CN115068474A - Application of dehydrocavidine in preparing pharmaceutical composition for treating human lung adenocarcinoma - Google Patents
Application of dehydrocavidine in preparing pharmaceutical composition for treating human lung adenocarcinoma Download PDFInfo
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- CN115068474A CN115068474A CN202210834158.3A CN202210834158A CN115068474A CN 115068474 A CN115068474 A CN 115068474A CN 202210834158 A CN202210834158 A CN 202210834158A CN 115068474 A CN115068474 A CN 115068474A
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- dehydrocavidine
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- human lung
- lung adenocarcinoma
- pharmaceutical composition
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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Abstract
The invention discloses an application of dehydrocavidine in preparing a pharmaceutical composition for treating human lung adenocarcinoma, and discusses the influence and action mechanism of the dehydrocavidine on the proliferation and apoptosis of human lung adenocarcinoma A549 cells. And (4) conclusion: the dehydrocavidine can inhibit the proliferation of human lung cancer A549 cells, promote the apoptosis of the human lung cancer A549 cells, also has the inhibiting effect on the growth of nude mouse transplanted tumors, and the mechanism of the dehydrocavidine can be related to the reduction of Survivin expression, the up-regulation of Caspase-3 to inhibit the proliferation activity of transplanted tumor cells and the induction of cancer cell apoptosis.
Description
[ technical field ] A method for producing a semiconductor device
The invention belongs to the technical field of medical application, and relates to application of dehydrocavidine in preparation of a pharmaceutical composition for treating human lung adenocarcinoma.
[ background of the invention ]
With the development of human society and the disruption of the natural environment, lung cancer remains the leading cause of cancer death, with non-small cell lung cancer predominating, and in part, the poor prognosis is due to late diagnosis with no obvious symptoms at the early stage of disease progression, with most patients (approximately 75%) coming to the hospital and having advanced disease (stage III/IV). Despite significant advances in recent years with respect to treatment of advanced lung cancer, survival rates and quality of life remain low.
The lung cancer is treated by adopting comprehensive modes such as operation, radiotherapy, chemotherapy, targeted therapy, immunotherapy and the like so as to improve the life quality of patients and prolong the survival time. However, in clinic, many lung cancer patients lose surgical opportunities due to low immunity, significant cachexia, or become intolerant to chemotherapeutic drugs, which tends to fail the treatment. As a medical system with unique advantages in China, the traditional Chinese medicine becomes an indispensable important component for the adjuvant therapy of the lung cancer, and plays a great role in the prognosis and improvement of the lung cancer.
Corydalis saxicola bunting total alkaloids are prepared from corydalis saxicola bunting of corydalis of Papaveraceae by extracting effective alkaloid, and have bitter taste and cool nature, and have effects of clearing heat and detoxicating, promoting diuresis, relieving pain and stopping bleeding. In Guangxi Zhuang autonomous region, it is commonly used by folks to treat acute icteric hepatitis, liver cirrhosis, liver cancer, furuncle, pyogenic infections, acute gastroenteritis, etc. In recent years, the research finds that the total alkaloids of the corydalis saxicola bunting can inhibit the proliferation of tongue squamous carcinoma cells and promote the apoptosis of the tongue squamous carcinoma cells, and the total alkaloids of the corydalis saxicola bunting have been proved in the clinical treatment of liver cancer. In the research aspect of lung cancer, the inventor discovers that the corydalis saxicola bunting total alkali can reduce the expression of an anti-apoptotic protein Survivin by activating an apoptotic protein Caspase-3, induce apoptosis of a549 cell of human lung adenocarcinoma and inhibit proliferation of the cell adenocarcinoma A549 cell, can also inhibit the expression of cell division cyclin 42(Cdc42), reduces the expressions of matrix metalloproteinases MMP2 and MMP9, and inhibits migration and invasion of the lung cancer cell, so that the anti-tumor activity is exerted, while dehydrocavidine (dehydrocavidine) is taken as an important quaternary alkaloid compound separated from the corydalis saxicola bunting total alkali and one of main effective monomer components, the inventor speculates that dehydrocavidine can be one of effective components for inhibiting proliferation, apoptosis, migration and invasion of the lung cancer, and the research on the aspect of resisting the lung cancer is not reported in domestic and foreign documents at present.
