CN113116914A - Pharmaceutical composition with synergistic inhibition effect on proliferation of non-small cell lung cancer A549 cells and application thereof - Google Patents
Pharmaceutical composition with synergistic inhibition effect on proliferation of non-small cell lung cancer A549 cells and application thereof Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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Abstract
The invention discloses an anti-tumor pharmaceutical composition with synergistic effect and application thereof. The composition has a good effect of inhibiting proliferation of non-small cell lung cancer A549 cells, and the combination of cinnamaldehyde and camellia saponin has an effect of inhibiting growth of solid tumors by combining pathological experiments of a nude mouse transplanted tumor model in the research of tumor pathogenesis.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a pharmaceutical composition with a synergistic effect of inhibiting proliferation of non-small cell lung cancer A549 cells and application thereof.
Background
At present, the incidence and mortality of lung cancer are the first in malignant tumors, wherein non-small cell lung cancer (NSCLC) accounts for more than 80% of the incidence of lung cancer, surgical treatment is generally adopted for patients with NSCLC in stage I or II, chemotherapy and immunotherapy are mainly adopted for patients with NSCLC in stage III, and the survival rate of patients with NSCLC in stage III within five years after treatment is only 15%, the overall prognosis is poor [ Yoon SM, Shaikh T, Hallman m.therapeutic management options for stage III non-small cell lung cancer, world J clear Oncol, 2017; 8(1): 1-20). With the continuous improvement of Chemotherapy schemes in recent years, the survival rate of Lung cancer patients has been improved to some extent, but long-term Chemotherapy can cause drug Resistance of tumor cells and seriously affect the curative effect, for example, cisplatin, a common Lung cancer chemotherapeutic drug has wide drug Resistance phenomenon in clinical treatment [ Zhang Yajuan, Chang De, Zhang Jianpen. research in drugs to Platinum-based Chemotherapy in Lung cancer. acta Acad Med Sin,2017,39(1): 150-. Immunodetection point inhibitors represented by PD-1/L1, CTLA-4 and the like are main means for immunotherapy of advanced lung cancer, but have the problems of high cost, prevention of metastasis ambiguity, excessive immunity, frequent adverse reactions mediated by T cells and the like in the treatment process, so that the further development of the immunodetection point inhibitors [ Loranthel, Lound, Yajialiang, Tianjiahui, clinical research progress of lung cancer immunotherapy. Therefore, the development of new drugs and the application of new drug combinations have important significance for the breakthrough of the treatment progress of the lung cancer.
Cinnamaldehyde (Cinnamadehyde, CA), as shown in formula I, is an olefine aldehyde compound extracted from cortex Cinnamomi, and is also the main component of cortex Cinnamomi volatile oil. Pharmacological research shows that the cinnamaldehyde has various pharmacological activities of resisting inflammation, relieving fever and pain, resisting tumor and the like. Chinese patent also discloses application of cinnamaldehyde in the fields of antipyresis [ CN201811042361 ], analgesia [ CN201810315891 ], treatment of skin and mucous membrane diseases [ CN201810821967, CN201810019853 ], anticancer [ CN201810973728 ] and the like.
Theabrin (OCS) has a structure shown in formula II, is ellagic acid derivative extracted from Camellia Chysantha, and is also main ingredient of methanol extract of Camellia Chysantha. In recent years, research on chemical components and pharmacological actions of golden camellia is gradually carried out, a plurality of natural active components including flavone, polysaccharide, plant polyphenol, saponin and the like are found, and in vitro and in vivo pharmacological experiments prove that the golden camellia shows potential medicinal values in the aspects of tumor resistance, oxidation resistance, inflammation resistance, blood sugar and blood fat regulation, allergy resistance and the like [ He D, Li X, Sai X, et al.
At present, the report of inhibiting the proliferation of the non-small cell lung cancer A549 cells by using the composition consisting of the cinnamaldehyde and the Theobromin is not available.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a pharmaceutical composition with the efficacy of synergistically inhibiting the proliferation of non-small cell lung cancer A549 cells.
The second purpose of the invention is to provide an application of a pharmaceutical composition with the efficacy of synergistically inhibiting the proliferation of non-small cell lung cancer A549 cells in preparing a medicament for treating non-small cell lung cancer.
The technical scheme of the invention is summarized as follows:
a pharmaceutical composition with synergistic effect in inhibiting proliferation of non-small cell lung cancer A549 cells comprises cinnamaldehyde and Theobromoside.
