CN115990162B - Application of 4-hydroxy-2-pyridone alkaloid in preparation of medicines for treating gastric cancer - Google Patents
Application of 4-hydroxy-2-pyridone alkaloid in preparation of medicines for treating gastric cancer Download PDFInfo
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- CN115990162B CN115990162B CN202310074792.6A CN202310074792A CN115990162B CN 115990162 B CN115990162 B CN 115990162B CN 202310074792 A CN202310074792 A CN 202310074792A CN 115990162 B CN115990162 B CN 115990162B
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- gastric cancer
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- alkaloid
- pyridone
- apatinib
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Classifications
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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 relates to application of 4-hydroxy-2-pyridone alkaloid in preparing a drug for treating gastric cancer, wherein the 4-hydroxy-2-pyridone alkaloid has a structure shown in a formula (I):the 4-hydroxy-2-pyridone alkaloid with the specific structure not only has a good function of inhibiting mTorrC 1 signal paths, but also has a function of enhancing the sensitivity of apatinib to gastric cancer, so that the alkaloid has good activity of treating gastric cancer, meets the requirement of medication safety under the dosage of exerting the drug effect, and can be used for preparing medicines for treating gastric cancer.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of 4-hydroxy-2-pyridone alkaloid in preparation of medicines for treating gastric cancer.
Background
Gastric cancer is one of the most common malignant tumors in the world, with the incidence rate being the fifth and mortality rates being the fourth among all tumors. Approximately 60% of gastric cancer patients are diagnosed with local or distant metastasis at the time of initial diagnosis, and these patients have a total 5-year survival rate of only about 30% and 5%, respectively. Surgical resection and perioperative adjuvant chemotherapy increase the survival of locally advanced gastric cancers, but treatment strategies for patients with local or distant metastasis remain limited. Targeted therapy in the form of small molecule inhibitors and monoclonal antibodies has become an important aspect of gastric cancer multimodal therapy. Trastuzumab as a HER2 monoclonal antibody has been approved for first line treatment of advanced HER2 positive gastric cancer (e.g., trastuzumab mutant IgG and uses thereof). In addition, ramucirumab, an antibody targeting vascular endothelial growth factor receptor 2 (VEGFR-2), and either nivolumab or pamglizumab, an antibody targeting programmed cell death protein 1 (PD-1), also significantly improved progression free survival and overall survival of gastric cancer patients as a two-wire and three-wire treatment. However, in clinical treatment, targeted therapeutic drugs for gastric cancer patients remain relatively scarce, and these drugs are only effective for specific patients. Therefore, there is an urgent need to explore new and effective targeted drugs for gastric cancer patients to improve the effectiveness of clinical treatments.
Mammalian target rapamycin (Mammalian Target of Rapamycin, mTOR) is a highly conserved serine/threonine protein kinase that is widely found in yeast to animal cells and belongs to the family of phosphoinositide kinase related kinases. mTOR is involved in multiple biological functions such as gene transcription, protein translation, ribosome synthesis, etc. by integrating multiple extracellular signals in the physiological or pathological processes of cells, and ultimately regulates cell growth, differentiation, apoptosis and autophagy. In organisms, mTOR exists in the form of two complexes, mTORC1 and mTORC 2. mTORC1 comprises mTOR, an mTOR Regulatory-related Protein (regulator-associated Protein of mTOR, raptor), mLST8 (Mammalian Lethal with SEC Protein 8), a Proline-rich Akt substrate (Proline-rich Akt Substrate 40kda, PRAS40) and a Deptr (DEP-domain containing mTOR-interacting Protein). Raptor is a 150kDa scaffold-linked protein responsible for assembly of mTORC1 and promoting binding of substrate to mTORC 1. mLST8 may be involved in the assembly and stabilization of mTORC 1. PRAS40 and Deptor negatively regulate mTORC1 function. The phosphoinositide 3-kinase (PI 3K)/protein kinase B (AKT)/mTOR pathway is an important intracellular signaling pathway during cell growth and apoptosis. Activated AKT phosphorylates directly the Ser2448 site of mTOR, activates mTOR and its downstream eukaryotic translation initiation factor 4E (Eukaryotic Translation Initiation Factor E, eIF-4E) binding Protein (Translation Factor eIF E-binding Protein 1,4E-BPl) and ribosomal Protein S6 Kinase 1 (Ribosomal Protein S6 Kinase 1, S6K 1), and ultimately regulates mRNA translation. Recent studies have demonstrated that the PI3K/AKT/mTOR signaling pathway is active in a variety of tumors. In recent years mTORC1 has become a potential target for cancer treatment due to its critical role. However, few inhibitors are approved for clinical use due to the significant side effects and lack of efficacy of mTORC1 inhibitors.