[ summary of the invention ]
Aiming at the problems of low survival rate and low quality of life for treating the human lung adenocarcinoma in the prior art, the invention provides the application of dehydrocavidine in preparing the pharmaceutical composition for treating the human lung adenocarcinoma.
The purpose of the invention is realized by the following technical scheme:
the influence of dehydrocavidine on the proliferation and apoptosis of human lung adenocarcinoma A549 cells and the action mechanism thereof are researched.
The method comprises the following steps:
1. intervening human lung adenocarcinoma A549 cells in logarithmic growth phase by using dehydrocavidine with different concentrations, detecting the influence on the proliferation of the human lung adenocarcinoma A549 cells by using a CCK8 method, and detecting the influence on the apoptosis and cell cycle of the human lung adenocarcinoma A549 cells by using a flow cytometry;
2. establishing a lung cancer nude mouse transplantation tumor model by using lung adenocarcinoma A549 cells, and randomly dividing the lung cancer nude mouse transplantation tumor model into a control group and a treatment group (a high-dose group and a low-dose group); drawing a growth curve of the transplanted tumor according to the change of the tumor volume, calculating the inhibition rate according to the mass of the terminal tumor, observing the morphology of transplanted tumor cells by adopting HE staining, and detecting the antigen expression of the transplanted tumor tissue cells Caspase-3 and Survivin by adopting an immunohistochemical SP method.
Application of dehydrocavidine in preparing pharmaceutical composition for treating lung adenocarcinoma is provided.
Furthermore, the dehydrocavidine is applied to the preparation of the pharmaceutical composition for treating the lung adenocarcinoma of the human, and the pharmaceutical composition is prepared into a clinically acceptable pharmaceutical preparation by taking the dehydrocavidine as a main component and adding pharmaceutically acceptable auxiliary materials or auxiliary components.
Furthermore, the application of the dehydrocavidine in preparing the pharmaceutical composition for treating the human lung adenocarcinoma comprises two dosage forms of an oral preparation and an injection preparation.
Furthermore, the dehydrocavidine is applied to the preparation of the pharmaceutical composition for treating the human lung adenocarcinoma, the oral preparation is an oral capsule, and the injection preparation is intravenous injection.
Generally, the drugs are clinically applied after being prepared into preparations. The pharmaceutical composition of the present invention can be prepared according to a method known in the art as a pharmaceutical composition. The pharmaceutical compositions of the present invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of dehydrocavidine in its pharmaceutical composition according to the invention is generally 0.01-95% (w/w).
The pharmaceutical composition of the invention or the pharmaceutical composition containing the same can be administered in unit dosage form, and the administration route can be intestinal or parenteral, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The pharmaceutical composition can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems. To formulate the pharmaceutical composition of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the adhesive can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to encapsulate the administration unit, the pharmaceutical composition of the present invention as an active ingredient may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the active ingredients of the pharmaceutical composition of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used for preparing the pharmaceutical composition tablets of the invention can also be used for preparing capsules of the pharmaceutical composition of the invention.
In order to prepare the pharmaceutical composition of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
Compared with the prior art, the invention has the following advantages:
1. the application of the dehydrocavidine in the preparation of the pharmaceutical composition for treating the lung adenocarcinoma is proved by previous researches of an inventor that the corydalis saxicola bunting total alkaloid can inhibit the expression of cell division cyclin 42(Cdc42), reduce the expression of matrix metalloproteinases MMP2 and MMP9 and inhibit the migration and invasion of the lung adenocarcinoma cells so as to play the anti-tumor activity.
