CN117815223A - Application of ginkgo biflavone in preparing medicine for resisting esophageal squamous carcinoma - Google Patents
Application of ginkgo biflavone in preparing medicine for resisting esophageal squamous carcinoma Download PDFInfo
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- CN117815223A CN117815223A CN202410252314.4A CN202410252314A CN117815223A CN 117815223 A CN117815223 A CN 117815223A CN 202410252314 A CN202410252314 A CN 202410252314A CN 117815223 A CN117815223 A CN 117815223A
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- esophageal squamous
- ginkgo
- squamous carcinoma
- pharmaceutically acceptable
- ginkgetin
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Abstract
The invention provides an application of ginkgo biflavone in preparing an anti-esophageal squamous carcinoma drug. Experimental results show that the ginkgo biflava has remarkable growth inhibition, invasion inhibition and apoptosis induction effects on esophageal squamous carcinoma cell lines KYSE410, KYSE150, KYSE450 and KYSE510, and the ginkgo biflava can be used for preparing medicines for preventing and treating esophageal squamous carcinoma.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of ginkgetin in preparation of medicines for resisting esophageal squamous cell carcinoma.
Background
Esophageal cancer is a malignant tumor which seriously endangers the health of people worldwide, and China is a country with higher incidence rate and mortality rate of esophageal cancer. Esophageal cancer is largely divided into two histological types, esophageal squamous carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC). In China, most of esophageal cancers are ESCC, and the survival rate of 5 years is lower than 15%. ESCC is extremely prone to malignant progression and metastasis, more than half of ESCC patients cannot undergo surgical excision or have metastasized at the time of initial diagnosis, and the 5-year survival rate of patients with metastasized advanced ESCC is less than 5%. With the progress of diagnosis and treatment level, the survival rate of malignant tumor patients in 5 years is obviously improved, but the death rate of metastatic tumor patients is still extremely high, and compared with the prior art, the death rate is not obviously improved, and the main reason is that the comprehensive cognition of the tumorigenesis development mechanism is lacking at present. The first-line medicine for clinically treating esophageal squamous carcinoma is a platinum compound, but is extremely easy to generate drug resistance, and tumor recurrence easily occurs after treatment.
Currently, there is no clear standard regimen for pre-operative chemotherapy of esophageal squamous carcinoma. Platinum, paclitaxel, fluorouracil, immunotherapy, and the like are mostly used in most clinical studies. Although these therapies work in combination to achieve a certain effect, patient tolerance is still acceptable and there is no increase in intraoperative complications. However, due to the effects of the dose of the chemotherapeutic agent, the chemotherapy cycle, and the time span of surgery after chemotherapy, the effects of the combination of these chemotherapeutic agents on the survival and survival status of the patient cannot be accurately determined. The use of these esophageal squamous carcinoma therapies remains to be further studied and elucidated.
The flavonoid compound is a polyphenol compound widely existing in the nature, has the biological effects of resisting oxidization and inflammation, and has low toxic effect. Can be used for treating cardiovascular and cerebrovascular diseases, hypertension, atherosclerosis and autoimmune diseases. The biflavanoid compound is a compound formed by condensing two molecules of flavone or derivatives thereof. The biflavanoid compound has a plurality of condensation modes, can be condensed through carbon-carbon bonds, can also be condensed through ether oxygen bonds, and has different condensation positions.
Ginkgo biflavone (Ginkgetin) is a flavonoid compound from ginkgo with anti-inflammatory and antioxidant biological effects:
ginkgo biflavone has application in various cardiovascular and cerebrovascular diseases. The anti-tumor effect of ginkgo biflava is reported to be less, and the effect of ginkgo biflava in the malignant progress of esophageal squamous carcinoma is not reported yet.
Disclosure of Invention
The invention discovers that the biflavone compound has very remarkable effect in the treatment of esophageal squamous carcinoma, and can block malignant progress of esophageal squamous carcinoma cells in the aspects of apoptosis induction, growth, invasion inhibition and the like.
Therefore, the invention provides application of ginkgo biflavone or pharmaceutically acceptable salt thereof in preparing medicines for resisting esophageal squamous cell carcinoma.
In one embodiment, the medicament comprises ginkgetin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
In another aspect, the invention provides a pharmaceutical composition for treating esophageal squamous carcinoma, which comprises ginkgetin or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary agents.
In the invention, the anti-esophageal squamous carcinoma comprises at least one of inhibiting the growth of esophageal squamous carcinoma cells, inhibiting the invasion of esophageal squamous carcinoma cells and inducing the apoptosis of esophageal squamous carcinoma cells.
