CN112843052B - Application of epigenetic factor inhibitor 2800Z in preparation of liver cancer resistant drug sensitizer - Google Patents

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

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CN112843052B
CN112843052B CN202110327877.1A CN202110327877A CN112843052B CN 112843052 B CN112843052 B CN 112843052B CN 202110327877 A CN202110327877 A CN 202110327877A CN 112843052 B CN112843052 B CN 112843052B
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liver cancer
drug
sensitizer
inhibitor
sorafenib
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CN112843052A (en
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李专
张晨
毛思宇
刘博豪
唐文斌
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Hunan Normal University
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/4174Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
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    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

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Abstract

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

Description

Application of 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 an 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 the hepatoma cells and the toxicity of the anti-hepatoma drugs cause lower use concentration and less killing activity, the chemotherapy effect is poor, and the chemosensitizer refers to a drug which has no anti-hepatoma effect or little anti-hepatoma effect under the use concentration or measurement and can affect the cytotoxic effect of the known anti-hepatoma drugs, so that the killing effect of the anti-hepatoma drugs on hepatoma cells can be enhanced or the toxicity of the anti-hepatoma drugs on normal tissue cells can be reduced, and therefore, the search for the high-efficiency and low-toxicity sensitizer has important significance in the development of the anti-hepatoma drugs.
Disclosure of Invention
In order to solve the technical problems, the invention screens out a specific sirt7 inhibitor 2800Z by adopting a molecular docking method to perform molecular docking with a sirt7 target site, 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 an epigenetic factor inhibitor 2800Z as shown in a formula I in preparation of a liver cancer resistant drug sensitizer.
Figure RE-GDA0003660568730000021
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 an 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 beneficial effects 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 required in the embodiments will be briefly described below, 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 that other drawings can be obtained according to the 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 is available 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 conditions, 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: chemotherapy drugs Sorafenib (Sorafenib), inhibitor 2800Z (2800Z), combination (Sorafenib +2800Z) and control (control), wherein chemotherapy is knownThe IC50 value of the drug sorafenib is 10uM, the concentration of the formulated chemotherapy drug sorafenib is 4uM, the concentration of the formulated chemotherapy drug sorafenib is 60uM, and sorafenib solutions, inhibitor 2800Z solutions, sorafenib solutions and inhibitors with the above 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 conditions, and culturing HEPG2 cells at 3 × 104cells/ml were plated on 96-well plates at a density of cells/ml, and after 24 hours of culture, 60uM of inhibitor 2800Z was added, and after another 48 hours of culture, the activity of the cells was analyzed by a CCK8 assay. According to the determination, the cell activity of the normal liver cells is more than 80% under the concentration of the 60uM inhibitor 2800Z, so the 2800Z with the concentration of 60uM has low cytotoxicity, and the liver cancer sensitizer can be applied to liver cancer.
As can be seen from FIG. 1, under the condition that sorafenib and the inhibitor 2800Z are used alone, the cytotoxicity on HEPG2 is poor, the combined medication group of sorafenib and the inhibitor 2800Z has strong cytotoxicity on HEPG2 cells, and when the concentration of the anti-liver cancer drug sorafenib is 4uM, the lethality of the HEPG2 cells is more than 50%, so that the IC50 value of the anti-liver cancer drug is greatly reduced, namely 2800Z can remarkably enhance the killing effect of sorafenib on HEPG2 cells.
Example 2
In vivo anti-hepatoma experiment
20 adult mice were injected subcutaneously with 1X 106the/HEPG 2 cells are cultured in nude mice for 2 weeks in SPF level environment to induce tumor formation, and are randomly divided into four groups, and are respectively administered: the results of counting the volumes of liver cancer in mice on days 2, 4, 6, 8, 10, 12 and 14 as blank controls in the case of inhibitor 2800Z (dose of 4mg/kg), sorafenib (dose of 1mg/kg), inhibitor 2800Z (dose of 4mg/kg) + sorafenib (dose of 1mg/kg) administered three times a week by intraperitoneal injection for two weeks, and no administration in the other group are shown in FIG. 2.
As can be seen from FIG. 2, when the administration of Sorafenib is carried outThe dosage is 1mg/kg, and the inhibitor 2800Z has a dosage of 4mg/kg, which has weak effect in inhibiting mouse liver cancer, and the volume of liver cancer is about 1000mm after 14 days3Similar 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 anti-liver cancer medicament sorafenib and can be used as a sensitizer of the anti-liver cancer medicament sorafenib.
While the foregoing is directed to the preferred embodiment of the present invention, it will be appreciated by those skilled in the art that various changes and modifications may be made therein without departing from the principles of the invention as set forth in the appended claims.

Claims (6)

1. An application of an epigenetic factor inhibitor 2800Z in the preparation of a sensitizer for an anti-liver cancer drug is sorafenib:
Figure FDA0003660568720000011
2. the anti-liver cancer pharmaceutical composition is characterized by comprising an anti-liver cancer drug and a sensitizer, wherein the sensitizer is an epigenetic factor inhibitor 2800Z shown as a formula I, and the anti-liver cancer drug is sorafenib:
Figure FDA0003660568720000012
3. the anti-liver cancer pharmaceutical composition according to claim 2, further comprising a pharmaceutically acceptable carrier.
4. The anti-liver cancer pharmaceutical composition of claim 2, further comprising a pharmaceutically acceptable excipient.
5. The pharmaceutical composition for treating liver cancer according to claim 2, wherein the pharmaceutical composition for treating liver cancer further comprises pharmaceutically acceptable adjuvants.
6. The anti-liver cancer pharmaceutical composition of claim 2, further comprising a pharmaceutically acceptable vehicle.
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