CN115804776A - Application of aromatic hydrocarbon receptor inhibitor and 5-fluorouracil in combination in tumor treatment and inhibition drugs - Google Patents
Application of aromatic hydrocarbon receptor inhibitor and 5-fluorouracil in combination in tumor treatment and inhibition drugs Download PDFInfo
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- CN115804776A CN115804776A CN202211620904.5A CN202211620904A CN115804776A CN 115804776 A CN115804776 A CN 115804776A CN 202211620904 A CN202211620904 A CN 202211620904A CN 115804776 A CN115804776 A CN 115804776A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses an application of an aromatic hydrocarbon receptor inhibitor and 5-fluorouracil in combination in tumor inhibition drugs, in particular to an application of an aromatic hydrocarbon receptor inhibitor SR1 and 5-fluorouracil in combination in drugs for treating colon cancer. 5-fluorouracil is used as an anti-tumor drug and is a first-line drug for treating patients with advanced colorectal cancer. By combining with SR1, the synergistic inhibition effect is exerted on the proliferation of colon cancer cells, and a new drug approach is provided for the clinical treatment of colon cancer.
Description
Technical Field
The invention belongs to the field of pharmacy, and relates to application of an aromatic hydrocarbon receptor inhibitor and 5-fluorouracil in combination in a medicine for treating and inhibiting tumors. The combination of the aromatic hydrocarbon receptor inhibitor and 5-fluorouracil can inhibit the proliferation of tumor cells, and the aromatic hydrocarbon receptor inhibitor SR1 and 5-fluorouracil are used in combination in the medicine for treating colon cancer.
Technical Field
Tryptophan is one of essential amino acids in human body, and is involved in protein synthesis and metabolic regulation. Tryptophan has four metabolic pathways in the body: firstly, 5-hydroxytryptamine is generated under the action of hydroxylase, secondly, tryptamine is generated through decarboxylation, thirdly, indolylpyruvic acid is generated through transamination, and fourthly, various metabolites such as kynurenine and the like are generated through a kynurenine metabolic pathway. Of these, about 95% of tryptophan is metabolized via the kynurenine pathway.
In recent years, it has been found that tryptophan metabolism influences tumorigenesis and development mainly through tryptophan catabolism resulting in tryptophan depletion and accumulation of metabolites. Tumor cells induce high expression of IDO1 through secretion of gamma-interferon, and the high expression of IDO1 accelerates tryptophan metabolism, so that the tryptophan concentration in a tumor microenvironment is reduced. Tryptophan depletion can not only increase the level of intracellular uncharged tRNA and activate the pressure response kinase GCN2, thereby inhibiting the translation process of protein in T cells and participating in immune regulation; tryptophan depletion can also induce autophagy by blocking the amino acid-sensitive kinase GLK1, inhibiting the target rapamycin mTOR and the T-cell receptor regulatory kinase PKC- Θ.
Tryptophan metabolites are reported to inhibit T cell function and induce T cell apoptosis, and the mechanism of involvement of kynurenine in tumor immune escape is the most deeply studied. The aromatic hydrocarbon receptor is an important ligand-activated transcription factor, participates in biological processes such as regulation of cell cycle, immune response and cell differentiation, and plays a key role in embryonic development and tumorigenesis. Kynurenine is an endogenous ligand of an aromatic hydrocarbon receptor, and activates the activity of a transcription factor after being combined with the aromatic hydrocarbon receptor to regulate the expression of a downstream target gene. Activation of kynurenine-arene receptor signaling promotes FoxP3 + Treg cell differentiation accompanied by increased secretion of inflammatory factors such as IL-6 and IL-10, and promotion of tumor cell proliferationAnd (4) growing the cells. It is currently believed that the aromatic hydrocarbon receptor acts in a variety of ways during the development of tumors and is a potential target for tumor therapy.
Colorectal cancer is a common malignant disease of the digestive tract, and the mortality rate of the colorectal cancer is the third highest worldwide. 5-fluorouracil is taken as an antimetabolic antitumor drug and is a first-line drug for treating patients with advanced colorectal cancer. However, the chemical resistance generated during clinical treatment severely limits the efficacy of the drug. Therefore, the inventor proposes that the combination of an aromatic hydrocarbon receptor inhibitor SR1 (Stem Regenin 1) and 5-fluorouracil can enhance the drug sensitivity and improve the clinical curative effect.
Disclosure of Invention
The invention aims to provide application of the combination of an aromatic hydrocarbon receptor inhibitor and 5-fluorouracil in preparing a medicament for treating and inhibiting tumors.
The invention aims to provide the following scheme to realize: an application of the combination of aromatic hydrocarbon receptor inhibitor and 5-fluorouracil in preparing the medicines for treating and suppressing tumor features that the aromatic hydrocarbon receptor inhibitor and 5-fluorouracil are used to suppress the proliferation of tumor cells.
The aromatic hydrocarbon receptor inhibitor is Stem Regenin 1 (SR 1).
Preferably, the mass ratio of SR1 to 5-fluorouracil is 1.
The tumor cell is a colon cancer cell.
The invention proves that the SR1 and the 5-fluorouracil are combined to play a synergistic inhibition effect on the proliferation of human primary colon cancer cell lines, including SW620 and HCT116 colon cancer cells. Therefore, the 5-fluorouracil and the aromatic hydrocarbon receptor inhibitor SR1 which are used together have wide application prospects in the drug treatment of colon cancer.
Drawings
FIG. 1 inhibition of proliferation of SW620 cells in each group 7 days after administration;
FIG. 2 inhibition of proliferation of HCT116 cells in each group 7 days after administration.
