CN117503744A - Application of meclofenamic acid in preparation of medicines for treating gastric cancer - Google Patents
Application of meclofenamic acid in preparation of medicines for treating gastric cancer Download PDFInfo
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- CN117503744A CN117503744A CN202311591617.0A CN202311591617A CN117503744A CN 117503744 A CN117503744 A CN 117503744A CN 202311591617 A CN202311591617 A CN 202311591617A CN 117503744 A CN117503744 A CN 117503744A
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- 208000005718 Stomach Neoplasms Diseases 0.000 title claims abstract description 59
- 206010017758 gastric cancer Diseases 0.000 title claims abstract description 59
- 201000011549 stomach cancer Diseases 0.000 title claims abstract description 59
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960003803 meclofenamic acid Drugs 0.000 title claims abstract description 34
- 239000003814 drug Substances 0.000 title claims abstract description 25
- 229940079593 drug Drugs 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 21
- 206010027476 Metastases Diseases 0.000 claims abstract description 14
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- VQAYFKKCNSOZKM-UHFFFAOYSA-N NSC 29409 Natural products C1=NC=2C(NC)=NC=NC=2N1C1OC(CO)C(O)C1O VQAYFKKCNSOZKM-UHFFFAOYSA-N 0.000 description 2
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- 101000914035 Homo sapiens Pre-mRNA-splicing regulator WTAP Proteins 0.000 description 1
- 101000959153 Homo sapiens RNA demethylase ALKBH5 Proteins 0.000 description 1
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- 102000016397 Methyltransferase Human genes 0.000 description 1
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- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000009650 gentamicin protection assay Methods 0.000 description 1
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- 239000011159 matrix material Substances 0.000 description 1
- 229940013798 meclofenamate Drugs 0.000 description 1
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- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
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- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
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- 150000003384 small molecules Chemical class 0.000 description 1
- OGPIIGMUPMPMNT-UHFFFAOYSA-M sodium meclofenamate (anhydrous) Chemical compound [Na+].CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C([O-])=O)=C1Cl OGPIIGMUPMPMNT-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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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)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of meclofenamic acid in preparing a medicine for treating gastric cancer, which can inhibit the expression of EMT related molecules such as HBEGF and the like by selectively inhibiting the activity of FTO demethylase, thereby inhibiting the metastasis potential of gastric cancer cells, providing a new candidate medicine for treating gastric cancer, and widening the new application for clinical application of MA.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of meclofenamic acid in preparing a medicine for treating gastric cancer.
Background
According to the GLOBOCAN project estimate, 109 tens of thousands of gastric cancer cases were diagnosed worldwide in 2020, with the incidence in the fifth place, 77 tens of thousands of deaths from gastric cancer, and the fourth rank among all cancer types. The occurrence rate of gastric cancer has obvious regional difference, and the gastric cancer high incidence area in China, 43.9% of total gastric cancer cases and 48.6% of gastric cancer death cases in the world occur in China. Tumor metastasis is one of the most leading causes of death in gastric cancer patients, and most patients have advanced to middle and late stages when diagnosed, and cancer cells have spread widely. For patients in the progressive stage, the treatment measures such as surgery, chemotherapy, radiotherapy and the like have unsatisfactory effects. Therefore, based on the molecular biological mechanism of gastric cancer development, exploring molecules targeting the metastatic potential of gastric cancer would be helpful to improve the treatment of gastric cancer.
N6-methyladenosine (N6-methyladenosine, m) 6 A) Is the most abundant RNA modification form in eukaryotic cells, and the modification is dynamically regulated by methyltransferases such as METTL3, METTL14, WTAP and the like, demethylases FTO and ALKBH5, and methylation recognition proteins such as YTDVC 1/2, YTDDF 1/2/3, IGF2BP1/2/3 and the like, thereby mediating m 6 A has the metabolic functions of RNA processing, transportation, translation, degradation and the like. In recent years, m 6 The key role of a and its regulator in tumor progression has been well documented. Some target m 6 Small molecule inhibitors of the a regulatory factor have been shown to have good anti-tumor effects, these results being the clinical use of m 6 The A inhibitor provides a molecular theory basis and a preclinical basis. Our study showed that FTO is highly expressed in gastric cancer tissue and is closely related to poor prognosis in patients. FTO may depend on its m 6 The activity of the A demethylase promotes the gastric cancer cell EMT process, thereby promoting the metastasis of gastric cancer. Meclofenamic acid (meclofenamic acid, MA) is the only FDA approved nonsteroidal anti-inflammatory drug in known FTO inhibitors, and research proves that MA can specifically inhibit FTO demethylase function, and MA is very likely to be a new strategy for gastric cancer treatment.
