raji cell line was used to construct a NON / SCID subcutaneous xenograft model to evaluate the therapeutic significance of YW2301 on Burkitt lymphoma. Doxorubicin (Doxorubicin, Dox) was used as a positive control drug. The mice were divided into four groups: Control group (normal saline group), DOX group, YW2301 Low (low concentration) group, YW2301 High (high concentration group) group, each group of 14, of which 7 were used to observe the tumor volume, and the other 7 were used to observe the survival time of tumor-bearing mice. The Control group was given intraperitoneal administration every 2 days, the Dox group was given intraperitoneal administration every 7 days (dose: 1 mg / kg), the YW2301 Low group was given intraperitoneal administration every 2 days (dose: 2 mg / kg), and the YW2301 High ​Group was administered intraperitoneally every 2 days (dose: 6 mg / kg). According to the ethical principles, when the tumor length exceeded 1.5 cm, the mice were deemed to be dead, and the follow-up and the mice were sacrificed. The results are shown in Figure 2 YW2301 High Group significantly reduced the tumor volume (the average tumor volume of the Control group was 611.54 ± 97.23 mm 3 , the average tumor volume of the YW2301 High group was 94.52 ± 48.03 mm 3 , Control group vs. YW2301 High group, n = 7, P = 6.44 x 10 -7 ), and the tumor volume of the YW2301 Low group was also reduced (the average tumor volume of the YW2301 Low group was 212.77 ± 34.67 mm 3 , Control group vs. YW2301 Low group, n = 7, P = 1.10 x 10 -5 ), and the tumor volume of the DOX group was also reduced (the average tumor volume of the DOX group was 280.82 ± 36.99 mm 3 , Control group vs. DOX group, n = 7, P = 3.80 x 10 -5 ) Figure 2 , A-B). Compared with the Control group, the tumor weight of the YW2301 High group, the YW2301 Low group, and the DOX group was significantly reduced (the average tumor weight of the Control group was 0.42 ± 0.07 g, the average tumor weight of the YW2301 High group was 0.07 ± 0.05 g, the average tumor weight of the YW2301 Low group was 0.19 ± 0.05 g, and the average tumor volume of the DOX group was 0.18 ± 0.04 g, n = 7, Control group vs. YW2301 High group, P = 1.94 x 10 -7 ; Control group vs. YW2301 Low group, P = 2.60 x 10 -5 ; Control group vs. DOX group, P = 7.00 x 10 -6 ) Figure 2, C). Kaplan-Meier analysis showed that YW2301 treatment significantly prolonged the overall survival of tumor-bearing mice (P < 0.05, Fig. 4D). Figure 2 , D). The above results show that YW2301 can effectively inhibit the tumorigenicity of Burkitt lymphoma cells and the growth rate of transplanted tumors, and can be used as a candidate small molecule for targeted therapy of Burkitt lymphoma.

[0024] Example 3: YW2301 down-regulates the expression of ALDH18A1 and c-Myc in Burkitt lymphoma cell transplanted tumor tissues

[0025] The expression of ALDH18A1 and c-Myc protein in Burkitt lymphoma transplanted tumor tissue sections was detected by immunohistochemical staining. The results showed that compared with the control, the expression of ALDH18A1 and c-Myc protein in the YW2301 group was significantly down-regulated. High The expression of ALDH18A1 and c-Myc protein in the YW2301 group was significantly down-regulated compared with the control. Low The expression of ALDH18A1 and c-Myc protein in the YW2301 group and the DOX group was also down-regulated compared with the control. Figure 3 , A-C). The above results show that YW2301 can effectively down-regulate the expression of ALDH18A1 and c-Myc protein in Burkitt lymphoma tissues, further proving that it can be used as a candidate small molecule for targeted therapy of Burkitt lymphoma.

[0026] The above examples are only preferred embodiments for fully illustrating the present application, and the protection scope of the present application is not limited thereto. Any equivalent replacement or transformation made by those skilled in the art based on the present application is within the protection scope of the present application. The protection scope of the present application is subject to the claims.

Claims

1. The application of YW2301 in the preparation of drugs for treating Burkitt lymphoma, characterized in that, The drug exerts its effect by inhibiting the expression of ALDH18A1 and c-Myc proteins in Burkitt lymphoma cells; the molecular formula of YW2301 is C 32 H 55 BrN4O, the molecular structural formula is: 。 2. The application according to claim 1, characterized in that, The drug inhibits the proliferation of Burkitt lymphoma cells.

3. The application according to claim 1, characterized in that, The drug inhibits the tumorigenicity of Burkitt lymphoma cells.

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