CN115381959A - Combined medicine for treating liver cancer - Google Patents
Combined medicine for treating liver cancer Download PDFInfo
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- CN115381959A CN115381959A CN202211229129.0A CN202211229129A CN115381959A CN 115381959 A CN115381959 A CN 115381959A CN 202211229129 A CN202211229129 A CN 202211229129A CN 115381959 A CN115381959 A CN 115381959A
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- Prior art keywords
- sorafenib
- liver cancer
- aromatic hydrocarbon
- hydrocarbon receptor
- inhibitor
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- 201000007270 liver cancer Diseases 0.000 title claims abstract description 32
- 208000014018 liver neoplasm Diseases 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims abstract description 15
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims abstract description 32
- 229960003787 sorafenib Drugs 0.000 claims abstract description 32
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims abstract description 20
- 108091006082 receptor inhibitors Proteins 0.000 claims abstract description 20
- 102000005962 receptors Human genes 0.000 claims abstract description 8
- 108020003175 receptors Proteins 0.000 claims abstract description 8
- 239000003112 inhibitor Substances 0.000 claims abstract description 3
- 229940124303 multikinase inhibitor Drugs 0.000 claims abstract description 3
- 150000003384 small molecules Chemical class 0.000 claims abstract description 3
- BGFHMYJZJZLMHW-UHFFFAOYSA-N 4-[2-[[2-(1-benzothiophen-3-yl)-9-propan-2-ylpurin-6-yl]amino]ethyl]phenol Chemical group N1=C(C=2C3=CC=CC=C3SC=2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C=C1 BGFHMYJZJZLMHW-UHFFFAOYSA-N 0.000 claims description 24
- 210000004027 cell Anatomy 0.000 claims description 22
- 210000004881 tumor cell Anatomy 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 230000004663 cell proliferation Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 230000002195 synergetic effect Effects 0.000 abstract description 5
- 230000009702 cancer cell proliferation Effects 0.000 abstract 1
- 230000035755 proliferation Effects 0.000 description 10
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 4
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 3
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 230000033540 T cell apoptotic process Effects 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- -1 aromatic amino acid Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000000459 effect on growth Effects 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000009703 regulation of cell differentiation Effects 0.000 description 1
- 230000012121 regulation of immune response Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of an aromatic hydrocarbon receptor inhibitor SR1 and sorafenib in combination in treating liver cancer. SR1 is an inhibitor of an aromatic hydrocarbon receptor, and sorafenib is an oral small-molecule multi-kinase inhibitor for treating late-stage liver cancer. The invention discovers that the SR1 and sorafenib combined drug has a synergistic effect on inhibition of liver cancer cell proliferation, and provides a combined drug method for clinical treatment of liver cancer.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a combined medicament for treating liver cancer, namely the combined use of an aromatic hydrocarbon receptor inhibitor SR1 and sorafenib for treating the liver cancer.
Technical Field
Liver cancer is one of the common malignant tumors worldwide and also the second leading cause of death due to tumors. Worldwide, each year, the number of new liver cancer cases is about 70 thousands, the incidence and the death rate of the new liver cancer cases are higher than those of the first three malignant tumors, and the new liver cancer cases are second to lung cancer and gastric cancer. Patients with early or locally restricted liver cancer usually undergo surgical resection, and patients with middle or late stage and recurrent liver cancer usually undergo chemotherapy. However, drug resistance and tumor heterogeneity limit the efficacy of drugs, resulting in transient or even non-response of patients to chemotherapy.
Tryptophan is one of essential amino acids of human body, belongs to aromatic amino acid, and is involved in protein synthesis and metabolism regulation. The liver is the major site of tryptophan metabolism. In recent years, it has been found that tryptophan metabolism influences tumorigenesis and development mainly through its catabolism leading to tryptophan depletion and accumulation of metabolites.