In the present invention, the pharmaceutically acceptable salts include salts of ginkgetin with pharmaceutically acceptable acids or bases, and particularly salts of pharmaceutically acceptable inorganic or organic acids may be mentioned.
The medicaments and pharmaceutical compositions of the invention are suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) or pulmonary administration.
The medicaments/pharmaceutical compositions of the invention suitable for oral administration may for example be presented in discrete units, e.g. capsules, tablets, each containing a predetermined amount of the active ingredient. Or as a supplement in an oil-in-water liquid emulsion, a water-in-oil liquid emulsion, or an aqueous solution. The active ingredient may also be presented as a pill, suppository or paste. The medicaments/pharmaceutical compositions according to the invention suitable for topical administration may be formulated, for example, as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. Alternatively, the formulation may comprise a patch or dressing, such as a bandage or plaster, to which the active ingredient is applied, and optionally one or more excipients or diluents. The pharmaceutical/pharmaceutical compositions of the present invention suitable for topical application to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly a sterile aqueous solvent for the agent. The medicament/pharmaceutical composition of the invention for rectal administration may be provided in the form of suppositories. The medicaments/pharmaceutical compositions of the invention suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active compound such carriers as are known in the art to be appropriate. The pharmaceutical/pharmaceutical compositions of the present invention suitable for nasal administration include meal powders having, for example, a particle size in the range of about 20 to about 500 microns. The pharmaceutical/pharmaceutical compositions of the present invention suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain preservatives, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the patient. Aqueous and non-aqueous sterile suspensions may include suspending and thickening agents, as well as liposome or other microparticle systems, which aim to target the compound to a blood component or organ or organs.
It will be appreciated that the pharmaceutical/pharmaceutical compositions of the present invention may include other agents conventional in the art regarding the type of formulation in question, in addition to the ingredients specifically mentioned above. For example, formulations suitable for oral administration may include other agents such as sweetening agents, thickening agents and flavouring agents.
Various delivery systems are known and may be used to administer the therapeutic agents of the present invention, e.g., encapsulated in liposomes, microparticles, microcapsules, and the like. Delivery methods include, but are not limited to, intra-arterial, intramuscular, intravenous, intranasal, and oral routes. In a specific embodiment, the drug/pharmaceutical composition of the invention may be topically applied to an area in need of treatment. Such local administration may be achieved, for example, by local infusion during surgery, by injection or by catheter.
Thus, the drug/pharmaceutical composition of the present invention may be one of tablets, powders, granules, pills, capsules, solutions, eye drops, emulsions, suspensions, ointments, oils, pastes, foams, sprays, injections, skin patches, suppositories, liposome preparations, microparticle preparations, microcapsule preparations.
In the drug/pharmaceutical composition according to the present invention, the ginkgo biflavone or a pharmaceutically acceptable salt thereof may be present in an amount of 0.01% to 50%, preferably 0.1% to 10%, more preferably 0.5% to 5%, most preferably 1% to 2% of the total weight.
The amount of treatment can be determined empirically and will vary with the pathology being treated, the weight of the subject being treated, and the efficacy and toxicity of the agent. Similarly, one skilled in the art can readily determine suitable dosage formulations and methods of administering the agents. For example, for adult patients, the ginkgo biflavones or pharmaceutically acceptable salts thereof of the present invention can be orally or parenterally administered as an administration amount of 0.001mg to 500mg for 1 day, 1 time or divided into several times for 1 day.
Advantageous effects
The invention provides application of ginkgo biflavone in preparing an anti-esophageal squamous carcinoma drug. Experimental results show that ginkgo biflava has remarkable apoptosis induction effect on esophageal squamous carcinoma cell lines KYSE410, KYSE150, KYSE450 and KYSE510, and can remarkably induce activation of apoptosis related proteins caspase 3 and PARP. The ginkgo biflava is capable of dose-dependently inhibiting the growth of the esophageal squamous carcinoma cell lines KYSE410, KYSE150, KYSE450 and KYSE510 as assessed by MTS method. The ginkgetin can inhibit the invasion of esophageal squamous carcinoma cell lines KYSE410, KYSE150, KYSE450 and KYSE510 in a dose-dependent manner by evaluating through a Transwell method. In KYSE450 and KYSE510 tumor-bearing mouse models, ginkgetin can effectively inhibit the increase of tumor volume and has good anticancer effect. Therefore, the ginkgo biflava can be used for preparing medicines for preventing and treating esophageal squamous cell carcinoma.