Therefore, further development of novel and effective medicines for treating gastric cancer is urgently needed.
Disclosure of Invention
The primary purpose of the invention is to overcome the problems of poor effect or obvious side effect of the existing medicines for treating gastric cancer, and provide the application of 4-hydroxy-2-pyridone alkaloid in preparing medicines for treating gastric cancer. The 4-hydroxy-2-pyridone alkaloid with the specific structure has the good effect of inhibiting mTorrC 1 signal path, and also has the effect of enhancing the sensitivity of apatinib to gastric cancer, so that the alkaloid has good activity of treating gastric cancer, meets the requirement of medication safety under the dosage of exerting the drug effect, and can be used for preparing medicines for treating gastric cancer.
The above object of the present invention is achieved by the following technical solutions:
the application of 4-hydroxy-2-pyridone alkaloid in preparing medicines for treating gastric cancer is provided, wherein the 4-hydroxy-2-pyridone alkaloid has a structure shown in a formula (I):
the 4-hydroxy-2-pyridone alkaloid (Arttpyrone M) of the present invention is a small molecule compound having the formula C 24 H 31 NO 7 The molecular weight was 445. The inventor researches find that the 4-hydroxy-2-pyridone alkaloid with the specific structure has the good effect of inhibiting mTORC1 signal path, and also has the effect of enhancing the sensitivity of apatinib to gastric cancer, so that the alkaloid has good activity of treating gastric cancer, meets the requirement of medication safety under the dosage of exerting the drug effect, and can be used for preparing medicines for treating gastric cancer.
Preferably, the 4-hydroxy-2-pyridone alkaloid is applied to the preparation of medicines for inhibiting invasion, infiltration, growth, proliferation or cloning of gastric cancer cells.
The research shows that the 4-hydroxy-2-pyridone alkaloid can inhibit the invasion, infiltration, growth, proliferation and cloning of gastric cancer cells.
Preferably, the 4-hydroxy-2-pyridone alkaloid is applied to the preparation of a gastric cancer drug for inhibiting mTorrC 1 signal path.
The 4-hydroxy-2-pyridone alkaloid can inhibit the mTorrC 1 signal path, so that the 4-hydroxy-2-pyridone alkaloid can be used for preparing targeted gastric cancer drugs for inhibiting the mTorrC 1 signal path, provides a good treatment strategy for improving gastric cancer resistance, and has wide application in slowing down gastric cancer resistance drugs.
Preferably, the 4-hydroxy-2-pyridone alkaloid and the apatinib are combined for preparing medicines for treating gastric cancer.
The research shows that the 4-hydroxy-2-pyridone alkaloid can enhance the sensitivity of the apatinib to gastric cancer, and the combination of the apatinib and the 4-hydroxy-2-pyridone alkaloid can further inhibit the growth of gastric cancer cells and further inhibit the clone formation of gastric cancer cells.
More preferably, the mass ratio of the 4-hydroxy-2-pyridone alkaloid to the apatinib in the medicament is 1: (24-26).
Preferably, the content of 4-hydroxy-2-pyridone alkaloid in the medicine is 0.25-1 mu M.