2. In order to understand the effect of the dehydrocavidine on lung cancer, the application of the dehydrocavidine in preparing the pharmaceutical composition for treating human lung adenocarcinoma discovers that the dehydrocavidine can obviously inhibit the proliferation of A549 cells through the detection result of an in vitro CCK8 method, and also discovers that the dehydrocavidine can induce the apoptosis of the A549 cells through the detection result of a flow cytometry method, and finally observes the expression of Caspase-3 and Survivin in a nude mouse A549 transplantation tumor tissue of the dehydrocavidine effect through in vivo experiment immunohistochemistry, so that the dehydrocavidine can inhibit the proliferation of the A549 cells and induce the apoptosis of the A549 cells by activating the Caspase-3 and reducing the expression of the anti-apoptotic protein Survivin, and an important scientific basis is provided for explaining the treatment of the dehydrocavidine on lung cancer.
[ description of the drawings ]
FIG. 1 is a graph of the proliferation rate of dehydrocavidine versus human lung adenocarcinoma A549 cells at different concentrations in the experimental examples of the present invention;
FIG. 2 is a graph of the inhibition of the cell cycle of human lung adenocarcinoma A549 by dehydrocavidine at various concentrations in the experimental examples of the present invention;
FIG. 3 is a graph showing that dehydrocavidine induces apoptosis of human lung adenocarcinoma A549 cells at the same concentration in the experimental examples of the present invention;
FIG. 4 is a graph showing a relative growth curve of a subcutaneous transplanted tumor in a nude mouse in an experimental example of the present invention;
FIG. 5 is a graph showing the sizes of transplanted tumors in each group in the experimental example of the present invention;
FIG. 6 is a drawing showing the histomorphometric observation (HE staining) (400) of transplanted tumors in various groups of human lung cancer nude mice in the experimental example of the present invention;
FIG. 7 is a graph showing immunohistochemical results (DAB, 400) of Caspase-3 protein in experimental examples of the present invention;
FIG. 8 is a graph showing immunohistochemical results (DAB, 400) of Survivin protein in the experimental examples of the present invention.
[ detailed description ] embodiments
The following examples are provided to further illustrate the embodiments of the present invention.
Example 1:
the application of dehydrocavidine in preparing the pharmaceutical composition for treating human lung adenocarcinoma comprises the following steps:
according to the existing process requirements, the hard capsules are prepared.
Example 2:
the application of dehydrocavidine in preparing the pharmaceutical composition for treating human lung adenocarcinoma comprises the following steps:
according to the existing process requirements, the injection is prepared.
Experimental example:
1. materials and instruments
1.1 Experimental cells and animals: human lung adenocarcinoma a549 cell strain purchased from kunming cell bank, chinese academy of sciences. BALB/c nude mice, 24, male, weighing 18-20g, were purchased from Schleddar, Hunan. The nude mice are bred in the animal room (SPF grade) of the experimental center of Guilin medical college, the room temperature is 22-26 ℃, and the relative humidity is 40-60%.
1.2 Main reagents and Equipment
Dehydrocavidine was purchased from china institute for food and drug assay (111667), cisplatin injection was purchased from shandong qilu pharmaceutical co ltd, 1640 culture solution was purchased from Gibico, Fetal Bovine Serum (FBS) was purchased from south american import fetal bovine serum Gemini, phosphate buffer powder, trypsin-EDTA digestive fluid, EDTA-free trypsin, streptomycin mixed solution was purchased from beijing solibao science ltd, PI dye and rnase a were purchased from american Sigma, Cell Counting Kit-8 was purchased from beijing solibao science ltd, BD apoptosis Kit was purchased from BD company. Absolute ethanol was purchased from the chemical reagent works of Synechol, Surviin, Caspase3 were purchased from Abcam, xylene was purchased from the national pharmacy group, embedding paraffin was purchased from the national pharmacy group, hematoxylin was purchased from Beijing Solebao science and technology Co., Ltd, hydrochloric acid was purchased from Ailiam chemical reagent Co., Ltd, and Dako REAL Environment protection System was purchased from Agilent (Dako);
OLYMPUS ckx31 inverted microscope (OLYMPUS corporation, Japan), OLYMPUS IXTIFL inverted fluorescence phase contrast microscope (OLIPBAS corporation, Japan), mLDEL680 enzyme-labeling apparatus (Bio-RAD, USA), microscope (OLIPBAS BX53 type biomicroscope).