Drawings
FIG. 1 is a graph showing the results of the growth inhibitory effect of ginkgo biflavone of example 1 on esophageal squamous carcinoma cell lines. Wherein,P<0.05,/>P<0.01,/>P<0.001,/>P<0.0001 vs control (ginkgetin 0. Mu.M).
FIG. 2 is a graph showing the results of the invasion inhibition effect of ginkgo biflavone of example 2 on esophageal squamous carcinoma cell lines. Wherein,P<0.05,/>P<0.01,/>P<0.001 vs control group (ginkgetin 0. Mu.M); cont means that ginkgo biflavone is 0 mu M.
FIG. 3 is a graph showing the results of apoptosis induction of esophageal squamous carcinoma cell lines by ginkgo biflava of example 3. Wherein cont represents 0 μm of ginkgetin.
FIG. 4 is a schematic diagram showing the results of the induction of apoptosis key proteins of esophageal squamous carcinoma cell line by ginkgo biflava of example 4. Wherein,P<0.01,/>P<0.001 vs cont (ginkgo biflavone 0. Mu.M).
FIG. 5 is a graph showing the anti-tumor effect of ginkgo biflava of example 5 on tumor-bearing mice of esophageal squamous carcinoma cell lines KYSE450 and KYSE 510. Wherein,P<0.001 vs cont (ginkgo biflavone 0. Mu.M).
FIG. 6 is a graph showing the comparison of the antitumor effects of ginkgo biflavone and other flavonoid compounds of example 6. Wherein cont represents the administration amount of 0. Mu.M.
FIG. 7 is a comparative schematic of the ginkgo biflavone anti-esophageal squamous carcinoma and other types of tumors of example 7. Wherein cont represents 0 μm of ginkgetin
Detailed Description
Hereinafter, preferred examples of the invention will be described in detail. The examples are presented for better presentation of the invention and are not intended to be limiting. Insubstantial modifications and adaptations of the embodiments in accordance with the summary of the invention remain within the scope of the invention.
The experimental methods in the following examples are conventional methods unless otherwise specified. The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications.
Example 1: growth inhibition effect of ginkgo biflavone on esophageal squamous carcinoma cell line
1. Cell culture
Human esophageal squamous carcinoma cell lines KYSE410, KYSE150, KYSE450 and KYSE510 were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin streptomycin. The incubator temperature was 37℃and contained 5% CO 2 。
2. Cell growth ability assay
KYSE410, KYSE150, KYSE450 and KYSE510 cell lines were used in 3X 10 3 Density of individual/wells was seeded in 96-well plates and after cell attachment, different concentrations of ginkgetin (1, 2.5, 5, 10, 25, 50 μm) were added. After 72 hours, a 10% MTS solution was prepared in RPMI 1640 medium, the cultured cells were removed, the upper medium was discarded, the prepared MTS was added for incubation for 2 hours, and absorbance was measured under conditions of a microplate reader 490 nm.
Referring to fig. 1, the results show that ginkgo biflava is capable of inhibiting the growth of various esophageal squamous carcinoma cell lines in a dose-dependent manner.
Example 2: invasion inhibition effect of ginkgo biflavone on esophageal squamous carcinoma cell line
1. Cell invasiveness detection
KYSE410, KYSE150, KYSE450 and KYSE510 cell lines were cultured in serum free medium for 24 hours. Penetration using an 8 μm pore sizeAnd a chamber cell, wherein 100 mu L of matrigel is added into an upper chamber of the cell, and the matrigel is solidified after incubation for 1 hour at 37 ℃. The prepared KYSE410, KYSE150, KYSE450 and KYSE510 cell lines were used for 1×10 5 The density of each well was inoculated into the upper chamber of the puncture chamber, the lower chamber was filled with 1. 1 mL RPMI 1640 medium containing 20% fetal bovine serum, and with different concentrations of ginkgo biloba biflava (2.5, 5, 10, 25. Mu.M), and the puncture chamber was placed in an incubator for incubation for 24 hours. After removal, the inner wall of the upper chamber was wiped clean with a cotton swab, and the upper chamber was stained with a 2% crystal violet solution for 30 minutes. After the dyeing is finished, the floating color is slowly washed by flowing water, the upper chamber is dried, and the total number of cells passing through the upper chamber is counted by photographing.
Referring to fig. 2, the results show that ginkgo biflava is capable of inhibiting the invasion of various esophageal squamous carcinoma cell lines in a dose-dependent manner.