Preferably, the medicament further comprises a pharmaceutically acceptable salt or solvate of 4-hydroxy-2-pyridone alkaloid.
It is understood that "acceptable salts" refers to the acid and/or base salts of 4-hydroxy-2-pyridone alkaloids or stereoisomers thereof, with inorganic and/or organic acids and bases, and also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base as appropriate (for example, equivalent). These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium.
More preferably, the pharmaceutically acceptable salt is a pharmaceutically acceptable inorganic or organic salt.
Specifically, pharmaceutically acceptable salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate (mesylate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate; or ammonium salts (e.g., primary, secondary, tertiary, quaternary ammonium salts), metal salts (e.g., sodium, potassium, calcium, magnesium, manganese, iron, zinc, copper, lithium, aluminum salts).
Preferably, the medicament further comprises at least one of a pharmaceutically acceptable carrier, diluent or excipient.
It will be understood that by "pharmaceutically acceptable carrier, diluent or excipient" is meant a carrier, diluent or excipient, and/or the salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form, and physiologically compatible with the recipient.
Preferably, the medicament is in the form of injection, capsule, tablet, pill or granule.
Preferably, the 4-hydroxy-2-pyridone alkaloid is prepared by the following steps:
s1, preparing Arthrinium sp fermentation products;
s2, centrifuging the Arthrinium sp fermentation product to obtain a supernatant fermentation liquid and a precipitated mycelium; extracting the supernatant fermentation liquor to obtain a fermentation liquor extract for later use; leaching, distilling and extracting the precipitated mycelium to obtain mycelium extract for later use; and combining the fermentation liquid extract and the mycelium extract, and obtaining the 4-hydroxy-2-pyridone alkaloid after extraction, column chromatography and high performance liquid separation.
Specifically, the 4-hydroxy-2-pyridone alkaloid is prepared by the following steps:
s1, preparing Arthrinium sp fermentation products
Taking sorbitol, maltose, monosodium glutamate, peptone, potassium dihydrogen phosphate and magnesium sulfate, then dissolving in water, fixing volume, sterilizing at high temperature to obtain a culture medium for standby; inoculating Arthrinium sp to the culture medium, and shake culturing to obtain seed culture solution; inoculating the seed culture solution into the culture medium, and performing shake culture to obtain Arthrinium sp fermentation product;
separation and purification of S2.4-hydroxy-2-pyridone alkaloid
Centrifuging the fermentation product of Arthrinium sp to obtain supernatant fermentation liquid and precipitate mycelium. Extracting supernatant fermentation broth with ethyl acetate for 3 times under equal volume, and concentrating the ethyl acetate extract at a temperature lower than 40deg.C under reduced pressure to obtain fermentation broth extract; ultrasonic extracting the precipitate mycelium with acetone aqueous solution, distilling the extractive solution under reduced pressure, repeatedly extracting with ethyl acetate for 3 times, and concentrating the ethyl acetate extractive solution under reduced pressure below 40deg.C to obtain mycelium extract; mixing the fermented liquid extract and the mycelium extract, repeatedly extracting with petroleum ether solvent for three times, removing oil part, and obtaining crude extract; separating the crude extract by normal phase silica gel column chromatography, mixing, dry packing, and loading with CH 2 Cl 2 The MeOH (0-100%, v/v) gradient elution sequence gives component fr1, component fr2, component fr3, component fr4, component fr5, component fr6 and component fr7; subjecting the component fr4 to Sephadex LH-20 column chromatography, eluting with methanol as eluent, and purifying to obtain fraction fr4-1, fraction fr4-2, fraction fr4-3, fraction fr4-4, fraction fr4-5, and fraction fr4-6; the reaction mixture was collected with dichloromethane: methanol=10: 1v/v as fraction fr4-3 with a developer displacement value in the range of 0.4-0.6, fraction fr4-3 being detected at 210, 290 and 340nm wavelength, using a flow rate of 4mL/min, acetonitrile: performing isocratic elution with water (55:45, v/v) to obtain the 4-hydroxy-2-pyridone alkaloid (3.1 mg, retention time t) R 28.3min)。
Compared with the prior art, the invention has the beneficial effects that:
the 4-hydroxy-2-pyridone alkaloid with the specific structure has the good effect of inhibiting mTorrC 1 signal path, and also has the effect of enhancing the sensitivity of apatinib to gastric cancer, so that the alkaloid has good activity of treating gastric cancer, meets the requirement of medication safety under the dosage of exerting the drug effect, and can be used for preparing medicines for treating gastric cancer.
