CN111281872B - Afatinib-containing pharmaceutical composition and application thereof - Google Patents
Afatinib-containing pharmaceutical composition and application thereof Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition containing afatinib and application thereof, in particular to combination of afatinib, quercetin and luteolin and application of the composition in treating lung cancer. Based on the thought of the combined action of the traditional Chinese medicine and the western medicine, the inventor finds out the traditional Chinese medicine monomer quercetin and luteolin combined with afatinib and the synergistic interval when the two are combined, and provides a new technical scheme for clinically treating lung cancer.
Description
Technical Field
The application belongs to the field of medicines, and particularly relates to a pharmaceutical composition containing afatinib and application thereof.
Background
Lung cancer accounts for approximately 27% of the total cancer-related deaths worldwide, leading to the leading cause of cancer-related deaths. Over 180 million newly diagnosed cases per year, of which over 85% are non-small cell lung cancers. Most of solid tumors have high expression of EGFR, and it is widely believed that dysregulation of EGFR expression is closely related to tumor cell proliferation, angiogenesis, tumor metastasis and the like.
Afatinib (Afatinib) is a second-generation Tyrosine Kinase Inhibitor (TKI) that acts extensively on the ErbB family, binds irreversibly to EGFR, HER2, and HER4, and acts by inhibiting their enzymatic activities. Although afatinib blocks cancer cell growth more comprehensively and durably, it is inevitable to generate drug resistance, and together with a heavy economic burden, how to develop a more cost-effective treatment mode is one of the problems that needs to be solved urgently by current medical research.
The combined treatment of tumors by Chinese and western medicines is one of the current research hotspots, the combined use of the Chinese patent medicine and the western medicine with the same or similar pharmacological effects can possibly play a role in synergy, the dosage of the western medicine is reduced, the treatment period is shortened, but certain risks exist, such as reduction of the curative effect, when the plum blossom glossogyne and the like are used in combination with the acid medicines such as vitamin C, aspirin and the like, the saponin active ingredients in the plum blossom glossogyne can be decomposed, so that the curative effect is reduced; the astragaloside IV in the Jinfukang oral liquid can obviously inhibit the activity of CYP3A4 and CYP2C9 and the like, so that the specific combination needs experimental verification and condition groping, thereby promoting the rationality of the combined use of Chinese and western medicines.
In the existing research, afatinib combined with diuretic acid is reported to treat lung cancer, and the afatinib combined with diuretic acid has an inhibiting effect on the cell growth of A549 and H1975, but the reports on the lung cancer treated by combining afatinib and traditional Chinese medicines are few. Based on the thought of the combined action of the Chinese medicine and the western medicine, the application finds out the traditional Chinese medicine monomers of quercetin (quercetin) and luteolin (luteolin) combined with afatinib and the synergistic interval of the two when the two are combined, and provides a foundation for the clinical combined medication of the quercetin, the luteolin and the afatinib.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition for treating cancer, which consists of afatinib and traditional Chinese medicine monomers, wherein the traditional Chinese medicine monomers are quercetin and luteolin.
Further, the concentration ratio of quercetin to afatinib is 100-6.25: 0.315 to 5; the concentration ratio of luteolin to afatinib is 25-3.125: 0.315-5.
Preferably, the ratio of quercetin concentration to afatinib is 100-6.25: 0.625-2.5; the concentration ratio of luteolin to afatinib is 25-3.125: 0.625-2.5.
Preferably, the concentration ratio of quercetin to afatinib is 100-6.25: 1.5; the concentration ratio of luteolin to afatinib is 25-3.125: 1.5.
more preferably, when the medicine is used together, the concentration of afatinib is 1.5uM and the concentration of quercetin is 12.5-25 uM; when the medicine is used together, the concentration of afatinib is 1.5uM and the concentration of luteolin is 3.125-12.5 uM.
The invention aims to provide application of the pharmaceutical composition in preparing antitumor drugs.
Further, the tumor is lung cancer.
Further, the application of the pharmaceutical composition in preparing anti-tumor cell proliferation medicines.
Further, the application of the pharmaceutical composition in preparing a medicine for resisting tumor cell migration.
The invention has the advantages that:
the drug combination of afatinib, quercetin and luteolin can obviously improve the drug effect of the drug in the aspects of proliferation and migration of antitumor cells within a certain matching range, generate a synergistic effect, effectively reduce the drug cost and improve the clinical treatment effect, in particular to the combination of afatinib and luteolin.