Example 3: apoptosis induction effect of ginkgo biflavone on esophageal squamous carcinoma cell line
1. Observation of apoptosis morphology
KYSE410, KYSE150, KYSE450 and KYSE510 cell lines were inoculated in RPMI 1640 medium containing 10% foetal calf serum. After cell attachment, ginkgo biflavones (2.5, 5, 10, 25. Mu.M) were added at different concentrations. After 24 hours of incubation, changes in cell morphology were observed by microscopy.
Referring to fig. 3, the results show that ginkgo biflavones can destroy cell integrity and reduce cell volume in a dose-dependent manner, and become compact spherical bodies, namely, form apoptotic bodies.
Example 4: induction of apoptosis key protein of esophageal squamous carcinoma cell line by ginkgo biflava
KYSE410, KYSE150, KYSE450 and KYSE510 cell lines were inoculated in RPMI 1640 medium containing 10% foetal calf serum. After cell attachment, ginkgo biflavones (2.5, 5, 10, 25. Mu.M) were added at different concentrations. After 24 hours incubation, cells were collected along with supernatant, and after centrifugation at 12000 rpm for 10 minutes at 4℃the pellet was collected. RIPA lysate was added and lysed on ice for 1 hour, during which time shaking was performed every 10 minutes. After completion of the cleavage, the supernatant was collected after centrifugation at 12000 rpm at 4℃for 20 minutes to obtain a protein lysate. The sheared Poly (apyrase) ribose polymerase (Poly ADP-ribose polymerase, PARP) was further visualized by an Enzyme-linked immunosorbent assay (Enzyme-linked immunosorbnent assay, ELISA) method at high throughput. PARP is a cleavage substrate for caspases, a core member of apoptosis, and plays a key role in apoptosis. Increased shear of PARP means that the cells appear to undergo significant apoptosis. Protein lysate samples (100. Mu.L/well) were sequentially added to a proprietary shear type PARP ELISA 96 well plate and incubated at 37℃for 2.5 hours after sealing. After the incubation is completed, the sample is discarded, and the sample is cleaned for 4 times by using a cleaning liquid and discarded. Shear type PARP antibodies were added to 96-well plates (100. Mu.L/well), incubated for 1 hour at room temperature with shaking, washed 4 times with washing solution, and discarded. After adding a reaction substrate to each hole and incubating for 30 minutes at room temperature in a dark place, adding a reaction stopping solution, and measuring the absorbance value under the condition of a microplate reader 450 and nm.
Referring to fig. 4, the results show that ginkgo biflavone dose-dependently induces up-regulation of the expression of sheared PARP in multiple esophageal squamous carcinoma cell lines.
Example 5: antitumor effect of ginkgetin on esophageal squamous carcinoma cell lines KYSE450 and KYSE510 tumor-bearing mice
Will be 2.5X10 6 KYSE450 or KYSE510 cells were injected subcutaneously into the upper limb of nude mice until the tumor had grown to about 100 mm 3 After left and right, KYSE450 or KYSE510 tumor bearing mice were randomly divided into two groups, a control group and a ginkgetin group. Ginkgo Biflavone (15 mg/kg) groups were administered by intragastric administration once daily for a total of 3 weeks. The control group was administered with the same dose of physiological saline by daily gavage for 3 weeks. Tumor volumes were measured once a week. The tumor volume calculation formula is: volume = tumor long diameter x tumor transverse diameter 2 x 0.5. Tumor tissues were collected on day 28, paraffin-embedded, fixed, and sectioned to prepare paraffin-embedded sections, and expression of proliferation-critical Protein (PCNA) and apoptosis-critical protein (sheared PARP) in KYSE450 and KYSE510 tissues was observed through immunohistochemical experiments.
Referring to fig. 5, the results show that ginkgo biflava significantly inhibits the growth of KYSE450 and KYSE510 tumors in a xenogenic tumor-bearing mouse model. Ginkgetin significantly inhibits PCNA expression in KYSE450 and KYSE510 tumors; significantly up-regulates the expression of sheared PARP in KYSE450 and KYSE510 tumor tissues.