1.3 Experimental methods
1.3.1 cell culture: human lung adenocarcinoma A549 cells were cultured at 37 ℃ under 5% CO2, and cells in logarithmic growth phase were taken for experiments.
1.3.2 detection of toxicity of dehydrocavidine on human lung adenocarcinoma A549 cells at 37 deg.C with 5% CO 2 Incubating the cells for 12 hours under the saturated humidity condition, adding dehydrocavidine culture working solution (0, 0.0005mg/mL, 0.001mg/mL, 0.002mg/mL, 0.005mg/mL, 0.01mg/mL, 0.02mg/mL, 0.05mg/mL, 0.1mg/mL and 0.2mg/mL) with different concentrations for treating for 24 hours, 48 hours and 72 hours respectively, adding 100 mul of prepared CCK8 solution into each hole, using an enzyme labeling instrument to obtain an absorbance (A) value at 490nm, repeating the experiment for three times, and calculating the cell proliferation rate%: [1- (control group A value-Experimental group A value)/control group A value]×100％。
1.3.3 Effect of Dehydroarvetin in series concentrations on the cell cycle of human Lung adenocarcinoma A549 at 37 deg.C and 5% CO 2 Incubating the incubator for 12 hours under the saturated humidity condition, adding dehydrocavidine culture working solution (0, 0.01mg/mL, 0.02mg/mL, 0.05mg/mL and 0.1mg/mL) with different concentrations, treating for 24 hours, fixing each group without precooling absolute ethyl alcohol, dyeing by 1mLPI/Triton X-100, repeating the experiment for three times, calculating G0/G1%, S% and G2/M%, and further analyzing data.
1.3.4 series concentration of dehydrocavidine on apoptosis of human lung adenocarcinoma A549 at 37 deg.C and 5% CO 2 Culturing at constant temperature in incubator under saturated humidity condition for 12h, adding different concentrations of dehydrocavidine culture working solution (0, 0.01mg/mL, 0.02mg/mL, 0.05mg/mL, 0.1mg/mL, 02mg/mL) for 24h, sucking 100 μ L of single cell suspension per group, adding 5 μ L of Annexin V-FITC and 5 μ L of PI, incubating for 15min at room temperature in the dark, finally adding 1 × Binding Buffer to make the total volume 0.5mL, repeating each group experiment for 3 times, and determining apoptosis by flow cytometry.
1.3.5 establishment of lung cancer nude mouse model:
under strict aseptic conditions, 0.2mL of the above cell suspension was subcutaneously inoculated at 0.3-0.5cm of the armpit backrest of the right forelimb of each nude mouse, and the number of cells inoculated per mouse was about 2.0X 10 7 After inoculation, the nude mice were observed for general conditions, and the tumor sites were bleeding and ulcerated. The volume of the subcutaneous nodule is more than or equal to 200mm 3 Is the standard of tumor formation.
Measuring the length and the short diameter of the transplanted tumor by a vernier caliper every 5 days according to V ═ ab 2 ) The volume of the transplanted tumor is calculated by pi/6 formula, and the growth rate of the transplanted tumor is plotted according to the tumor growth rate (tumor volume at the time of measurement-tumor volume before administration)/tumor volume before administration, and finally the tumor weight is weighed to calculate the tumor inhibition rate, and the tumor weight (%) calculation formula is (average tumor weight of control group-average tumor weight of treatment group)/average tumor weight of control group x 100%.