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-aromatic receptor signaling promotes FoxP3 + Treg cells are differentiated, and the secretion of inflammatory factors such as IL-6 and IL-10 is increased, so that the growth of tumor cells is promoted. Aromatic receptors are currently thought to act in a variety of ways during the development of tumors and are potential targets for tumor therapy.
Disclosure of Invention
The invention provides a combined aromatic hydrocarbon receptor inhibitor and sorafenib.
Yet another object of the present invention is to: provides the application of the combined aromatic hydrocarbon receptor inhibitor and sorafenib.
The purpose of the invention is realized by the following technical scheme: a pharmaceutical composition containing aromatic hydrocarbon receptor inhibitor and sorafenib is used for inhibiting tumor cell proliferation.
Wherein the aromatic hydrocarbon receptor inhibitor is Stem Regenin 1 (SR 1).
The tumor cell is a liver cancer cell.
The mass ratio of SR1 to Sorafenib is 1.
The applicant finds in scientific research that: the aromatic hydrocarbon receptor inhibitor SR1 (Stem Regenin 1) and the liver cancer molecular targeted drug Sorafenib are combined for use, so that the drug sensitivity can be enhanced, and the clinical curative effect can be improved. In the research of the applicant, the SR1 and sorafenib are combined to play a synergistic inhibition effect on the proliferation of human primary liver cancer cell lines, including SMMC-7721 and PLC8024 liver cancer cells. Therefore, the combination use of the sorafenib and the aromatic hydrocarbon receptor inhibitor SR1 has wide application prospect in the drug treatment of liver cancer.
The invention also provides application of the aromatic hydrocarbon receptor inhibitor SR1 and sorafenib in combination in a medicament for treating liver cancer.
SR1 is an inhibitor of an aromatic hydrocarbon receptor, and sorafenib is an oral small-molecule multi-kinase inhibitor for treating late-stage liver cancer.
The combined SR1 and sorafenib provided by the invention has a synergistic inhibition effect on the proliferation of human primary liver cancer cell lines, including SMMC-7721 and PLC8024 liver cancer cells. Therefore, the combination use of the sorafenib and the aromatic hydrocarbon receptor inhibitor SR1 has wide application prospect in the drug treatment of liver cancer.
Drawings
FIG. 1 proliferation inhibition of groups of SMMC-7721 cells 7 days after administration;
FIG. 2 proliferation inhibition rate of PLC8024 cells in each group 7 days after administration.
Detailed Description
The present invention is explained in detail by the following examples, but is not limited thereto.
Provided is a combination of an aromatic hydrocarbon receptor inhibitor and sorafenib, which is verified by the following experiment for inhibiting the proliferation of tumor cells.
Effect on growth of hepatoma cells in combination with sorafenib:
cell source and culture: human primary hepatoma cell line SMMC-7721, PLC8024 was purchased from Shanghai Korea cell Bank. 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:
1, detecting the influence of the combined use of SR1 and sorafenib on the growth of liver cancer cells by adopting a CCK8 experimental method. The specific operation is as follows:
SMMC-7721 and PLC8024 cells were seeded at a density of 1000 cells/well in 96-well plates and cultured, dividing the cells into 4 groups:
1) Sorafenib groups were used alone at a dose of 10 μ M;
2) The SR1 group was used alone, and the dosage of SR1 was 2. Mu.M;
3) The combination of sorafenib and SR1 is used, the dose of sorafenib is 10 μ M, and the dose of SR1 is 2 μ M;
4) The Control group is a DMEM medium group without drug addition.
Each group of culture medium was changed every 48 hours, and was examined with a microplate reader 7 days after the culture.
FIG. 1 shows the proliferation inhibition rate of SMMC-7721 cells in each group 7 days after administration; FIG. 2 proliferation inhibition rate of PLC8024 cells in each group 7 days after administration.
