Application of YW2301 in preparation of anti-Burkitt lymphoma drugTechnical Field
The invention relates to the technical field of biological pharmacy, in particular to application of YW2301 in preparation of a medicine for resisting Burkitt lymphoma.
Background
Burkitt Lymphoma (BL) is a highly invasive B cell lymphoma that originates in the follicular germinal center. Because of its high malignancy, tumor cells multiply for a short time, and if not treated in time, patients often die within months. About 50% of BL patients are already in the disease progression stage when they are found. Therefore, the search for new therapeutic targets and related strategies has important clinical significance. Mutation-induced c-Myc dysregulation is one of the features of BL, and is of particular therapeutic significance. However, c-Myc is considered a "undruggable" target for therapeutic intervention. Therefore, targeting the expression of c-Myc protein by targeting a c-Myc upstream regulatory protein holds great promise.
As an important subtype in the acetaldehyde dehydrogenase family, ALDH18A1 plays an important role in metabolic reprogramming and epigenetic regulation of tumors. Studies show that ALDH18A1 has higher protein expression in Luminal B (ER+HER2-) breast cancer, is closely related to poor prognosis of patients, and has a significant positive correlation with MYC gene expression. Furthermore, MYC can regulate expression of ALDH18A1 in prostate cancer and Burkitt lymphoma. ALDH18A1 was also found in our earlier studies to be highly expressed in N-MYC expanded neuroblastoma cells and to regulate self-renewal of neuroblastoma.
It is shown that the gene promoter region of ALDH18A1 contains 2 c-Myc binding sites, which suggests that the ALDH18A1 gene may be a target gene of c-Myc, so that the small molecule inhibitor YW2301 of the ALDH18A1 can effectively inhibit proliferation and in vivo tumorigenicity of Burkitt lymphoma cells, and can become a potential target therapeutic candidate small molecule. The invention has potential clinical value for searching a new Burkitt lymphoma therapeutic target and improving the therapeutic effect of Burkitt lymphoma patients.
Disclosure of Invention
In view of the above, the invention aims to provide an application of YW2301 in preparing a medicine for treating Burkitt lymphoma.
In order to achieve the above purpose, the present invention provides the following technical solutions:
1. Application of YW2301 in preparing medicine for treating Burkitt lymphoma, wherein the molecular formula of YW2301 is C32H55BrN4 O, and the molecular structural formula is:
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in some embodiments of the invention, the use of YW2301 for the manufacture of a medicament for inhibiting Burkitt's lymphoma cell proliferation.
In some embodiments of the invention, the use of YW2301 in the manufacture of a medicament for inhibiting Burkitt's lymphoma cell neoplasia.
In some embodiments of the invention, the use of YW2301 for the manufacture of a medicament for inhibiting expression of ALDH18A1 and c-Myc proteins in Burkitt's lymphoma cell xenografts.
The invention has the beneficial effects that the invention discloses the application of YW2301 in preparing a medicine for resisting Burkitt lymphoma, CCK8 cell activity experiments are utilized to detect that YW2301 has inhibition capability on proliferation of Raji and CA46 cells, a NON/SCID subcutaneous transplantation tumor model is constructed by a Raji cell line, the therapeutic significance of YW2301 on Burkitt lymphoma is evaluated, the tumorigenicity of the Burkitt lymphoma cells and the growth speed of the transplantation tumor can be effectively inhibited by the YW2301, ALDH18A1 and c-Myc protein expression in the Burkitt lymphoma transplantation tumor tissue section are detected by adopting immunohistochemical staining, and the YW2301 can effectively regulate the expression of ALDH18A1 and c-Myc protein in the Burkitt lymphoma tissue in a down-regulated manner, so that the YW2301 can be further proved to be a candidate small molecule for targeted treatment of Burkitt lymphoma.
Drawings
In order to make the objects, technical solutions and advantageous effects of the present invention more clear, the present invention provides the following drawings for description:
FIG. 1 is the effect of YW2301 on the proliferative capacity of Burkitt's lymphoma cells.
FIG. 2 is a graph showing the effect of YW2301 on the in vivo tumorigenicity of Burkitt lymphoma.