Example 6: the ginkgetin can inhibit the growth of esophageal squamous carcinoma cell line more effectively than other flavonoid compounds
1. Cell culture
The human esophageal squamous carcinoma cell line KYSE450 was cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin streptomycin. The incubator temperature was 37℃and contained 5% CO 2 。
2. Cell growth ability assay
KYSE450 cell line was used at 3X 10 3 The density of the individual/well is inoculated into a 96-well plate, and after the cells are attached, different flavonoids (total of 8 flavonoids are added, each flavonoid dose is 5 mu M) including ginkgetin, procyanidin A2 (Procyanidin A2), glycitein (Glycitein), narcissin, schaftoside, robinin, firework glycoside (Nicotiforin) and Spinosin (Spinosin) are added. After 72 hours, a 10% MTS solution was prepared in RPMI 1640 medium, the cultured cells were removed, the upper medium was discarded, the prepared MTS was added for incubation for 2 hours, and absorbance was measured under conditions of a microplate reader 490 nm.
Referring to fig. 6, the results show that ginkgo biflava can inhibit the growth of esophageal squamous carcinoma cell lines more effectively than other flavonoid compounds.
Example 7: the ginkgetin can obtain more effective tumor growth inhibition effect on esophageal squamous carcinoma cells than other types of tumor cells
1. Cell culture
Human esophageal squamous carcinoma cell line KYSE450, human small-cell lung carcinoma cell line H446, human breast carcinoma cell line MDA231, human glioma cell line U87 and human gastric carcinoma cell line MGC803 are cultured in RPMI 1640 medium containing 10% of fetal bovine serum and 1% of penicillin streptomycin. The incubator temperature was 37℃and contained 5% CO 2 。
2. Cell growth ability assay
KYSE450, H446, MDA231, U87 and MGC803 cell lines were seeded at a density of 3X 103 cells/well in 96-well plates, and after cell attachment, ginkgo biloba biflavone (5. Mu.M) was added. After 72 hours, a 10% MTS solution was prepared in RPMI 1640 medium, the cultured cells were removed, the upper medium was discarded, the prepared MTS was added for incubation for 2 hours, and absorbance was measured under conditions of a microplate reader 490 nm.
Referring to fig. 7, the results show that ginkgo biflava can achieve more effective tumor growth inhibition in esophageal squamous carcinoma cells than in other types of tumor cells.
Example 8:
the ginkgo biflava is wrapped in liposome to prepare liposome ginkgo biflava as a medicament for treating esophageal squamous cell carcinoma.
Example 9:
mixing ginkgo biflavone and other flavonoid medicines according to a ratio (mass ratio=1:1), adding excipient according to a ratio required by a preparation, and preparing into tablets.
Example 10:
mixing ginkgo biflavone and other flavonoid medicines according to a ratio (mass ratio=1:1), adding an excipient according to a ratio required by a preparation, and preparing into powder.
Example 11:
mixing ginkgo biflava with other flavonoid medicines according to a proportion (mass ratio=1:1), performing spray granulation, drying, and granulating to obtain granules, wherein the granules are used as medicines for preventing and treating esophageal squamous cell carcinoma.
Example 12:
mixing ginkgo biflavone and other flavonoid medicines in a ratio (mass ratio=1:1), dissolving with water, fine filtering, packaging, sterilizing and preparing into injection.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (7)
1. Application of ginkgetin or pharmaceutically acceptable salt thereof in preparing medicine for resisting esophageal squamous cell carcinoma is provided.
2. The use according to claim 1, wherein the medicament comprises ginkgetin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
3. The use of claim 1, wherein the anti-esophageal squamous carcinoma comprises at least one of inhibiting esophageal squamous carcinoma cell growth, inhibiting esophageal squamous carcinoma cell invasion, and inducing esophageal squamous carcinoma cell apoptosis.
4. The use according to claim 1, wherein the pharmaceutically acceptable salt comprises a salt of ginkgetin with a pharmaceutically acceptable acid or base.
5. The use according to claim 1, wherein the medicament is suitable for oral, rectal, nasal, topical, vaginal, parenteral or pulmonary administration.
6. The use according to claim 1, wherein the medicament is one of a tablet, powder, granule, pill, capsule, solution, eye drop, emulsion, suspension, ointment, oil, paste, foam, spray, injection, skin patch, suppository, liposomal formulation, microparticle formulation, microcapsule formulation.
7. The use according to claim 1, wherein in the medicament the amount of ginkgetin or a pharmaceutically acceptable salt thereof is between 0.01% and 50% by total weight.
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WO1999020291A2 (en) * | 1997-10-23 | 1999-04-29 | Pharmaprint, Inc. | Pharmaceutical grade ginkgo biloba |
CN103214445A (en) * | 2013-05-08 | 2013-07-24 | 郑州大学 | Preparation method and use of quercetin amide derivative |
CN103239437A (en) * | 2013-05-08 | 2013-08-14 | 郑州大学 | Application of quercetin derivative in preparation of antitumor medicine |
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