CN112843052A

CN112843052A - Application of novel epigenetic factor inhibitor 2800Z in preparation of liver cancer resistant drug sensitizer

Info

Publication number: CN112843052A
Application number: CN202110327877.1A
Authority: CN
Inventors: 李专; 张晨; 毛思宇; 刘博豪; 唐文斌
Original assignee: Hunan Normal University
Current assignee: Hunan Normal University
Priority date: 2021-03-26
Filing date: 2021-03-26
Publication date: 2021-05-28
Anticipated expiration: 2041-03-26
Also published as: CN112843052B

Abstract

The invention belongs to the field of pharmacy, and particularly relates to application of a novel epigenetic factor inhibitor 2800Z in preparation of a liver cancer resistant drug sensitizer. The novel epigenetic factor inhibitor 2800Z provided by the invention can be used as a sensitizer for an anti-liver cancer drug, can obviously reduce the IC50 value of a chemotherapeutic drug when being combined with the anti-liver cancer drug, enhances the curative effect of the chemotherapeutic drug on liver cancer cells, and provides a new way for effectively treating liver cancer.

Description

Application of novel epigenetic factor inhibitor 2800Z in preparation of liver cancer resistant drug sensitizer

Technical Field

The invention belongs to the field of pharmacy, and particularly relates to application of a novel epigenetic factor inhibitor 2800Z in preparation of a liver cancer resistant drug sensitizer.

Background

Cancer is a serious disease harmful to human health, wherein liver cancer is one of common liver cancers, has the characteristics of high malignancy, quick disease progression, short life cycle and difficult cure, and the death rate of the liver cancer is gradually increased, so the liver cancer is a public health problem to be solved urgently.

At present, the main treatment means of liver cancer are operation treatment, radiotherapy and chemotherapy, wherein the common drugs aiming at the chemotherapy drugs of liver cancer are sorafenib, sunitinib, bevacizumab, erlotinib, and android and the like; however, because the primary and acquired drug resistance of liver cancer cells and the toxicity of anti-liver cancer drugs cause lower concentration and less killing activity, the chemotherapy effect is poor, and the chemosensitizer is a drug which has no anti-liver cancer effect or little anti-liver cancer effect under the concentration or measurement and can affect the cytotoxic effect of the known anti-liver cancer drugs, thereby enhancing the killing effect of the anti-liver cancer drugs on liver cancer cells or reducing the toxicity of the anti-liver cancer drugs on normal tissue cells, so that the search for the high-efficiency and low-toxicity sensitizer has important significance in the development of the anti-liver cancer drugs.

Disclosure of Invention

In order to solve the technical problems, the invention screens out a specific sirt7 inhibitor 2800Z by molecular docking with a sirt7 target site by adopting a molecular docking method, and performs an inhibition experiment on liver cancer cells HepG2 and an inhibition effect on the liver cancer cells in a mouse liver cancer model by combining a small dose of the inhibitor 2800Z with an anti-liver cancer drug, so that the inhibition effect on the liver cancer cells is small when the inhibitor 2800Z is in a small dose, and the curative effect of the anti-liver cancer drug can be obviously improved when the inhibitor is used in combination with the anti-liver cancer drug.

The invention aims to provide application of a novel epigenetic factor inhibitor 2800Z as shown in formula I in preparation of a liver cancer resistant drug sensitizer.

Further, the anti-liver cancer drug is sorafenib.

Based on the same inventive concept, the invention also provides an anti-liver cancer drug composition, which comprises an anti-liver cancer drug and a sensitizer, wherein the sensitizer is a novel epigenetic factor inhibitor 2800Z, and the anti-liver cancer drug is sorafenib.

Further, the anti-liver cancer pharmaceutical composition further comprises at least one of pharmaceutically acceptable carriers, excipients, diluents, adjuvants and vehicles.

Has the advantages that:

the inhibitor 2800Z shown as the formula I is used as a sensitizer for the anti-liver cancer chemotherapeutic drug for the first time, the curative effect is poor when the inhibitor 2800Z and the chemotherapeutic drug are independently used, and when the inhibitor 2800Z and the chemotherapeutic drug are jointly used, the drug resistance of liver cancer to the chemotherapeutic drug can be overcome, the curative effect of the chemotherapeutic drug on liver cancer cells can be obviously enhanced, and a new way is provided for effectively treating liver cancer.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without creative efforts.

FIG. 1 is a comparison graph of the inhibitory effect of the inhibitor 2800Z, sorafenib and a combination thereof on hepatoma cells, provided by an embodiment of the present invention;

FIG. 2 is a graph showing the comparison of the change in volume of liver cancer after administration of 2800Z inhibitor, sorafenib and a combination thereof to a neoplastic mouse.