FIG. 3 is a graph showing the effect of YW2301 on expression of ALDH18A1 and c-Myc proteins in Burkitt lymphoma cell xenografts.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to limit the invention, so that those skilled in the art may better understand the invention and practice it.
Chinese name of YW2301 is cetylammonium pyriminobac, molecular formula is C32H55BrN4 O, manufacturer is Tao Su, product number is T2188, CAS number is 553-08-2, molecular structural formula is:
Example 1 YW2301 inhibits the cell proliferation potency of Burkitt's lymphoma cells
The ability of YW2301 to inhibit proliferation of Raji and CA46 cells was tested using CCK8 cell activity assays. The results showed that the absorbance values were significantly reduced after YW2301 treatment of Raji and CA46 cells compared to the control group (fig. 1, a-B). The results show that the ALDH18A1 inhibitor YW2301 can significantly reduce the proliferation capacity of Burkitt lymphoma cells in vitro.
Example 2 YW2301 inhibits in vivo tumorigenicity of Burkitt lymphoma cells
A NON/SCID subcutaneous engraftment tumor model was constructed with Raji cell lines to evaluate the therapeutic significance of YW2301 on Burkitt lymphoma. Mice were divided into four groups, control (saline), dox, YW2301Low (low concentration), YW2301High (high concentration), each group of 14, 7 of which were used to observe tumor volume and 7 of which were used to observe survival time of tumor-bearing mice, using Doxorubicin (Doxorubicin, dox) as a positive Control. Wherein the Control group was administered intraperitoneally once every 2 days, the Dox group was administered intraperitoneally once every 7 days (dose: 1 mg/kg), the YW2301Low group was administered intraperitoneally once every 2 days (dose: 2 mg/kg), and the YW2301High group was administered intraperitoneally once every 2 days (dose: 6 mg/kg). When the tumor length exceeded 1.5 cm, mice were identified as dead, and the follow-up and sacrifice were terminated according to ethical principles. As a result, as shown in FIG. 2, the volume of the transplanted tumor in YW2301High was significantly reduced (the average volume of the tumor in Control group was 611.54.+ -. 97.23 mm3,YW2301High, the average volume of the tumor in Control group was 94.52.+ -. 48.03 mm3, the average volume of the tumor in Control group was vs. YW2301High, n=7, and P=6.44×10-7) compared with the Control group, the tumor volume in YW2301Low was also reduced (the average volume of the tumor in YW2301Low group was 212.77.+ -. 34.67 mm3, the average volume of the tumor in Control group was vs. YW2301Low, n=7, P=1.10×10-5), and the tumor volume in DOX group was also reduced (the average volume of the tumor in DOX group was 280.82.+ -. 36.99 mm3, the Control group vs. DOX group, n=7, and P=3.80×10-5) (FIG. 2, A-B). Compared with the Control group, the YW2301High group, the YW2301Low group, DOX group transplanted tumors significantly decreased in weight (Control group tumor average weight 0.42.+ -. 0.07 g, YW2301High group tumor average weight 0.07.+ -. 0.05 g, YW2301Low group tumor average weight 0.19.+ -. 0.05 g, DOX group tumor average volume 0.18.+ -. 0.04 g, n=7, control group vs. YW2301High group, P=1.94×10-7; control group vs. YW2301Low group, P=2.60×10-5; control group vs. DOX group, P=7.00×10-6) (FIG. 2, C). Kaplan-Meier analysis showed that YW2301 treatment significantly prolonged the overall survival of tumor-bearing mice (fig. 2, D). The 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 candidate small molecules for Burkitt lymphoma targeted therapy.
Example 3 YW2301 Down-regulates expression of ALDH18A1 and c-Myc in Burkitt's lymphoma cell transplantation tumor tissue
ALDH18A1 and c-Myc protein expression in Burkitt lymphoma engraftment tumor tissue sections was detected using immunohistochemical staining. The results showed that the expression of ALDH18A1 and C-Myc proteins was significantly down-regulated in YW2301High tissue sections compared to the control, and also in YW2301Low and DOX tissue sections (FIG. 3, A-C). The results show that YW2301 can effectively down-regulate the expression of ALDH18A1 and c-Myc proteins in Burkitt lymphoma tissues, and further prove that YW2301 can be used as a candidate small molecule for Burkitt lymphoma targeted therapy.
The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.