Application of YW2301 in preparation of medicine for resisting colorectal cancer

Abstract

The invention discloses application of YW2301 in preparation of medicines for resisting colorectal cancer, and finds that the YW2301 is a small-molecule inhibitor of ALDH18A1, and the YW2301 can effectively inhibit high expression of ALDH18A1 and c-Myc protein, so that proliferation and in-vivo tumorigenesis ability of colorectal cancer cells are inhibited, and the YW2301 possibly becomes a potential candidate small molecule for targeted therapy of colorectal cancer. The invention has potential clinical value for searching a new colorectal cancer treatment target and improving the treatment effect of a colorectal cancer patient.

Description

Technical Field

[0001] The invention relates to the field of biotechnology, and in particular to application of YW2301 in preparing drugs for resisting colorectal cancer. Background Art

[0002] Colorectal carcinoma (CRC) is a common malignant tumor of the digestive system, and its mortality rate ranks third among malignant tumors. Despite surgical resection, radiotherapy, chemotherapy and molecular targeted therapy, approximately 20%-45% of CRC patients experience local recurrence or distant metastasis, and the 5-year survival rate of patients with metastasis is only 14%. Therefore, it is of great clinical significance to find new therapeutic targets and related strategies. Studies have shown that c-Myc is overexpressed in approximately 70% of CRCs, and its therapeutic significance is particularly prominent. However, the c-Myc protein lacks specific binding sites for small molecule compounds and has a short half-life, making c-Myc a target that has always been considered an "undruggable" target. Therefore, researchers have extensively explored alternatives to c-Myc intervention, including inhibiting MYC transcription and translation, destroying the MYC / Max complex, and synthetic lethal factors associated with MYC overexpression, in order to achieve an ideal anti-tumor effect.

[0003] Metabolic abnormalities are an important feature of many malignant tumors, including colorectal cancer. Various metabolites can change the cell phenotype of tumor cells by regulating epigenetic states and the expression of tumor-related genes. Among them, ALDH18A1 is a key enzyme in the metabolic pathways of glutamine, arginine and proline. Our previous studies have found that ALDH18A1 is highly expressed in N-MYC amplified neuroblastoma cells and regulates the self-renewal of neuroblastoma. Therefore, the present invention aims to screen and obtain new small molecule inhibitors of ALDH18A1, and provide potential candidate small molecules for targeted therapy for the treatment of rectal cancer. Summary of the invention

[0004] In view of this, the object of the present invention is to provide the use of YW2301 in the preparation of anti-colorectal cancer drugs.

[0005] In order to achieve the above object, the present invention provides the following technical solutions: Use of YW2301 in the preparation of an anti-colorectal cancer drug, wherein the YW2301 molecular formula is C 32 H 55 Bn 4 O, molecular structure formula is: .

[0006] In some embodiments of the present invention, YW2301 is used in the preparation of a drug for inhibiting the proliferation of colorectal cancer cells.

[0007] In some embodiments of the present invention, YW2301 is used in the preparation of a drug for inhibiting the cloning ability of colorectal cancer cells.

[0008] In some embodiments of the present invention, YW2301 is used in the preparation of a drug for inhibiting the tumorigenicity of colorectal cancer cells.

[0009] In some embodiments of the present invention, YW2301 is used in the preparation of a drug for shortening the half-life of c-Myc in rectal cancer cells.

[0010] In some embodiments of the present invention, YW2301 is used in the preparation of a drug for inhibiting the expression of ALDH18A1 and c-Myc proteins.

[0011] The beneficial effects of the present invention are as follows: the present invention finds that YW2301 is a small molecule inhibitor of ALDH18A1, and YW2301 can effectively inhibit the high expression of ALDH18A1 and c-Myc proteins, thereby inhibiting the proliferation of colorectal cancer cells and the ability to form tumors in vivo, and may become a potential candidate small molecule for targeted treatment of colorectal cancer. The present invention has potential clinical value for finding new colorectal cancer treatment targets and improving the treatment effect of colorectal cancer patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] In order to make the purpose, technical solution and beneficial effects of the present invention clearer, the present invention provides the following drawings for illustration: Figure 1 To study the effect of YW2301 on the proliferation ability of colorectal cancer cells.

[0013] Figure 2 This is the effect of YW2301 on the plate clone-forming ability of colorectal cancer cells.

[0014] Figure 3 Effect of YW2301 on the half-life of c-Myc protein in colorectal cancer cells.

[0015] Figure 4 The effect of different doses of YW2301 on the tumor-forming ability of colorectal cancer in vivo.

[0016] Figure 5 Effects of different doses of YW2301 on the expression of ALDH18A1 and c-Myc in colorectal cancer tissues. DETAILED DESCRIPTION

[0017] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0018] The Chinese name of YW2301 in the present invention is: hexadecyl pyrimidine, molecular formula: C 32 H 55 Bn 4 O, manufacturer: Taosu, product number: T2188, CAS number: 553-08-2, molecular structure: Example 1: YW2301 inhibits the proliferation of colorectal cancer cells The CCK8 cell activity assay was used to detect the effect of YW2301 on the proliferation of HCT116 and HT29 cells. The results showed that compared with the control group, the absorbance values ​​of HCT116 and HT29 cells treated with YW2301 decreased significantly ( Figure 1 , AB). The above results show that the ALDH18A1 inhibitor YW2301 can significantly reduce the in vitro proliferation ability of colorectal cancer cells.

