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A kind of polypeptide and its application in preparation of medicine for treating breast cancer

A breast cancer and drug technology, applied in the field of medicine, can solve the problems of reduced specificity of targeted enzyme active center and poor prognosis of breast cancer patients

Active Publication Date: 2022-06-07
TIANJIN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinical data analysis shows that the prognosis of breast cancer patients with high expression of PHF8 and TOPBP1 is worse
Although abnormally activated histone demethylases are ideal drug targets in the development of tumors, the specificity of targeting the active center of the enzymes is greatly reduced due to the conservation of the active domains of the demethylase family enzymes

Method used

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  • A kind of polypeptide and its application in preparation of medicine for treating breast cancer
  • A kind of polypeptide and its application in preparation of medicine for treating breast cancer
  • A kind of polypeptide and its application in preparation of medicine for treating breast cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Identification of PHF8 and TOPBP1 Interaction Modes from a Molecular Biology Perspective

[0038] 1. Molecular biological methods to identify the interaction site of PHF8 and TOPBP1

[0039] Domain deletion bodies (ΔBRCT0-2, ΔBRCT3, ΔBRCT4-5, ΔBRCT6 and ΔBRCT7-8) and domain truncated bodies (BRCT0-2, BRCT3, BRCT4-5, BRCT6 and BRCT7-8) of TOPBP1 were constructed, and the After transfection into HeLa cells, 72 hours later, co-immunoprecipitation experiments were used to find the key domains of the interaction, and the results were as follows figure 1 As shown in A, TOPBP1 binds to PHF8 through its BRCT7-8. At the same time, we constructed the truncated body of PHF8 (N, C, C1, C2, C3, C4), transfected HeLa cells and carried out co-immunoprecipitation experiments. We found that PHF8 was responsible for binding to TOPBP1 through its C-terminal APS. We further conducted a co-immunoprecipitation experiment to determine whether PHF8 deletion of APS would affect th...

Embodiment 2

[0045] Example 2: Using APS in combination with CPT and the PARP inhibitor rucaparib to kill tumor cells at the cellular level

[0046] 1. Preparation of GFP-vector, GFP-APS, GFP-APS-C22 Stable Expression Cell Lines

[0047] Viruses were prepared by linearized polyacetimide (PEI) transfection. The 293T cells were cultured in a 10cm petri dish. When the cells grew to 70%, the plasmid and PEI mixture were added in the ratio of plasmid (μg):PEI:OPTI-MEM=1:5:100. Plasmids include packaging plasmids (pMDLg / pRRE, pRSV-REV and pVSVG) and target plasmids (GFP-vector, GFP-APS, GFP-APS-C22). Viral supernatants were collected at 48 hours and 72 hours, respectively. Prepare the cell lines to be infected in advance, such as U2OS, MDA-MB-231, and leave a blank control group. After adding the virus solution for 24 hours, change to the normal medium for screening with puromycin.

[0048] 2. APS inhibits the activation of ATR signaling pathway in tumor cells

[0049] CPT was used at a conc...

Embodiment 3

[0055] Example 3: Inhibition of tumor growth using APS combined with cisplatin or rucaparib using a breast cancer mouse model

[0056] 1.PyMT Breast Tumor Primary Culture

[0057] PyMT mice with a tumor size of 15 mm × 15 mm were sacrificed, and their mammary tumors were removed, isolated and processed aseptically. Tumors were first washed extensively with ice-cold PBS to remove visible tissue pieces. Tumor tissue was minced with dissecting scissors in DMEM to homogenize to approximately 1 mm 3 The tissue was then resuspended and digested in digestion buffer (160 μg / ml collagenase and 25 μg / ml hyaluronidase) for 1 hour at 37°C, filtered through a 40 μm pore size cell strainer, and then seeded into in DMEM medium containing non-essential amino acids.

[0058] 2. Construction of PyMT breast tumor cells stably expressing GFP-APS and GFP-APS-C22

[0059] Viruses were prepared by linearized polyacetimide (PEI) transfection. The 293T cells were cultured in a 10cm petri dish. Wh...

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Abstract

The invention relates to a polypeptide and its application in the preparation of drugs for treating breast cancer. The sequence of the polypeptide is: GACFKDAEYIYPSLESDDDDPA. The present invention has the following beneficial effects: 1) the polypeptide (APS) can specifically destroy the combination of PHF8 and TOPBP1, but will not affect the other functions of PHF8; 2) the polypeptide (APS) is effective for tumor cells, especially breast cancer 3) The polypeptide (APS) combined with chemotherapy drugs cisplatin or PARP inhibitors can kill tumor cells more effectively, providing new ideas for tumor treatment.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a polypeptide and its application in preparing a medicine for treating breast cancer. Background technique [0002] The global incidence of breast cancer has been increasing since the late 1970s. Although China is not a country with a high incidence of breast cancer, the growth rate of breast cancer incidence in my country in recent years has been 1 to 2 percentage points higher than that of high incidence countries. The British "Independent" also pointed out that from 2000 to 2013, the average annual growth rate of breast cancer in China was about 3.5%, while that in the United States fell by 0.4% during the same period. The current status of breast cancer in my country is not optimistic: First, in terms of incidence, the report "Status and Trends of Cancer in China in 2017" released by the National Cancer Center shows that the incidence of breast cancer ranks firs...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/00A61K38/16A61K33/243A61P35/00A61P15/14
CPCC07K14/00A61K38/16A61K33/243A61P35/00A61P15/14A61K38/00A61K2300/00
Inventor 石磊杨娜姚智马帅曹程车世友
Owner TIANJIN MEDICAL UNIV
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