Drawings
FIG. 1 is a graph showing the effect of Art-M of the present invention on mTorrC 1 signaling pathway related molecules; FIG. 1A is a graph showing the effect of Art-M on mRNA of mTORC1 signaling pathway-related genes HMGCS1, AURKA, PLK1, MVK, MVD and IDH1 in gastric cancer cells; FIG. 1B is a graph showing the effect of Art-M on T-mTOR, p-mTOR, T-p70S6K and p-p70S6K related proteins in the gastric cancer cell mTORC1 signaling pathway.
FIG. 2 is a graph showing the proliferation and metastasis results of the Art-M inhibiting gastric cancer cells of the present invention; FIG. 2A is a graph showing the results of inhibiting gastric cancer cell viability at different concentrations of Art-M; FIG. 2B is a graph showing the cloning of gastric cancer cells with increasing concentration of the drug; FIG. 2C shows a statistical plot of the cloning of gastric cancer cells with increasing drug concentration of Art-M; FIG. 2D shows the invasion pattern of gastric cancer cells with increasing concentration of the drug for Art-M; FIG. 2E is a statistical graph showing invasion of gastric cancer cells with increasing concentration of the drug.
FIG. 3 is a graph showing the results of inhibition of tumor growth in gastric cancer cells by the combination of Art-M and apatinib of the present invention; FIG. 3A is a graph showing the results of inhibition of gastric cancer cell viability by apatinib alone, by Art-M alone, and by Art-M in combination with apatinib; FIG. 3B shows results of inhibition of the cloning of gastric cancer cells by apatinib alone, by Art-M alone, and by Art-M in combination with apatinib.
FIG. 4 is a graph showing the results of inhibiting gastric cancer tumor growth in an in vivo model by the combination of Art-M and apatinib of the present invention; FIG. 4A is a graph showing tumor volume statistics of nude mice during 24 days of administration of each group in a stomach cancer mouse tumor transplantation model; FIG. 4B shows the appearance of subcutaneous gastric cancer tumors obtained by killing mice 24 days after administration of each group; FIG. 4C shows a statistical plot of subcutaneous gastric cancer tumor weights obtained by taking the samples of mice sacrificed 24 days after administration of each group.
FIG. 5 is a graph showing the results of HE staining of each group of heart, liver, spleen, lung and kidney in the stomach cancer mouse engraftment tumor model of example 6.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples for the purpose of illustration and not limitation, and various modifications may be made within the scope of the present invention as defined by the appended claims. The reagents and materials used in the present invention are commercially available unless otherwise specified.
Example 1 4 preparation of hydroxy-2-pyridone alkaloid
1. Preparation of Arthrinium sp fermentation products
Taking 20g of sorbitol, 20g of maltose, 10g of monosodium glutamate, 3g of peptone, 0.5g of monopotassium phosphate and 0.3g of magnesium sulfate, then dissolving in a proper amount of water, fixing the volume to 1000mL with water, and sterilizing at the high temperature of 121 ℃ for 30min to obtain a culture medium for later use. Inoculating Arthrobacter sp to the above culture medium, shake culturing at 28deg.C for 3 days to obtain seed culture solution, and shake culturing at 28deg.C for 12 days with 5% seed culture solution to obtain Arthrobacter sp fermentation product.