Drawings
FIG. 1 is a graph showing the measurement of IC50 values of quercetin;
FIG. 2 is a graph showing the determination of the IC50 value of luteolin;
FIG. 3 is a graph of the migration of cells in the control group when the drug alone was administered, the left graph was photographed at 0h, and the right graph was photographed at 24 h;
FIG. 4 is a graph showing the migration of cells when quercetin was administered alone, the upper left graph was photographed at 0h after the administration of drugs at a concentration of 12.5uM, the upper right graph was photographed at 24h after the administration of drugs at a concentration of 12.5uM, the lower left graph was photographed at 0h after the administration of drugs at a concentration of 50uM, and the lower right graph was photographed at 24h after the administration of drugs at a concentration of 50 uM;
FIG. 5 is a graph showing migration of cells when luteolin is administered alone, wherein the upper left graph is photographed at 0h at a concentration of 6.25uM, the upper right graph is photographed at 24h after the administration at a concentration of 6.25uM, the lower left graph is photographed at 0h at a concentration of 25uM, and the lower right graph is photographed at 24h after the administration at a concentration of 25 uM;
FIG. 6 is a graph of cell migration of Afatinib alone, the left graph is photographed at 0h at 6.25uM, and the right graph is photographed at 24h after dosing at 6.25 uM;
FIG. 7 is a graph showing the cell migration when quercetin and afatinib are administered in combination, the upper left graph is photographed at 0h when the concentration of quercetin is 12.5uM + the concentration of afatinib is 1.5uM, the upper right graph is photographed at 24h after the administration when the concentration of quercetin is 12.5uM + the concentration of afatinib is 1.5uM, the lower left graph is photographed at 0h when the concentration of quercetin is 50uM + the concentration of afatinib is 1.5uM, and the lower right graph is photographed at 24h after the administration when the concentration of quercetin is 50uM + the concentration of afatinib is 1.5 uM;
FIG. 8 is a graph showing the cell migration in the case of the combination of luteolin and afatinib, wherein the upper left is photographed at 0h when the concentration of luteolin is 6.25uM and the concentration of afatinib is 1.5uM, the upper right is photographed at 24h after the drug is added when the concentration of luteolin is 6.25uM and the concentration of afatinib is 1.5uM, the lower left is photographed at 0h when the concentration of luteolin is 25uM and the concentration of afatinib is 1.5uM, and the lower right is photographed at 24h after the drug is added when the concentration of luteolin is 25uM and the concentration of afatinib is 1.5 uM.
Detailed Description
The present invention is further illustrated below with reference to specific examples, which are intended to be illustrative only and are not to be construed as limiting the invention. Those of ordinary skill in the art will understand that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents. The following examples are examples of experimental methods not indicating specific conditions, and the detection is usually carried out according to conventional conditions or according to the conditions recommended by the manufacturers.
Example 1
1. Experiment main reagent
2. Experiment main instrument
| Name of instrument | Instrument type | Manufacturer of the product |
| Cell culture box | STERI-CYCLE | Thermo |
| Desk type low-speed centrifuge | TDZ4A-WS | Hunan instrument |
| Inverted biological microscope | BM-37XB | Shanghai Pieim optical instruments manufacturing Ltd |
| Electric heating constant temperature water bath | HI1220 | Leica |
| Sterilizing filter (0.22uM) | SLGV033RB | Millex-HV |
| Disposable aseptic syringe (10ml) | 202004 | Shanghai Zhiyu medical instruments Ltd |
| Enzyme linked immunosorbent assay (ELISA) detector | SpectraMax M5 | Molecular Devices |
3. Experimental methods
3.1 cell culture and grouping
(1) Cell culture: human lung cancer cells (A549) were cultured in a medium containing 10% FBS, 100units/ml penicillin, 100ug/ml streptomycin, and 89% 1640 at 37 deg.C under 5% CO2 and saturated humidity. And replacing the culture medium and carrying out passage at proper time.
(2) Grouping cells:
a549-blank cell-free Medium
A549-control Normal culture cell
A549- -1 Quercetin treatment group (different concentration gradients)
A549- -2 luteolin (luteolin) treatment group (different concentration gradients)
A549-3 Afatinib (Afatinib) treatment group
A549- -5 Quercetin (quercetin) + Afatinib (Afatinib) treatment groups (different concentration gradients)
A549- -6 luteolin (luteolin) + Afatinib (Afatinib) treatment groups (different concentration gradients)
3.2MTT assay
(1) MTT solution (250mg of MTT dissolved in 50ml of PBS solution, 0.22 μm microporous membrane filtration, 4 ℃ photoprotection storage).
(2) Adding human lung cancer cells into culture solution PRIM-1640 (containing 10% newborn calf serum and 1% double antibody), culturing in a 5% CO2 incubator at 37 deg.C, changing the culture solution 1 time every other day, and digesting with 0.25% pancreatin-EDTA, subculturing and freezing.