The results are shown in fig. 1 and fig. 2, when sorafenib and the aromatic hydrocarbon receptor inhibitor SR1 are used alone, the proliferation of the liver cancer cells can be inhibited to a certain extent, the inhibition effect of the combination of 10 mu M of sorafenib and 2 mu M of SR1 on the proliferation of SMMC-7721 and PLC8024 cells is obviously enhanced, and the synergistic effect is achieved.
In conclusion, the invention provides a combined medicament for treating liver cancer. The invention discovers for the first time that the aromatic hydrocarbon receptor inhibitor SR1 and sorafenib are combined to play a synergistic inhibition role in the proliferation of human primary liver cancer cell lines. Therefore, the combination use of the sorafenib and the aromatic hydrocarbon receptor inhibitor SR1 has wide application prospect in the medicaments for treating liver cancer.
Claims (5)
1. A pharmaceutical composition containing aromatic hydrocarbon receptor inhibitor and sorafenib is used for inhibiting tumor cell proliferation.
2. The combination of an aromatic hydrocarbon receptor inhibitor and sorafenib according to claim 1, wherein: the aromatic hydrocarbon receptor inhibitor is Stem Regenin 1.
3. The combination of an aromatic hydrocarbon receptor inhibitor and sorafenib according to claim 2, wherein: the tumor cell is a liver cancer cell.
4. The combination of an aromatic hydrocarbon receptor inhibitor and sorafenib according to claim 3, wherein: the mass ratio of SR1 to Sorafenib is 1.
5. An application of a medicine for treating liver cancer by combining aromatic hydrocarbon receptor inhibitor SR1 and sorafenib; SR1 is an inhibitor of an aromatic hydrocarbon receptor, and sorafenib is an oral small-molecule multi-kinase inhibitor for treating late-stage liver cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211229129.0A CN115381959A (en) | 2022-09-30 | 2022-09-30 | Combined medicine for treating liver cancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211229129.0A CN115381959A (en) | 2022-09-30 | 2022-09-30 | Combined medicine for treating liver cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115381959A true CN115381959A (en) | 2022-11-25 |
Family
ID=84128279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211229129.0A Pending CN115381959A (en) | 2022-09-30 | 2022-09-30 | Combined medicine for treating liver cancer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115381959A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115804776A (en) * | 2022-12-16 | 2023-03-17 | 国纳之星(上海)纳米科技发展有限公司 | Application of aromatic hydrocarbon receptor inhibitor and 5-fluorouracil in combination in tumor treatment and inhibition drugs |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107405364A (en) * | 2014-12-31 | 2017-11-28 | 人类起源公司 | NK and application thereof |
| CN108265028A (en) * | 2016-12-30 | 2018-07-10 | 联亘生物科技（上海）有限公司 | For the cultivating system of amplifying candidate stem cell in vitro |
| CN113301897A (en) * | 2018-10-17 | 2021-08-24 | 美真达治疗公司 | Methods of treating cancer with arene receptor antagonists |
-
2022
- 2022-09-30 CN CN202211229129.0A patent/CN115381959A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107405364A (en) * | 2014-12-31 | 2017-11-28 | 人类起源公司 | NK and application thereof |
| CN108265028A (en) * | 2016-12-30 | 2018-07-10 | 联亘生物科技（上海）有限公司 | For the cultivating system of amplifying candidate stem cell in vitro |
| CN113301897A (en) * | 2018-10-17 | 2021-08-24 | 美真达治疗公司 | Methods of treating cancer with arene receptor antagonists |
Non-Patent Citations (1)
| Title |
|---|
| KUO-LIANG WEI ET AL.: "Sorafenib is an antagonist of the aryl hydrocarbon receptor", TOXICOLOGY, vol. 470, pages 1 - 10 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115804776A (en) * | 2022-12-16 | 2023-03-17 | 国纳之星(上海)纳米科技发展有限公司 | Application of aromatic hydrocarbon receptor inhibitor and 5-fluorouracil in combination in tumor treatment and inhibition drugs |
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Application publication date: 20221125 |