2. Separation and purification of 4-hydroxy-2-pyridone alkaloid
Centrifuging the Arthrinium sp fermentation product at 3600rpm to obtain supernatant fermentation liquid and precipitate mycelium. Extracting supernatant fermentation broth with ethyl acetate for 3 times under equal volume, and concentrating the ethyl acetate extract at a temperature lower than 40deg.C under reduced pressure to obtain fermentation broth extract; ultrasonic leaching the precipitated mycelium with 85% acetone aqueous solution, distilling the extractive solution under reduced pressure, repeatedly extracting with ethyl acetate for three times, and concentrating the ethyl acetate extractive solution under reduced pressure at a temperature below 40deg.C to obtain mycelium extract; mixing the fermented liquid extract and mycelium extract, repeatedly extracting with petroleum ether solvent for three times, and removing oil part to obtain crude extract. Separating the crude extract by normal phase silica gel column chromatography, mixing the sample, loading into column by dry method,by CH 2 Cl 2 The MeOH (0-100%, v/v) gradient elution sequence yielded 7 fractions (fr 1-fr 7). Component fr4 (CH) 2 Cl 2 MeOH=95:5v/v eluted components) through Sephadex LH-20 column chromatography, eluting with methanol as eluent, and analyzing according to thin layer chromatography result to obtain 6 fractions (fr 4-1-fr 4-6); the reaction mixture was collected with dichloromethane: methanol=10: 1v/v as fraction fr4-3 with a developer displacement value in the range of 0.4-0.6, fraction fr4-3 being detected at 210, 290 and 340nm wavelength, using a flow rate of 4mL/min, acetonitrile: semi-preparative high performance liquid phase separation by isocratic elution with water (55:45, v/v) and HPC (YMC-pack ODS-A, 10X 250mm,5 μm) gave Compound 1 (3.1 mg, retention time t) R 28.3min)。
Compound 1 1 H and 13 c NMR data (CD) 3 OD,500 MHz) is shown in table 1.
TABLE 1 Compound 1 1 H and 13 CNMR Data (CD) 3 OD，500MHz)
The compound 1 is 4-hydroxy-2-pyridone alkaloid, and has the following structure:
example 2 4-hydroxy-2-pyridone alkaloid (Arttpyrone M, abbreviated Art-M) inhibits mTorrC 1 Signaling in gastric cancer cells
(1) Cell culture
AGS, MGC803 cells used in this example were cultured in RPIM-1640 medium containing 10% Fetal Bovine Serum (FBS) and 1% penicillin/streptomycin, and the cells were placed in a medium containing 5% CO 2 The cells were cultured in a cell incubator at 37 ℃.
(2) Fluorescent quantitative PCR
1) Total RNA extraction from cells
(1) After the cells were treated with 1. Mu.M Art-M for 48h, the medium was blotted and washed twice with PBS, trizol was added to the fume hood, the cells were repeatedly blown off within 5min until the cells were completely shed, and then the cell lysate was transferred to a 1.5mL centrifuge tube without RNase;
(2) adding chloroform, shaking up and down for 15s, standing at room temperature for 10min, centrifuging at 12000rpm for 15min, carefully sucking the upper transparent liquid into a new 1.5mL centrifuge tube, adding isopropanol, gently blowing with a pipetting gun, and standing at room temperature for 10min;
(3) centrifuging at 4deg.C and 12000rpm for 15min, carefully discarding supernatant, adding 75% fresh pre-cooled ethanol solution, mixing gently, and centrifuging at 4deg.C and 12000rpm for 15min;
(4) discarding the supernatant, airing to obtain RNA precipitate, adding DEPC water according to the precipitation amount to dissolve RNA, measuring the concentration of RNA by using Nanodrop, and then marking the concentration of RNA and then placing at-80 ℃ for later use.
2) Template DNA was obtained by reverse transcription.
3) Based on RNA concentration, 10. Mu.L of sample system was prepared using DNA template (2 ug), primer and 2XSYBR for fluorescent quantitative PCR and the results were analyzed statistically.
The fluorescent quantitative PCR primers are shown in Table 2 below.