(3) Taking cells in logarithmic growth phase, adjusting cell suspension concentration, adding into 96-well culture plate, and adding 100 μ l cell suspension (containing 1 × 10 cells per well)4Individual cell) for 24h
(4) After the cells adhere to the wall, adding drug culture media with different components for treatment, and setting blank zero-adjusting groups (only adding culture solution), cell control groups (cell suspension without drug treatment) and drug treatment groups (5 concentration levels are set for the drug concentration of each group) in experiments, wherein Afatinib (Afatinib) is 0.3125, 0.625, 1.25, 2.5, 5, 10 and 20 uM; quercetin (quercetin)3.125, 6.25, 12.5, 25, 50, 100, 200 uM; luteolin (luteolin)1.5625, 3.125, 6.25, 12.5, 25, 50, 100uM, each group is provided with 3 multiple holes, and different drugs act for 24 h.
(5) The drug-containing medium was aspirated, and after changing the drug-free letter box medium, 20. mu.L of MTT solution (5mg/mL) was added to each well, incubated for 4 hours, centrifuged, and the supernatant was discarded.
(6) Add DMSO 150. mu.L per well and shake for 10 min. The enzyme linked immunosorbent assay (ELISA) detects the absorbance (OD) value of each hole with the wavelength of 570 nm.
3.3 measurement of IC50 value and determination of Effect of combination
(1) Calculation of median inhibitory concentration (IC50) values: half maximal inhibitory concentration (IC50) values were calculated using GraphPad Prism7 software based on the effect of different concentrations of drug on cells.
(2) After the termination of the culture, the cells were collected, and the activity of each group of cells was measured by the MTT method to calculate the inhibition ratio (inhibition ratio ═ control group OD value-administration group OD value)/control group OD value × 100%).
(3) And (3) judging the effect of the double-medicine combination:
the calculation method for judging the effect of the combined medication comprises the following steps: and judging by adopting a gold positive mean q value method. The q value is obtained by the following formula: q ═ PA+B/(PA+PB-PA×PB). In the formula PA、PBAnd PA+BRespectively the treatment rates of the A medicine group, the B medicine group and the combination of the two medicines. q is less than 1, which indicates that the two medicines generate antagonism after being used together; q is more than 1, which indicates that the two drugs produce synergistic effect after being combined together, and q is 1, which indicates that the two drugs produce additive effect after being combined together.
3.4 cell scratch test
Adjusting the cell density to 1X 105And (3) inoculating the cells/ml in a 6-well plate, after the cells adhere to the wall, absorbing the culture medium, washing with PBS, drawing a straight line in the center of each well of the culture plate along the direction of a longitudinal axis by using a 200-mu-l gun head, washing with PBS, adding the normal culture medium and the culture medium containing the medicine respectively, continuing to culture, and taking pictures under an inverted microscope when the time is 0 hour and 24 hours respectively. Image J software measures groups of cellsMigration distance.
4. Results of the experiment
4.1 determination of IC50 values
The results show that the mean inhibition rates of quercetin of 3.125, 6.25, 12.5, 25, 50, 100, 200uM are 2.97%, 6.63%, 15.63%, 39.90%, 67.22, 78.29%, and 83.80%, respectively, and the median inhibitory concentration (IC50) value is 27.06 (see fig. 1 in particular) calculated using GraphPad Prism7 software; luteolin 1.5625, 3.125, 6.25, 12.5, 25, 50, 100uM mean inhibition rates of 7.30%, 11.70%, 21.50%, 45.23%, 65.96%, 77.61% and 87.50%, respectively, and GraphPad Prism7 software was used to calculate the half maximal inhibitory concentration (IC50) value of 13.80 (see FIG. 2 in particular); similarly, the value of the half inhibitory concentration (IC50) of afatinib was found to be 2.81.