1.3.6 configuration and grouping of drugs:
preparing a dehydrocavidine stock solution: the dehydrocavidine stock solution with the final concentration of 10mg/mL is diluted into a dehydrocavidine experimental group with the concentrations of 20mg/kg and 40mg/kg, and the volume (mL) of the medicine injected into the abdominal cavity every time is calculated according to the body mass.
Cisplatin working solution: the volume (mL) of the medicine injected into the abdominal cavity at each time is calculated according to the body mass according to 2 mg/kg.
1.3.7 grouping and administration: taking blank administration as a negative control group and cisplatin as a positive control group, and respectively administering dehydrogenation cavidine experimental groups containing 20mg/kg and 40mg/kg to intervene in a tumor-forming nude mouse, wherein the action time is 21 days;
1.3.8HE staining for transplanted tumor histomorphology: the transplanted tumor is fixed, embedded, sectioned, and the morphological change of the tissue is observed under an optical microscope through hematoxylin-eosin (HE) staining.
1.3.9 immunohistochemical method for detecting the expression conditions of Caspase-3 and Survivin in transplanted tumor tissues of nude mice, fixing the transplanted tumor tissues of nude mice stripped by 4% paraformaldehyde for 48h, embedding, tissue slicing, adding primary antibody: the rabbit monoclonal Caspase3 antibody and the rabbit monoclonal Survivin antibody are subjected to optical density analysis on immunohistochemical photographs by using IPP6.0 software, 3 400-fold photographs are selected from each section for optical density analysis, the average optical density values of Caspase-3 and Survivin in each 3 visual fields of each section of each group are detected, and the influence of a medicament on tumor Caspase-3 and Survivin proteins is judged.
1.3.10 statistical methods
Data processing was performed with SPSS 19.0 software. All the above experiments were repeated 3 times. All data are mean. + -. standard deviation
And (3) representing that single-factor analysis of variance is compared by adopting a plurality of samples, a pair of samples are compared by adopting a t test, the test level alpha is 0.05, and P is less than 0.05 to represent that the difference has statistical significance.
2, results:
2.1 Effect of different concentrations of dehydrocavidine on the proliferation of human lung adenocarcinoma A549 cells:
compared with a blank control group, the dehydrocavidine can inhibit the proliferation of the human lung adenocarcinoma A549 cells, the action time is prolonged along with the increase of the drug concentration within 24 h-48 h, an obvious time-dose dependent effect is presented, and the optimal inhibition concentrations of the dehydrocavidine on the human lung adenocarcinoma A549 cells after 24h, 48h and 72h are respectively 0.02mg/mL, 0.002mg/mL and 0.002 mg/mL. And the action time is 24 hours, and the concentrations are respectively 0.01mg/mL, 0.02mg/mL, 0.05mg/mL and 0.1mg/mL, and the dehydrocavidine is used as the concentration of the lung adenocarcinoma A549 cell culture solution to carry out periodic and apoptosis experimental observation (see figure 1).
FIG. 1: the proliferation rate curve of dehydrocavidine to human lung adenocarcinoma A549 cells under different concentrations.
2.2 Effect of Dehydrocarbutin on the cell cycle of human Lung adenocarcinoma A549:
compared with a negative control group, the dehydrocavidine can block the G0/G1 phase of the cell cycle, reduce the number of cells entering the S phase and the G2/M phase and inhibit the proliferation of the A549 cells of the human lung adenocarcinoma (see figure 2).
FIG. 2: the dehydrocavidine in different concentrations can block the cell cycle of the human lung adenocarcinoma A549 (A. flow cytometry is used for detecting the blocking level of each cycle of the cell; B. quantitative analysis is used for detecting the blocking result of each cycle of the cell, ★ P＜0.05， ▽ p is less than 0.05VS control group; a1: a control group; a2: 0.01 mg/mLYHL-DC; a3: 0.02 mg/mLYHL-DC; a4: 0.05 mg/mLYHL-DC; a5: 0.1 mg/mLYHL-DC; b: YHL-DC concentration).