[0019] Example 2: YW2301 reduces the plate-forming ability of colorectal cancer cells The plate cloning experiment was used to evaluate whether the ALDH18A1 inhibitor YW2301 could inhibit the cloning ability of colorectal cancer cells. The results showed that after YW2301 was used to treat HCT116 and HT29 cells, the number of colony formation of colorectal cancer cells was significantly reduced compared with the control group ( Figure 2 , AC). The above results show that the ALDH18A1 inhibitor YW2301 can significantly inhibit the plate cloning ability of colorectal cancer cells.

[0020] Example 3: YW2301 reduces the half-life of c-Myc in colorectal cancer cells The cycloheximide (CHX) protein stability assay was used to detect the effect of YW2301 on the half-life of c-Myc in colorectal cancer cells. After YW2301 (4 μM) was used to treat HCT116 and HT29 cells, the half-life of c-Myc in colorectal cancer cells was significantly shortened compared with the control group ( Figure 3 , AD). The above results further indicate that the ALDH18A1 inhibitor YW2301 can significantly shorten the half-life of c-Myc in colorectal cancer cells.

[0021] Example 4: YW2301 affects the tumorigenicity of colorectal cancer cells in vivo The NON / SCID subcutaneous transplant tumor model was constructed using the HCT116 cell line to evaluate the therapeutic significance of YW2301 for colorectal cancer. 5-Fluorouracil (5-FU) was used as a positive control drug, and the mice were divided into four groups: Control group (normal saline group), 5-FU group, YW2301 group, Low (Low concentration) group, YW2301 Hih (High concentration) group, each group has 14 mice, 7 of which are used to observe the tumor volume, and the other 7 are used to observe the survival time of tumor-bearing mice. The control group (normal saline) was intraperitoneally administered once every 2 days, the 5-FU group was intraperitoneally administered once every 2 days (dose: 40 mg / kg), YW2301 Low The group was intraperitoneally administered once every 2 days (dose: 2 mg / kg), YW2301 Hih The mice were intraperitoneally administered once every 2 days (dose: 6 mg / kg). According to ethical principles, when the tumor length exceeded 1.5 cm, the mice were considered dead, and the follow-up was terminated and the mice were killed. Figure 4 Shown: Compared with the control group, YW2301 High The volume of transplanted tumors in the control group was significantly reduced (the average volume of tumors in the control group was 761.06 ± 175.13mm 3 ,YW2301 High The average tumor volume in the group was 56.93 ± 9.20 mm 3 , Control group vs. YW2301 High group, n = 7, P = 4.00 × 10 -5 Compared with the Control group, the 5-FU group and YW2301 Low The tumor volume of the YW2301 group was also reduced. Low The average tumor volume in the group was 208.33 ± 39.72 mm 3 , Control group vs. YW2301 Low group, n = 7, P = 3.00 × 10 -6 The average tumor volume in the 5-FU group was 289.18 ± 50.52 mm 3 , Control group vs. 5-FU group, n =7, P = 1.80×10 -5 )( Figure 4 , AB). Compared with the Control group, the 5-FU group, YW2301 High The weight of transplanted tumors in the control group was significantly reduced (the average weight of tumors in the control group was 0.68 ± 0.24 g, and the average weight of tumors in the YW2301 group was 0.68 ± 0.24 g). HighThe average tumor weight in the YW2301 group was 0.05 ± 0.02 g. Low The average tumor weight of the group was 0.18 ± 0.05 g, and the average tumor volume of the 5-FU group was 0.30 ± 0.05 g, n = 7, Control group vs. YW2301 High group, P = 0.0004; Control group vs. YW2301 Low group, P = 0.0014; Control group vs. DOX group, P = 0.0053) ( Figure 4 , C). Kaplan-Meier analysis showed that YW2301 treatment significantly prolonged the overall survival of tumor-bearing mice ( Figure 4 , D). The above results indicate that YW2301 can effectively inhibit the tumorigenicity of colorectal cancer cells and the growth rate of transplanted tumors, and may be used as a candidate small molecule for targeted therapy of colorectal cancer.

[0022] Example 5: YW2301 down-regulates the expression of ALDH18A1 and c-Myc in colorectal cancer cell transplanted tumor tissues Immunohistochemistry (IHC) was used to detect the expression of ALDH18A1 and c-Myc proteins in colorectal cancer transplanted tumor tissue sections. The results showed that compared with the control, YW2301 Hih The expression of ALDH18A1 and c-Myc proteins in the tissue sections of the YW2301 group was significantly downregulated compared with the control group. Low The expression of ALDH18A1 and c-Myc proteins in the tissue sections of the 5-FU group and the 5-FU group was also downregulated ( Figure 5 , AC). The above results indicate that YW2301 can effectively downregulate the expression of ALDH18A1 and c-Myc proteins in colorectal cancer tissues, further proving that it may be a candidate small molecule for targeted therapy of colorectal cancer.

[0023] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. The use of YW2301 in the preparation of a drug for treating colorectal cancer, characterized in that: The molecular formula of YW2301 is C 32 H 55 BrN4O, molecular structure formula is: 。 2. The use according to claim 1, characterized in that: The use of YW2301 in the preparation of drugs for inhibiting the proliferation of colorectal cancer cells.

3. The use according to claim 1, characterized in that: The use of YW2301 in the preparation of drugs for inhibiting the cloning ability of colorectal cancer cells.

4. The use according to claim 1, characterized in that: The use of YW2301 in the preparation of drugs for inhibiting the tumorigenicity of colorectal cancer cells.

5. The use according to claim 1, characterized in that: Application of YW2301 in the preparation of drugs for shortening the half-life of c-Myc in rectal cancer cells.

6. The use according to claim 1, characterized in that: Use of YW2301 in the preparation of drugs for inhibiting the expression of ALDH18A1 and c-Myc proteins.

Images