TABLE 2 fluorescent quantitative PCR primers
(3) Western Blot (Western Blot)
After 48h of treatment of the cells with 1. Mu.M Art-M, the cells were collected. The collected cells were treated with cell lysate RIPA for about 15 minutes, after which the lysate was centrifuged at 15000rpm at 4 ℃ for 15 minutes. Supernatant was collected and transferred, and protein concentration was quantified by BCA protein assay. Then 5 Xloading buffer was added and the protein supernatant was boiled for denaturation. And adding a proper amount of protein supernatant into 6-15% polyacrylamide gel, separating a sample by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) for about 100min, and transferring to a nitrocellulose membrane (PVDF membrane). The membrane was blocked with skimmed milk powder for 1h at room temperature, then washed 3 times with TBS-T solution and incubated overnight at 4℃with the corresponding primary antibody. The next day was incubated with rabbit secondary antibody for 1h at room temperature. Finally, the protein bands on the membrane were visually analyzed using a developing instrument.
(4) Experimental results
The experimental results are shown in FIG. 1, and FIG. 1A shows that Art-M can inhibit mRNA expression of mTorrC 1 signal pathway related genes HMGCS1, AURKA, PLK1, MVK, MVD and IDH1, which indicates that Art-M can inhibit mTorrC 1 signal pathway; FIG. 1B shows that Art-M is able to time-dependently inhibit protein expression of p-mTOR and p-p70S6K, while protein expression of T-mTOR and T-p70S6K is not significantly altered, indicating that Art-M is able to time-dependently inhibit mTORC1 signaling pathway.
Example 3Art-M inhibits proliferation and metastasis of gastric cancer cells
(1) Determination of cell viability by CCK8 method
1) 500 cells were uniformly diluted in 100. Mu.L of medium and plated in 96-well plates. After cell culture for 24h, art-M was diluted sequentially to different concentrations and added to each well in 50 μl of medium;
2) Cell-Titer GLO reagent was added after 4 consecutive days of Cell incubation. 96-well plates at 5% CO 2 Incubation is continued for 1-2 hours in an incubator at 37 ℃;
3) Absorbance was measured at 450nm according to the manufacturer's instructions. The final results are shown as percentages. Finally, the in vitro IC is calculated by adopting GraphPad Prism 7 software 50 Values.
(2) Plate cloning experiments
1) Uniformly inoculating 500 cells in logarithmic growth phase into a six-well plate;
2) After culturing cells for 24h, adding different concentrations (0. Mu.M, 0.25. Mu.M, 0.5. Mu.M, 1. Mu.M) of Art-M, and continuing to incubate six well plates in a 37℃incubator with 3 duplicate wells per group;
3) Changing fresh culture medium every three days, and adding the Art-M with different concentrations again;
4) After 10-12 days of incubation, cells were washed with Phosphate Buffered Saline (PBS) and fixed with 4% paraformaldehyde for 15 minutes. Finally, the dye was used for 20 minutes in the dark with a crystal violet solution. Cell colony counts were performed after washing the crystal violet solution with PBS and the experiment was repeated 3 times.
(3) Transwell chamber invasion assay
1) Cell invasion assay using 24 wellsThe plate is performed. Adding a serum-free medium, immersing the membrane of the cell in the serum-free medium, and maintaining in an incubator at 37 ℃ for 1h or overnight to activate the cell;
2) Cells treated for 48 hours at different concentrations of Art-M in six well plates were digested and counted.
3) Will contain 2X 10 4 mu.L of serum-free medium from each cell was added uniformly to the upper chamber of the Transwell chamber, and 500. Mu.L of medium containing 10% fetal bovine serum was added to the lower chamber. The cells were placed in a chamber containing 5% CO 2 Culturing overnight in an incubator at 37 ℃;
4) After 24h incubation, cells were fixed with 4% paraformaldehyde for 15min, and stained with crystal violet for 30min in the dark;
5) Gently washing the crystal violet dye solution by using PBS, and gently scraping cells on the upper layer of the cell by using a cotton swab;
6) And taking a picture under a microscope after the cells are dried, and counting.