2.3 Effect of Dehydrocarbutin on apoptosis of human Lung adenocarcinoma A549 cells:
compared with the control group, the dehydrocavidine can induce the apoptosis of the human lung adenocarcinoma A549 cells, and the apoptosis rate of the cells shows obvious dose dependence with the increase of the concentration of the dehydrocavidine (see figure 3).
FIG. 3: the dehydrocavidine induces the apoptosis of the human lung adenocarcinoma A549 cells under different concentrations (A, detecting the apoptosis level by flow cytometry; B, quantitatively analyzing the result of detecting the apoptosis level by flow cytometry, ★ P＜0.05， ◆ p <0.05 VS control).
2.4 establishment of a nude mouse subcutaneous transplantation tumor model of human lung adenocarcinoma A549:
and (2) observing in a general state, wherein solid nodules can be seen at the inoculated part 7-10 days after inoculation, the average diameter of the tumor reaches 5mm, then the nodules are enlarged to reach the experimental neoplasia standard for about 15 days, the general condition of each treatment group of nude mice is good before and after the experiment, no significant change is generated with a control group, the surface of the tumor body is not broken obviously in the treatment process, and each group of nude mice survive after the experiment.
2.5 Effect of groups of drugs on the growth of subcutaneous transplanted tumors in nude mice:
the volume growth rates of the transplanted tumors of the negative control group, the dehydrocavidine group of 20mg/kg, the dehydrocavidine group of 40mg/kg and the cisplatin group are respectively as follows: (3685.90 +/-653.113)%, (715.30 +/-87.24)%, (583.06 +/-12.92)%, (272.63 +/-16.07), the tumor body growth rate of the dehydrocavidine group has statistical significance (P is less than 0.05) compared with the difference of a negative control group; the tumor volumes of the medicinal group and the cis-platinum group of the dehydrocavidine are both smaller than the tumor volume of the negative control group; and the cisplatin group has more obvious effect of inhibiting the growth speed of the transplanted tumor. (see fig. 4, 5);
FIG. 4: relative growth curve of subcutaneous transplanted tumor in nude mouse. With the increase of the concentration of the dehydrocavidine and the prolonging of the action time, the dehydrocavidine can inhibit the increase of the tumor volume.
FIG. 5: the sizes of the transplanted tumors in each group (A: control group; B: YHL-DC 20mg/kg group; C: YHL-DC40mg/kg group; D: cis-platinum group).
2.6 the influence of each group of medicines on the quality of a nude mouse transplanted tumor body and the tumor inhibition rate are as follows:
after the administration is completed for 3 weeks, the tumor weight of each medicine is obviously lower than that of a control group, the cisplatin group is most obvious, and the tumor inhibition rates of the dehydrocavidine group are 20.18 percent, 32.34 percent and 48.25 percent respectively, 40mg/kg of the dehydrocavidine group and the cisplatin group.
2.8 HE staining morphological observation of transplanted tumor tissues of nude mice of each drug group:
the tumor tissue cells of the control group are dense, the hemorrhagic necrosis of the tumor tissue is increased along with the increase of the concentration of the dehydrocavidine group, the number of tumor cells in the tumor tissue is reduced, the cancer cells are round or oval, the ratio of nuclear plasma is disordered, the abnormal shape is obvious, pathological nuclear division can be seen, the cell size is different, and the cisplatin group is more obvious than the dehydrocavidine group and the control group (see figure 6).
FIG. 6: histomorphosis observation (HE staining) of transplanted tumor of each group of human lung cancer nude mice (400) (A (400), B (400), C (400) and D (400), wherein A is a control group, B is 20mg/kg of dehydrocavidine group, C is 40mg/kg of dehydrocavidine group, and D is 2mg/kg of cis-platinum group);
with increasing concentrations of dehydrocavidine and prolonged duration of action, the number of tumor cells in the tumor tissue decreases.