Disclosure of Invention
In view of the above, the invention aims to provide an application of meclofenamic acid in preparing a drug for treating gastric cancer.
In order to achieve the above purpose, the present invention provides the following technical solutions:
1. application of meclofenamic acid in preparing medicine for treating gastric cancer is provided.
The invention preferably relates to application of meclofenamic acid in preparing medicines for inhibiting gastric cancer cell invasion and metastasis capability.
The invention preferably relates to application of meclofenamic acid in preparing medicines for inhibiting gastric cancer cell metastasis.
The invention preferably relates to application of meclofenamic acid in preparing a medicament for inhibiting expression of gastric cancer cell HBEGF.
Preferably, the meclofenamic acid is used for preparing the drugs for inhibiting gastric cancer cells m 6 Use of a demethylase active agent in medicine.
The invention preferably relates to application of meclofenamic acid in preparing medicines for inhibiting gastric cancer cell EMT process.
The invention preferably relates to application of meclofenamic acid in preparing medicines for inhibiting gastric cancer EMT process and reducing invasion and metastasis potential of gastric cancer cells.
The invention preferably relates to application of meclofenamic acid in preparing medicines for inhibiting gastric cancer progression.
The invention has the beneficial effects that: the invention provides an application of meclofenamic acid in preparing a drug for treating gastric cancer, and researches show that meclofenamic acid reduces m 6 A level, inhibiting HBEGF expression, reducing EMT related molecule expression, inhibiting gastric cancer metastasis, providing a new target for gastric cancer treatment, and providing a new application for meclofenamic acid.
Drawings
In order to make the objects, technical solutions and advantageous effects of the present invention more clear, the present invention provides the following drawings for description:
FIG. 1 shows that meclofenamic acid inhibits the gastric cancer cell EMT process induced by the expression of HBEGF (A: gastric cancer cells MKN45 and AGS were treated with DMSO or MA (100. Mu.M) for 24 hours, and cell M was detected by Dot blot experiment 6 A level change; b: after MKN45 and AGS cells were treated with DMSO or MA, HBEGF expression was changed; c: protein level, P<0.01 represents P<0.001; d: changes in EMT marker molecule expression following DMSO or MA treatment).
Fig. 2 shows the effect of meclofenamic acid on inhibiting metastasis of gastric cancer cells (a, C: the effect of MA treatment on migration and invasiveness of gastric cancer cells MKN45 (a) and AGS (C); B, D: respectively, statistical figures of a, C; P < 0.001).
FIG. 3 shows the effect of meclofenamic acid on inhibiting gastric cancer cell metastasis in mice (A: intravenous injection of gastric cancer cell MKN45 in the tail of a rat, treatment with MA (50 mg/kg/3 d) and DMSO for 30 days, 5 in each group, effect of in vivo bioluminescence imaging MA treatment on gastric cancer lung metastasis; B: graph A bioluminescence statistics, representing P < 0.001).
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to limit the invention, so that those skilled in the art may better understand the invention and practice it.
Meclofenamic acid of the invention was purchased from MCE, cat: HY-B1320.
The gastric cancer cell lines of the present invention were MKN45 and AGS, both purchased from ATCC.
Example 1
The gastric cancer cell EMT process induced by the expression of HBEGF is inhibited in vitro by meclofenamic acid (meclofenamic acid, MA), and the specific steps are as follows:
inoculating gastric cancer cells in logarithmic phase into 6-well plate, each of which is about 2-7X10 5 A cell; incubating overnight at 37 ℃; adding 100 μm MA or equal volume of DMSO into cell culture solution, standing at 37deg.C and 5% CO 2 Culturing in incubator for 24h; RNA extraction and Dot Blot detection m 6 Level A, qRT-PCR detecting HBEGF expression; protein samples were extracted and Western Blot was used to detect expression of HBEGF and EMT marker molecules, and the results are shown in FIG. 1. The results show that meclofenamate inhibits the expression of HBEGF and the gastric cancer cell EMT process.
Example 2
Uses meclofenamic acid to inhibit the invasion and transfer capacity of gastric cancer cells in vitro.