Detailed Description

In order to make the technical problems, technical solutions and advantages of the present invention more apparent, the following detailed description is given with reference to the accompanying drawings and specific embodiments, but the scope of the present invention is not limited to the following specific embodiments.

Unless otherwise defined, all terms of art used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.

Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods. The inhibitor 2800Z was purchased from ceramic Biotechnology, Inc.

Example 1

In vitro cytotoxicity assay

Adding 10% fetal calf serum solution into DMEM medium, inoculating HEPG2 cells at 37 deg.C and 5% CO₂Culturing for one day under the condition, and culturing HEPG2 cells at 3 × 10⁴cells/ml were inoculated onto 96-well plates at a density, and after 24h of culture, randomly divided into four groups, each: the chemotherapy drug Sorafenib (Sorafenib), the inhibitor 2800Z group, (2800Z), the combination group (Sorafenib +2800Z) and the control group (control), wherein the IC50 value of the known chemotherapy drug Sorafenib is 10uM, the concentration of the prepared chemotherapy drug Sorafenib is 4uM, the concentration of the prepared chemotherapy drug Sorafenib is 60uM, and the Sorafenib solution, the inhibitor 2800Z solution, the Sorafenib solution and the inhibitor with the concentrations are respectively added into the four groups without any drug. The results of recording the cell activities for 12h, 24h and 36h are shown in FIG. 1.

2800Z cytotoxicity assay: adding 10% fetal calf serum solution into DMEM medium, inoculating HEPG2 cells at 37 deg.C and 5% CO₂Culturing for one day under the condition, and culturing HEPG2 cells at 3 × 10⁴cells/ml are inoculated on a 96-well plate, 60uM inhibitor 2800Z is added after 24h of culture, and the activity of the cells is analyzed after 48h of continuous culture by a CCK8 experiment. According to the determination, the cell activity of the normal liver cells is more than 80% under the concentration of the inhibitor 2800Z of 60uM, so the 2800Z with the concentration of 60uM has low cytotoxicity, and the liver cancer sensitizer can be applied to the liver cancer.

As can be seen from fig. 1, under the condition of using sorafenib and the inhibitor 2800Z alone, the cytotoxicity on HEPG2 is poor, while the combined medication group of sorafenib and the inhibitor 2800Z has stronger cytotoxicity on HEPG2 cells, and when the concentration of sorafenib serving as an anti-liver cancer drug is 4uM, the mortality of HEPG2 cells is greater than 50%, so that the IC50 value of the anti-liver cancer drug is greatly reduced, that is, 2800Z can significantly enhance the killing effect of sorafenib on HEPG2 cells.

Example 2

In vivo anti-liver cancer experiment

20 adult mice were injected subcutaneously with 1X 10⁶The cells of/HEPG 2 are cultured in nude mice for 2 weeks in SPF environment, induced to form tumor, divided into four groups randomly and respectively administered: the results of the statistics of the volumes of liver cancer in mice on days 2, 4, 6, 8, 10, 12 and 14 as blank controls, in which the inhibitor 2800Z (administered amount is 4mg/kg), sorafenib (administered amount is 1mg/kg), inhibitor 2800Z (administered amount is 4mg/kg) + sorafenib (administered amount is 1mg/kg), were administered three times per week by intraperitoneal injection for two weeks, and the other group was not administered, are shown in FIG. 2.

As can be seen from FIG. 2, when the administration dosage of sorafenib is 1mg/kg and the administration dosage of the inhibitor 2800Z is 4mg/kg, the inhibition effect of sorafenib on liver cancer of mice is weak, and after 14 days, the volume of liver cancer is about 1000mm³Similar to the results of the group without administration, the volume of liver cancer was about 100mm 14 days after administration of the combination of Sorafenib and 2800Z inhibitor³The inhibition effect on liver cancer is obviously enhanced, namely the inhibitor 2800Z obviously enhances the curative effect of the liver cancer resistant medicament sorafenib and can be used as a sensitizer of the liver cancer resistant medicament sorafenib.

While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. A novel epigenetic factor inhibitor 2800Z is the application in preparing anti-liver cancer drug sensitizer as shown in formula I:

2. the use according to claim 1, wherein the anti-liver cancer drug is sorafenib.

3. The anti-liver cancer pharmaceutical composition is characterized by comprising an anti-liver cancer drug and a sensitizer, wherein the sensitizer is a novel epigenetic factor inhibitor 2800Z, and the anti-liver cancer drug is sorafenib.

4. The anti-liver cancer pharmaceutical composition of claim 4, further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.