(4) Experimental results
The experimental results are shown in FIG. 2. FIG. 2A shows that Art-M is capable of significantly inhibiting gastric cancer cell viability in a concentration-dependent manner (AGS: IC) 50 ＝0.5203μM；MGC803：IC 50 = 0.3574 μm); FIG. 2B shows that Art-M can significantly inhibit the clonal formation of gastric cancer cells; FIG. 2C is a statistical chart showing the results of the formation of the Art-M inhibitory clone; FIG. 2D shows that Art-M is capable of exhibiting a concentration-dependent inhibition of the invasive capacity of gastric cancer cells; fig. 2E is a statistical diagram of the corresponding attack results.
Example 4 Art-M and Apatinib combination to inhibit gastric cancer cell growth
(1) Cell count assay for cell growth
1) Taking each cell in logarithmic growth phase2×10 4 Density of wells/density of wells was evenly seeded in six well plates and cells were placed in 5% CO 2 Culturing overnight in an incubator at 37 ℃;
2) After the cells adhere to the wall, adding corresponding DMSO into a control group; art-M group was added with 0.25. Mu.M of Art-M drug; the apatinib group was added with 10 μm apatinib drug; the combination was added with 0.25. Mu.M Art-M and 10. Mu.M apatinib;
3) After 96h of drug treatment, cells were digested and subjected to microscopic cell counting.
(2) Cloning experiments on plates As in example 3 (2)
(3) Experimental results
The experimental results are shown in fig. 3, and fig. 3A shows that the combined administration (Combine) of the Art-M and the apatinib can significantly inhibit the growth of gastric cancer cells compared with the single use of the Art-M or the apatinib; FIG. 3B shows that the combination of Art-M and apatinib significantly inhibited the clonogenic potential of gastric cancer cells compared to either Art-M or apatinib alone.
EXAMPLE 5Art-M and Apatinib combination in vivo model inhibition of gastric cancer tumor growth
(1) Mouse subcutaneous gastric cancer cell transplantation tumor model
1) Log-growing gastric cancer cells were counted for digestion, and cells were resuspended after mixing pre-chilled PBS with Matrigel (1:1). Will be 5X 10 6 mu.L of the cell suspension was injected subcutaneously on both sides of the ventral back of nude mice;
2) When the average volume of subcutaneous tumor reaches 50-80 mm 3 When left and right, mice were randomly divided into four groups as required. The group and dosing settings were as follows: a control group to which a placebo (i.e., solvent for dissolution: 15% castor oil +85% sterile PBS) was administered daily for intraperitoneal injection; apatinib group, daily administration, gastric lavage, 50mg/kg dose; art-M group, administered daily, intraperitoneally at a dose of 2mg/kg; the Art-M+Apatinib combination (Combine) is administered daily, wherein the Art-M dose is 2mg/kg, the Abatinib dose is 50mg/kg and the stomach is irrigated;
3) Mice body weight and tumor volume were measured periodically for 24 days of continuous dosing. Tumor volume was measured as pi/6 (length. Times. Width) 2 ) Calculating;
4) Mice were sacrificed after the end of the experiment, and tumor tissues were collected for photographing and weighing.
(2) Experimental results
The experimental results are shown in fig. 4, and fig. 4A shows the tumor volume change graph during the operation of the mouse subcutaneous gastric cancer cell transplantation tumor model, wherein the growth of the nude mice subcutaneous tumor can be inhibited by the Art-M or the apatinib single group; compared with a single-use group, the combined administration group of the Art-M and the apatinib can remarkably inhibit the growth of subcutaneous tumors of nude mice, and shows that the Art-M and the apatinib have better combined effect in vivo; FIG. 4B is a view showing the appearance of the collected subcutaneous tumor of gastric cancer 24 days after administration; the tumor volume of the single Art-M or Apatinib group is obviously smaller than that of the control group, and the tumor volume of the combined Art-M+Apatinib group is smaller than that of the single Art-M or Apatinib group; figure (4C) shows that the use of Art-M in combination with apatinib can significantly reduce the weight of gastric cancer subcutaneous tumors.