4.2 Effect of combination
The combined effect of the quercetin, the luteolin and the afatinib is as follows:
| grouping | Inhibition rate | Q value |
| Quercetin (100uM) | 0.7830 | - |
| Quercetin (50uM) | 0.6722 | - |
| Quercetin (25uM) | 0.3990 | - |
| Quercetin (12.5uM) | 0.1563 | - |
| Quercetin (6.25uM) | 0.0664 | - |
| Afatinib (1.5uM) | 0.2453 | - |
| Quercetin (100uM) + Afatinib (1.5uM) | 0.8611 | 1.029793459 |
| Quercetin (50uM) + Afatinib (1.5uM) | 0.7722 | 1.026000472 |
| Quercetin (25uM) + Afatinib (1.5uM) | 0.8418 | 1.540447669 |
| Quercetin (12.5uM) + Afatinib (1.5uM) | 0.4403 | 1.212170462 |
| Quercetin (6.25uM) + Afatinib (1.5uM) | 0.2725 | 0.92239267 |
| Luteolin (50uM) | 0.7761 | - |
| Luteolin (25uM) | 0.6596 | - |
| Luteolin (12.5uM) | 0.4523 | - |
| Luteolin (6.25uM) | 0.2151 | - |
| Luteolin (3.125uM) | 0.1170 | - |
| Luteolin (50uM) + Afatinib (1.5uM) | 0.8201 | 0.986833329 |
| Luteolin (25uM) + Afatinib (1.5uM) | 0.7700 | 1.036130877 |
| Luteolin (12.5uM) + Afatinib (1.5uM) | 0.8596 | 1.465271748 |
| Luteolin (6.25uM) + Afatinib (1.5uM) | 0.5794 | 1.421359565 |
| Luteolin (3.125uM) + Afatinib (1.5uM) | 0.4647 | 1.393084094 |
From the results, it can be seen that quercetin and afatinib show synergistic inhibitory effects on lung cancer cells within a certain proportion interval; luteolin and afatinib show synergistic inhibition effect on lung cancer cells within a certain proportion interval.
4.3 scratch test results
The cell scratch test is mainly used for verifying the cell migration capacity in tumor research. The migration ability of the cells was judged by judging the distance between the control group and the test group. Lower rates of healing indicate greater effect of the drug on the ability of the tumor cells to migrate. In this experiment, first, when the control group, quercetin (12.5uM), quercetin (50uM), luteolin (25uM), luteolin (6.25uM) and afatinib (1.5uM) were measured, the healing rates of the control group (see fig. 3 in particular), quercetin (12.5uM) and quercetin (50uM) were 70.8% and 68.6% respectively (see fig. 4), luteolin (25uM) and luteolin (6.25uM) were 56.9% and 72.2% respectively (see fig. 5), and afatinib (1.5uM) was 70.8% respectively (see fig. 6). Further selecting 2 combinations to perform a scratch test according to the inhibition rate result of the combined medicine, and calculating the healing rate, wherein the healing rate is 62.4% in the combined medicine group of quercetin (12.5uM) and afatinib (1.5 uM); in the combined drug group of quercetin (50uM) and afatinib (1.5uM), the healing rate was 57.5% (see fig. 7 in particular); in the combined medicine group of luteolin (6.25uM) and afatinib (1.5uM), the healing rate is 64.2%; in the combination of luteolin (25uM) and afatinib (1.5uM), the healing rate was 25.8% (see fig. 8 in particular).
Claims (5)
1. A pharmaceutical composition for treating lung cancer, which consists of afatinib and traditional Chinese medicine monomers, is characterized in that the traditional Chinese medicine monomers are luteolin, and the molar concentration ratio of the luteolin to the afatinib is 25-3.125: 1.5.
2. the pharmaceutical composition according to claim 1, wherein afatinib is present at a concentration of 1.5uM and luteolin is present at a concentration of 3.125-12.5 uM.
3. Use of a pharmaceutical composition according to any one of claims 1-2 for the manufacture of a medicament for the treatment of lung cancer.
4. The use of claim 3, wherein the pharmaceutical composition is for use in the preparation of an anti-lung cancer cell proliferation medicament.
5. The use of claim 3, wherein the pharmaceutical composition is for use in the preparation of a medicament for resisting lung cancer cell migration.
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Non-Patent Citations (4)
| Title |
|---|
| Afatinib-based combination regimens for the treatment of solid tumors: rationale, emerging strategies and recent progress;Jaafar Bennouna等;《Future Oncology》;20151125;第12卷(第3期);第355-372页，特别是第357页右栏第4段-358页左栏第2段 * |
| First-Line Afatinib versus Gefitinib in EGFRm+ Advanced NSCLC: Updated Overall Survival Analysis of LUX-Lung 7;Keunchil Park等;《Journal of Thoracic Oncology》;20170131;第12卷(第1S期);第335-336页，特别是参见第336页右栏第2段 * |
| 中药改善EGFR-TKIs治疗进展期非小细胞肺癌产生获得性耐药的机制研究进展;伍晓慧等;《中医药导报》;20171231;第23卷(第24期);第34-36页，特别是第35页第2节 * |
| 吉非替尼联合槲皮素对非小细胞肺癌PC9/GR细胞的协同抗肿瘤作用;王静;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20190115(第12期);E072-144页，特别是摘要、第7页第3段、第25页结论部分 * |
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