Preferably, the molar ratio of the cinnamaldehyde to the camellia saponin is 30 (6.25-200).
The application of the pharmaceutical composition in preparing a medicament for treating non-small cell lung cancer.
The invention has the advantages that:
the cinnamic aldehyde and the Theabroside are used together, the drug effect is larger than that of single use, and the product has the inhibition effect on the proliferation of A549 cells.
The composition provided by the invention can inhibit the growth of A549 cells and has anti-tumor efficacy through determination, and the using amount of the composition is less than that of the single medicine.
The invention does not limit the medicament form, and all the acceptable medicament forms in the field of medicaments are in the protection scope of the invention.
The composition has the effect of resisting non-small cell lung cancer, and the combination of cinnamaldehyde and theaside in the research on the pathogenesis of tumors and the use of a pathological experiment of a relevant nude mouse transplantation tumor model finds that the composition has a stronger effect of inhibiting the growth of solid tumors compared with the monomer administration. Therefore, the cinnamaldehyde and the camellia saponin have synergistic effect and can be applied to treating the non-small cell lung cancer.
Drawings
FIG. 1 shows the IC of two drugs tested separately on the effect of different cell lines by CCK-8 assay50The value is obtained.
FIG. 2 shows the inhibition of A549 cells by the combination of two drugs tested by the CCK-8 assay and the synergy index (CI value) of the combination of the two drugs calculated by the CompuSyn software. FIG. 2 shows the CI values for the combination of two drugs.
FIG. 3 shows the effect of the combination of two drugs on the change in the tumorigenic volume of A549-luc transplantable tumors in experimental animals and the change in body weight of experimental animals, compared to the corresponding single drug. FIG. 3a is a statistic of mean tumor volume of groups of experimental nude mice; FIG. 3b is the average body weight statistics of the experimental nude mice in each group.
FIG. 4 shows the effect of the combination of two drugs on the tumorigenic fluorescence values of A549-luc transplantable tumors in experimental animals compared to the corresponding single drug. FIG. 4 is the statistics of the mean fluorescence values of the tumors of the experimental nude mice of each group.
FIG. 5 shows the effect of a combination of two drugs on the size of the neoplasia of A549-luc transplantable tumors in experimental animals compared to the corresponding single drug. FIG. 5 is the average weight statistics of the exfoliated tumors in each group of experimental nude mice.
Detailed Description
In the experiment, cinnamic aldehyde (purchased from Shanghai Aladdin, with the product number of C110084) and camellia saponin (prepared and extracted from golden camellia by macroporous resin and medium pressure) are used.
The composition of the invention is obtained by mixing cinnamaldehyde and camellia saponin.
In a specific embodiment of the invention, the cell lines of different strains include: non-small cell lung cancer A549, human malignant melanoma cell A375, human liver cancer cell HepG2, cervical cancer cell Hela, macrophage RAW264.7, human normal lung epithelial cell BEAS-2B, cardiac muscle cell H9C2, fibroblast NIH-3T3, and human kidney epithelial cell 293T.
The invention selects non-small cell lung cancer A549 cells to carry out the synergistic experiment verification of the composition.
By using the composition, the drug concentration of the cinnamaldehyde is 10-30 micromoles/liter; the drug concentration of the camellia saponin is 6.25-20 micromoles/liter.
In a549 cells, preferred ranges of conditions are: 30 micromoles/liter of cinnamaldehyde and 6.25-200 micromoles/liter of camellia saponin.
In order to verify the results obtained by the cell experiments, two medicines with different proportions are selected in the preferable range to be combined and applied, and the experiments are carried out at the animal level. When the combination is administered in a nude mouse A549-luc transplantation tumor model, the administration mode is intraperitoneal injection. The usage amount of the camellia saponin is 10 mg (0.02 mmol) per kg/day; the amount of cinnamaldehyde used was 5 mg (0.0 mmol) per kg/day and 10 mg (0.08 mmol) per kg/day.
Modifications will occur to those skilled in the art in view of this disclosure. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the method and application of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the method and application described herein, as well as other suitable variations and combinations thereof, may be made without departing from the spirit and scope of the invention as defined by the appended claims.
The invention is further illustrated by the following examples:
example 1
Through a CCK-8 experiment, the proliferation inhibition effect of cinnamaldehyde and camellia saponin on different cell strains is examined.