2.9 immunohistochemical staining for detecting the expression of Caspase-3 and Survivin in transplanted tumor tissues of various drug groups
The average optical density values expressed by Caspase-3 and Survivin are respectively used as the indexes for observing the apoptosis and proliferation of tumor cells in the transplanted tumor, and the immunohistochemistry is used for displaying that: the expression of Caspase-3 is increased by 20mg/kg in the dehydrocavidine group, 40mg/kg in the dehydrocavidine group and the positive control group compared with the positive control group ( * P＜0.05)，And the Survivin expression is reduced by 40mg/kg in the dehydrocavidine group and 40mg/kg in the cisplatin group compared with the control group ( * P is less than 0.05), the expression of Survivin is obviously reduced, the expression of Caspase-3 is increased and the difference has statistical significance in the cis-platinum group and the dehydrocavidine group ( * P <0.05) (see FIGS. 7 and 8).
(1) The expression conditions of Caspase-3 and survivin in different groups of nude mouse lung cancer transplantable tumors;
FIG. 7 immunohistochemical results (DAB, 400) for Caspase-3 protein (A: control group; B: YHL-DC 20mg/kg group; C: YHL-DC40mg/kg group; D: cisplatin group);
FIG. 8 immunohistochemical results (DAB, 400) for Survivin protein (A: control group; B: YHL-DC 20mg/kg group; C: YHL-DC40mg/kg group; D: cisplatin group);
with the increase of the concentration of the dehydrocavidine and the prolonging of the action time, the expression of Caspase-3 in tumor tissues is increased, and the expression of Survivin is reduced.
As a result:
1. the dehydrocavidine can block the cell cycle at the stage of G0/G1, inhibit the proliferation of the human lung adenocarcinoma A549 cells, and the optimal inhibition concentrations of the dehydrocavidine to the human lung adenocarcinoma A549 cells at 24h, 48h and 72h are respectively 0.02mg/mL, 0.002mg/mL and 0.002 mg/mL;
2. the dehydrocavidine can effectively promote the apoptosis of human lung adenocarcinoma A549 cells and has dose dependence;
3. the dehydrocavidine can inhibit the growth of transplanted tumor of lung cancer nude mice, and the tumor mass inhibition rates of the high and low dose groups are 69.00% and 45.09%, respectively. Compared with a negative control group, the antigen expression of the transplanted tumor tissues Caspase-3 and Survivin of each treatment group is obviously increased, and the high-dose group is especially obvious (P < 0.05).
And (4) conclusion: the dehydrocavidine can inhibit the proliferation of human lung cancer A549 cells, promote the apoptosis of the human lung cancer A549 cells, also has the inhibiting effect on the growth of nude mouse transplanted tumors, and the mechanism of the dehydrocavidine can be related to the reduction of Survivin expression, the up-regulation of Caspase-3 to inhibit the proliferation activity of transplanted tumor cells and the induction of cancer cell apoptosis.