As shown in the figure, the single use of 5-fluorouracil and an aromatic hydrocarbon receptor inhibitor SR1 can inhibit the proliferation of colon cancer cells to a certain extent, the combined use of 10 mu M5-fluorouracil and 5 mu M SR1 can obviously enhance the inhibition effect on the proliferation of SW620 and HCT116 cells, and a synergistic effect is achieved.
Detailed Description
The present invention is explained in detail by the following examples, but is not limited thereto.
Example 1
The application of the combination of an aromatic hydrocarbon receptor inhibitor SR1 and 5-fluorouracil in treating drugs for inhibiting human primary colon cancer cell lines SW 620:
cell source and culture: human primary colon cancer cell line SW620 was purchased from Shanghai's institute of technology cell Bank, and the cells were cultured in DMEM medium containing 10% fetal bovine serum, 100U/ml penicillin and 100. Mu.g/ml streptomycin at 37 ℃ in a 5% CO2 incubator.
The experimental method comprises the following steps: the CCK8 experiment method is adopted to detect the influence of the combined use of SR1 and 5-fluorouracil on the growth of colon cancer cells. The specific operation is as follows: the SW620 cells were seeded in a 96-well plate at a density of 800 cells/well and cultured; cells were divided into 4 groups:
1) The 5-fluorouracil group was used alone at a dose of 10 μ M;
2) SR1 group alone at a dose of 5. Mu.M;
3) The combined use group of 5-fluorouracil and SR1, the dose of 5-fluorouracil is 10 μ M, and the dose of SR1 is 5 μ M;
4) The control group was a DMEM medium group without drug.
After adding the drugs, the culture medium of each group is replaced every 48 hours, and the detection is carried out by using an enzyme-labeling instrument after the culture is carried out for 7 days.
The result is shown in figure 1, the single use of 5-fluorouracil and the aromatic hydrocarbon receptor inhibitor SR1 can inhibit the proliferation of colon cancer cells to a certain extent, the combined use of 10 mu M5-fluorouracil and 5 mu M SR1 can obviously enhance the inhibition effect on the proliferation of colon cancer cells, and the synergistic effect is obtained.
Example 2
The application of the combination of the aromatic hydrocarbon receptor inhibitor SR1 and 5-fluorouracil in the treatment of drugs for inhibiting the HCT116 of human primary colon cancer cell line,
cell source and culture: human primary colon cancer cell line HCT116 was purchased from Shanghai national academy of sciences cell banks, and the cells were cultured in DMEM medium containing 10% fetal bovine serum, 100U/ml penicillin and 100. Mu.g/ml streptomycin at 37 ℃ in a 5% CO2 incubator;
the experimental method comprises the following steps: the CCK8 experiment method is adopted to detect the influence of the combined use of SR1 and 5-fluorouracil on the growth of colon cancer cells. The specific operation is as follows: HCT116 cells were cultured at a density of 800 cells/well in 96-well plates, and the cells were divided into 4 groups:
1) The group of 5-fluorouracil was used alone at a dose of 10 μ M5-fluorouracil;
2) The SR1 group is used alone, and the dosage of SR1 is 5 μ M;
3) The combined use group of 5-fluorouracil and SR1, the dose of 5-fluorouracil is 10 μ M, and the dose of SR1 is 5 μ M;
4) The control group was a DMEM medium group without drug addition.
After adding the drugs, the culture medium of each group is replaced every 48 hours, and the detection is carried out by using an enzyme-labeling instrument after the culture is carried out for 7 days.
The result is shown in figure 2, the single use of 5-fluorouracil and the aromatic hydrocarbon receptor inhibitor SR1 can inhibit the proliferation of colon cancer cells to a certain extent, the combined use of 10 mu M5-fluorouracil and 5 mu M SR1 can obviously enhance the inhibition effect on the proliferation of colon cancer cells, and the synergistic effect is obtained.
In conclusion, the invention provides a combined medicament for treating colon cancer. The invention discovers for the first time that the combined use of the aromatic hydrocarbon receptor inhibitor SR1 and 5-fluorouracil exerts a synergistic inhibition effect on the proliferation of a human primary colon cancer cell line. Therefore, the combined use of the 5-fluorouracil and the aromatic hydrocarbon receptor inhibitor SR1 has wide application prospect in the medicaments for treating the colon cancer.
Claims (4)
1. The application of the combination of an aromatic hydrocarbon receptor inhibitor and 5-fluorouracil in preparing a medicament for inhibiting tumors is characterized in that: the aromatic hydrocarbon receptor inhibitor is Stem Regenin 1 (SR 1).
2. The use of the combination of an aromatic hydrocarbon receptor inhibitor according to claim 1 and 5-fluorouracil in the preparation of a medicament for inhibiting tumor growth, wherein: the tumor cells are colon cancer cells, including SW620 and HCT116 colon cancer cells.
3. Use of the combination of an aromatic hydrocarbon receptor inhibitor according to claim 1 or 2 and 5-fluorouracil in a medicament for inhibiting tumors, characterized in that: the tumor inhibiting medicine is SR1 and 5-fluorouracil, and the mass ratio of SR1 to 5-fluorouracil is 1.
4. A method of inhibiting a tumor using an aromatic hydrocarbon receptor inhibitor in combination with 5-fluorouracil, comprising the steps of: cell source and culture: human primary colon cancer cell lines SW620 and/or HCT116, cells were cultured in DMEM medium containing 10% fetal bovine serum, 100U/ml penicillin and 100. Mu.g/ml streptomycin at 37 ℃ in a 5% CO2 incubator;
the SW620 cells and/or HCT116 cells were seeded at a density of 800 cells/well in a 96-well plate for culture;
5-fluorouracil in combination with SR1 at a dose of 10 μ M5-fluorouracil and 5 μ M SR 1;
the culture medium was changed every 48 hours, and the medium was incubated for 7 days and then examined with a microplate reader.
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