Taking different cell strains in logarithmic growth phase, and fusing the cells until the cells grow to 80%Digesting at room temperature, inoculating 100 microliter of cell suspension into 96-well cell culture plate, and placing at 37 deg.C and 5% CO2Incubate overnight in a conditioned incubator. After the cells are attached to the wall, the original culture medium is discarded, cinnamaldehyde with different concentrations (7.5-30 micromoles/liter) and camellin with different concentrations (6.25-200 micromoles/liter) are respectively and uniformly mixed in the culture medium, 100 microliters of each well is added into a 96-well plate (a blank group is added with the culture medium and does not contain the cells and the drugs, a control group is added with the culture medium and the cells and does not contain the drugs), 6 multiple wells are arranged in each group, and the administration and the incubation are carried out for 72 hours. After the administration, 10 microliter of CCK-8 solution is added into each hole, incubated for about 1 hour at 37 ℃ in the dark, taken out, the absorbance of each hole is measured at 450 nm by using an enzyme-linked immunosorbent assay (ELISA), and IC is calculated50The value is obtained.
The results show that the cinnamic aldehyde and the Theobroma japonica glycosides are used independently, the proliferation inhibition effect on the non-small cell lung cancer A549, the human malignant melanoma cell A375, the human liver cancer cell HepG2 and the cervical cancer cell Hela is better, and the IC is better50Has low value, has poor inhibition effect on the proliferation of macrophage RAW264.7, human normal lung epithelial cell BEAS-2B, myocardial cell H9C2, fibroblast NIH-3T3 and human kidney epithelial cell 293T, and has IC50The value is higher (fig. 1). Finally, non-small cell lung cancer A549 cells are selected for carrying out the verification of the synergistic experiment of the composition.
Example 2
Through a CCK-8 experiment, the proliferation inhibition effect of the combined use of cinnamaldehyde and camellia saponin (the composition disclosed by the invention has a specific ratio shown in table 1) on non-small cell lung cancer A549 cells is investigated.
Taking cells in logarithmic growth phase, digesting when the cells grow to 80% fusion degree, inoculating 100 microliter of cell suspension into a 96-well cell culture plate, placing at 37 ℃ and 5% CO2Incubate overnight in a conditioned incubator. After the cells are attached to the wall, the original culture medium is discarded, the cinnamaldehyde and the russetoside of the combined medicine group are uniformly mixed in the culture medium, each hole is added into a 96-well plate by 100 microliters (the blank group is added with the culture medium and does not contain the cells and the medicines; the control group is added with the culture medium and the cells and does not contain the medicines), each group is provided with 6 multiple holes, and the administration and incubation are carried out for 72 hours. To the end of the administrationThen, 10. mu.l of CCK-8 solution was added to each well, incubated at 37 ℃ in the dark for about 1 hour, taken out, and the absorbance of each well was measured at 450 nm using a microplate reader.
And (4) evaluating the result: the inhibition rate of different compounds on various cell growth is calculated according to the following formula:
cell proliferation inhibition ratio (Fa) ═ ODControl well－ODExperiment hole)/(ODControl well－ODBlank hole). The comp usyn software was applied to analyze the CI values,<1 represents a synergistic effect, 1 is an additive effect,>1 is antagonistic.
The results show that the combined action of different concentrations of cinnamaldehyde and camellia saponin shows the synergistic inhibition effect on the non-small cell lung cancer A549 cells at partial concentrations (figure 2, table 1), and preferably, the molar ratio of the cinnamaldehyde to the camellia saponin is 30 (6.25-200).
TABLE 1 CI values after CA + OCS combination in A549 cells
Example 3
The nude mice are bred with BALB/c-nu (SPF grade), male, 4-6 weeks old and 18-22 g of body weight, and are subjected to diet management according to feeding standards and adaptive feeding for one week before being used for experiments.
The effect on A549-luc transplantation tumor in BALB/c-nu nude mice was observed by the method of combined administration of cinnamaldehyde and Theaflavin (composition of the present invention).