3. Discussion of the related Art
In recent years, invasion and migration of tumor cells are the main biological characteristics of malignant tumors and are the main causes of death of lung cancer patients, research aiming at proliferation, apoptosis, migration and invasion of lung cancer cells has become a hotspot of lung cancer treatment, Survivin, as a new member of an apoptosis-inhibiting protein family, has tumor specificity, is only expressed in tumor and embryonic tissues and is closely related to differentiation, proliferation and infiltration and metastasis of tumor cells, and the tumor cells are mainly inhibited from apoptosis through two ways: directly inhibiting the activity of apoptosis end effector enzymes Caspase-3 and Caspase-7, and blocking various stimulation induced apoptosis processes; ② interaction between Survivin and cyclin kinases CDK4 and CDK2 blocks apoptosis signal transduction pathway. In the early stage of tumor invasion, activation of the cytoskeleton is crucial for the migration of tumor cells, with cyclin 4(Cdc42 protein) being a very representative member of the Rho family of proteins, whose primary function involves rearrangement of fibrillar actin (F-actin) in the cytoskeleton and the formation of cell-invasive pseudopodia. It has been found that the Cdc42 gene is over-expressed in EGF continuous high expression non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma, and serves as a Dbl family protein Vav1 upstream of Cdc42, and subsequently Lazer et al experimentally confirm that Vav1 can also be abnormally expressed in lung cancer cell lines or tissues, especially in lung adenocarcinoma. Meanwhile, in melanoma cells, Vav1 can up-regulate the expression of MT1-MMP through the CXCR-4/Jak/Vav/RhoGTPases pathway, thereby increasing the invasive capability of tumors. In pancreatic adenocarcinoma, Vav1 can effectively promote the formation of invasive pseudopodia and the degradation of extracellular matrix through Src/Vav1/Cdc42 signaling pathway, thereby increasing the invasion and metastasis capacity of pancreatic adenocarcinoma cells. Furthermore, Vav1 induces oncogenic transformation through a variety of other signaling pathways, including Rac1, RhoA, NF-kB, and JNK. The inventor proves that the total alkaloids of the corydalis saxicola bunting can inhibit the expression of cell division cyclin 42(Cdc42), reduce the expression of matrix metalloproteinases MMP2 and MMP9, and inhibit the migration and invasion of lung cancer cells, thereby exerting the antitumor activity.
The natural product-derived anti-tumor active ingredients bring new hopes for anti-lung cancer treatment, and can inhibit the growth, proliferation and invasion capacity of lung cancer cells through various ways such as regulating various signal paths, promoting apoptosis, enhancing autophagy, blocking cell cycle and the like. The dehydrocavidine can be used as an important quaternary alkaloid compound separated from the total alkaloids of corydalis saxicola bunting and one of main effective monomer components, and in the aspect of tumor resistance, the dehydrocavidine can inhibit the proliferation of tongue cancer Tca8113 cells, and the mechanism of the dehydrocavidine is probably related to the inhibition of protein expression of hTERT (namely an important regulation subunit for regulating the activity of telomerase), the reduction of the activity of telomerase, the inhibition of the proliferation of cells and the prevention of the growth of tumors. In order to understand the effect of the dehydrocavidine on lung cancer, the research discovers that the dehydrocavidine can obviously inhibit the proliferation of A549 cells through the detection result of an in vitro CCK8 method, and also discovers that the dehydrocavidine can induce the A549 cells to apoptosis through the detection result of flow cytometry, and finally observes the expression of Caspase-3 and Survivin in nude mouse A549 transplantation tumor tissues under the action of the dehydrocavidine through in vivo experimental immunohistochemistry, so that the dehydrocavidine can inhibit the proliferation of the A549 cells and induce the apoptosis of the A549 cells by activating the apoptotic protein Caspase-3 and reducing the expression of the anti-apoptotic protein Survivin, and an important scientific basis is provided for clarifying the treatment of the lung cancer by the dehydrocavidine.
The above description is for the purpose of illustrating the preferred embodiments of the present invention, but the present invention is not limited thereto, and all changes and modifications that can be made within the spirit of the present invention should be included in the scope of the present invention.
Claims (3)
1. The application of dehydrocavidine in preparing the pharmaceutical composition for treating the lung adenocarcinoma is characterized in that: the pharmaceutical composition is a clinically acceptable pharmaceutical preparation prepared by taking dehydrocavidine as a main component and adding pharmaceutically acceptable auxiliary materials or auxiliary components, wherein the content of the dehydrocavidine in the pharmaceutical composition is usually 0.01-95% w/w.
2. Use of dehydrocavidine according to claim 1 for the preparation of a pharmaceutical composition for the treatment of human lung adenocarcinoma, characterized in that: the pharmaceutical preparation comprises two dosage forms of an oral preparation and an injection preparation.
3. Use of dehydrocavidine according to claim 2 for the preparation of a pharmaceutical composition for the treatment of human lung adenocarcinoma, characterized in that: the oral preparation is an oral capsule, and the injection preparation is intravenous injection.
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