EXAMPLE 6Art-M and its combination with apatinib in vivo models without significant toxicity to important mouse organs
(1) HE staining
1) Dewaxing paraffin sections: making paraffin sections from the heart, liver, spleen, lung and kidney of the mice killed in the example 5, and sequentially putting the paraffin sections into xylene I (10 min), xylene II (10 min), absolute ethyl alcohol I (5 min), absolute ethyl alcohol II (5 min), 95% alcohol (5 min), 90% alcohol (5 min), 80% alcohol (5 min), 70% alcohol (5 min) and distilled water for washing;
2) Hematoxylin staining: the sections were stained in hematoxylin for 3-8min, and rinsed with running water after staining. Then, the mixture was differentiated with 1% hydrochloric acid alcohol for several seconds, and rinsed with running water. Finally, returning to blue by using 0.6% ammonia water, and flushing by using running water;
3) Eosin staining: immersing the slice in eosin dye solution for 1-3min;
4) And (3) removing the water sealing piece: sequentially placing the slices into 95% alcohol I (5 min), 95% alcohol II (5 min), absolute alcohol I (5 min), absolute alcohol II (5 min), xylene I (5 min) and xylene II (5 min), dehydrating and transparentizing the slices, and sealing the slices with neutral resin after airing;
5) Sections were examined under a microscope, images were collected and analyzed.
(2) Experimental results
The experimental results are shown in FIG. 5, and FIG. 5 shows that the heart, liver, spleen, lung and kidney of the mice of the control group, the Art-M group, the apatinib group, the Art-M and the apatinib combination group were respectively HE stained after the subcutaneous gastric cancer cell transplantation tumor model of the mice was performed. As can be seen from fig. 5, there was no significant difference in HE staining results of the drug groups (Art-M group, apatinib group, art-m+apatinib combination group) compared with the control group, indicating that neither the single group nor the combination group had significant toxicity to the important organs of the mice. Therefore, the Art-M meets the requirement of medication safety at the dosage of exerting the drug effect, and can be used for preparing the drugs for treating the gastric cancer.
It is to be understood that the above examples of the present invention are provided by way of illustration only and not by way of limitation of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.
Claims (9)
- The application of 4-hydroxy-2-pyridone alkaloid in preparing medicines for treating gastric cancer is characterized in that the 4-hydroxy-2-pyridone alkaloid has a structure shown in a formula (I):formula (I).
- 2. The use according to claim 1, wherein the use of 4-hydroxy-2-pyridone alkaloid for the manufacture of a medicament for inhibiting invasion, infiltration, growth, proliferation or cloning of gastric cancer cells.
- 3. The use according to claim 1, wherein the use of the 4-hydroxy-2-pyridone alkaloid for the manufacture of a medicament for inhibiting gastric cancer of the mTORC1 signalling pathway.
- 4. The use according to claim 1, wherein the 4-hydroxy-2-pyridone alkaloid is used in combination with apatinib for the preparation of a medicament for the treatment of gastric cancer.
- 5. The use according to claim 4, wherein the mass ratio of the 4-hydroxy-2-pyridone alkaloid to the apatinib in the medicament is 1 (24-26).
- 6. The use according to claim 1, wherein the content of 4-hydroxy-2-pyridone alkaloid in the medicament is 0.25-1 μm.
- 7. The use according to claim 1, wherein the medicament further comprises a pharmaceutically acceptable salt of 4-hydroxy-2-pyridone alkaloid.
- 8. The use of claim 1, wherein the medicament further comprises at least one of a pharmaceutically acceptable carrier, diluent or excipient.
- 9. The use according to claim 1, wherein the medicament is in the form of an injection, capsule, tablet, pill or granule.
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