Subculturing the A549-luc cells in good state, digesting with pancreatin when the cells are cultured to a certain amount and in logarithmic growth phase, centrifuging at 800 rpm for 3 min at room temperature, collecting the cells, washing the cells with sterile normal saline for 2 times, and resuspending the cells to obtain the product with concentration of 1 × 107One/ml cell suspension, 100 μ l of cell suspension was inoculated in each nude mouse at the right underarm site. Observing the condition of the nude mice every day, and forming a spherical solid bulge at the right armpit of the nude mice after about one week of the construction of the transplantation tumor modelAnd the volume is about 100 cubic millimeters, namely the animal model is successfully constructed. Animals were randomly divided into 7 groups of 5 animals each. The grouping situation is as follows: (1) a model control group; physiological saline; (2) positive control group: doxorubicin (DOX)0.5 mg/kg/day; (3) camellia Saponin (OCS) group: 10 mg (0.02 mmol) per kg/day; (4): cinnamaldehyde (CA) group 1: 5 mg (0.04 mmol) per kg/day; (5) cinnamaldehyde (CA) group 2: 10 mg (0.08 mmol) per kg/day; (6) combination group 1: OCS 10 mg (0.02 mmol) per kg/day + CA 5 mg (0.04 mmol) per kg/day; (7) combination group 2: OCS 10 mg (0.02 mmol) per kg/day + CA 10 mg (0.08 mmol) per kg/day. The administration mode is intraperitoneal injection, and the dosage is 0.1 ml/dose/day, and the administration time is 26 days. Nude mice were measured and recorded daily for weight and tumor volume size changes.
The results show that the volume size of the A549-luc transplanted tumor is obviously reduced in the DOX group, the OCS group, the combination group 1 and the combination group 2 compared with the model control group, the growth of the A549-luc transplanted tumor is inhibited to a greater extent in the combination group 1 compared with the group administered alone, the combination group 2 has no significant difference compared with the group administered alone OCS, but the inhibition effect of the A549-luc transplanted tumor is more obvious compared with the group administered alone, and the weight average of animals is not significantly influenced by the administration alone or the combination. The combination group showed significantly higher inhibitory effect than the single group without significant toxicity (figure 3),#representing a federated group 1vs OCS group P<0.05，▲Representing a Joint group 2vs CA group 2P<0.05, representing DOX group, OCS group, CA group 1, CA group 2vs MOD group P < 0.001,△△△representing a combination group 1vs CA group 1P<0.001, the difference between groups was statistically significant.
Example 4
After the last day of administration of the nude mice in example 3, the nude mice were anesthetized by intraperitoneal injection of fluorogenic substrate (D-fluorescein potassium salt, 10 mg/ml, 150 μ l), and 5 μ l followed by intraperitoneal injection of pentobarbital sodium solution (40 mg/kg). And (3) fixing the nude mouse on a detection table and detecting by fluorescence imaging. And performing data analysis and acquisition of total light quantum number and fluorescence intensity pictures on a detection instrument.
The results show that the DOX group, OCS group, combination group 1 and combination group 2 are compared with the model control groupThe light quantum number is obviously reduced, the survival amount of A549-luc is obviously reduced compared with that of the independent administration group in the combination group 1, and the combination group 2 has no obvious difference compared with that of the independent administration group. Indicating that the combination group [ OCS 10 mg (0.02 mmol)/kg/day + CA 5 mg (0.04 mmol)/kg/day]The survival rate of A549-luc in nude mice is significantly lower than that of the group administered alone (FIG. 4),#representing a federated group 1vs OCS group P<0.05, represents the combined group 2vs MOD group P<0.05, OCS group vs MOD group P < 0.01, DOX group, combination group 1vs MOD group P < 0.001,△△△representing a combination group 1vs CA group 1P<0.001, the difference between groups was statistically significant.
Example 5
After in vivo fluorescence imaging of example 4, nude mice were sacrificed by cervical dislocation, and tumors were exfoliated and weighed to compare tumor size.
The results show that the tumor weight of the DOX group, the OCS group, the CA group 1, the combination group 1 and the combination group 2 is obviously reduced compared with that of the model control group, the tumor weight of the combination group 1 is obviously reduced compared with that of the single administration group, and the combination group 2 has no obvious difference compared with that of the single administration group. Indicating that the combination group [ OCS 10 mg (0.02 mmol)/kg/day + CA 5 mg (0.04 mmol)/kg/day]The growth inhibition effect on A549-luc is obviously higher than that of a single administration group (figure 5),#representing a federated group 1vs OCS group P<0.05, representing CA group 1vs MOD group P<0.05, representing DOX group, OCS group, combination group 1, combination group 2vs MOD group P < 0.001,△△△representing a combination group 1vs CA group 1P<0.001, the difference between groups was statistically significant.
Claims (2)
1. A pharmaceutical composition with the effect of synergistically inhibiting the proliferation of non-small cell lung cancer A549 cells is characterized by comprising cinnamaldehyde and russetoside; the molar ratio of the cinnamaldehyde to the camellia saponin is 30 (6.25-200).
2. The use of the pharmaceutical composition of claim 1 in the preparation of a medicament for inhibiting proliferation of non-small cell lung cancer a549 cells.
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