Gastric cancer migration experiment: the concentration of MKN45 and AGS cells in the logarithmic growth phase is adjusted, and after the cells are washed twice by sterile PBS, the cells are resuspended by serum-free DMEM; 200 μl containing 5×10 4 The individual cell suspensions were added to the upper layer of a Transwell chamber (24-well plate kit, 8 μm pore size, corning); 500. Mu.l of complete medium containing 10% FBS was added to the lower layer of the Transwell chamber; the cells were placed at 37℃with 5% CO 2 Culturing in an incubator for 24 hours; taking out the small chamber, wiping off cells in the upper chamber by using a cotton swab, and cleaning the upper chamber for 3 times by using PBS; 4% paraformaldehyde is fixed for 30min; sucking the paraformaldehyde, and washing with PBS for 2 times; dyeing for 20min with 1% crystal violet; the PBS was washed 3 times,cells were counted in 3 random fields under an inverted microscope.
Gastric cancer invasion assay: placing the matrix glue stored in split packaging at 4 ℃ overnight for melting; matrigel and serum-free medium were mixed on ice according to 1:8, configuration; uniformly dripping 100 mu l of the matrigel diluent prepared in the step into each hole of the upper chamber of the Transwell chamber, and incubating for 4-5 h at 37 ℃; 100 and 500 mu l of serum-free culture solution are respectively dripped into the upper chamber and the lower chamber for balancing for 12 hours; the upper and lower chamber liquids were removed and the rest were the same as the migration experiment.
The results are shown in FIG. 2. The results show a significant reduction in both cell migration and invasiveness after MA treatment of MKN45 and AGS cells compared to DMSO groups.
Example 3
The effect of meclofenamic acid on inhibiting gastric cancer cell lung metastasis in mice is utilized, and the specific steps are as follows:
male nude mice (Beijing Violet laboratory animal Co.) of 4-6 weeks old were housed in SPF-class laboratory, and all animal experiments were conducted according to laboratory animal ethical guidelines. Amplifying stable expression cell strains screened after infection of the luciferase lentivirus, collecting each group of cells, and regulating the concentration to 1X 10 by sterile PBS 7 Individual/ml; nude mice were randomly assigned to each experimental group, 5 animals per group, and after anesthesia, 200 μl of cell suspension was injected into the tail vein; and were intraperitoneally injected with DMSO or MA (50 mg/kg) every 3 days for 30 days. In vivo imaging of small animals was performed after the end of the experiment: nude mice were anesthetized, D-potassium fluorescein (150 mg/kg, primga corporation) was intraperitoneally injected, allowed to stand for 10min, bioluminescence was detected using a bruker imaging software system, and gastric cancer cell lung metastasis between groups was compared, and the results are shown in fig. 3. The results show that the MA treatment can obviously inhibit the lung metastasis of gastric cancer cells.
The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.
Claims (8)
1. Application of meclofenamic acid in preparing medicine for treating gastric cancer is provided.
2. The use according to claim 1, characterized in that: the application of meclofenamic acid in preparing medicaments for inhibiting the invasion and transfer capacity of gastric cancer cells.
3. The use according to claim 1, characterized in that: the application of meclofenamic acid in preparing medicines for inhibiting gastric cancer cell transfer is provided.
4. The use according to claim 1, characterized in that: the application of meclofenamic acid in preparing a medicament for inhibiting the expression of gastric cancer cell HBEGF.
5. The use according to claim 1, characterized in that: preparation of meclofenamic acid for inhibiting gastric cancer cell m 6 Use of a demethylase active agent in medicine.
6. The use according to claim 1, characterized in that: the application of meclofenamic acid in preparing medicines for inhibiting gastric cancer cell EMT process.
7. The use according to claim 1, characterized in that: the application of meclofenamic acid in preparing medicines for inhibiting gastric cancer EMT process and reducing invasion and metastasis potential of gastric cancer cells.
8. The use according to claim 1, characterized in that: the application of meclofenamic acid in preparing medicines for inhibiting gastric cancer progression.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311591617.0A CN117503744A (en) | 2023-11-27 | 2023-11-27 | Application of meclofenamic acid in preparation of medicines for treating gastric cancer |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311591617.0A CN117503744A (en) | 2023-11-27 | 2023-11-27 | Application of meclofenamic acid in preparation of medicines for treating gastric cancer |
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| CN202311591617.0A Pending CN117503744A (en) | 2023-11-27 | 2023-11-27 | Application of meclofenamic acid in preparation of medicines for treating gastric cancer |
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