CN114917231A - Application of beta-elemene and oxitinib medicine composition in preparing anti-lung cancer medicine - Google Patents
Application of beta-elemene and oxitinib medicine composition in preparing anti-lung cancer medicine Download PDFInfo
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- A61K31/01—Hydrocarbons
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses an effect of inhibiting IGF1R/vimentin/EMT process in preparing an antitumor drug combination. In the medicine combination for inhibiting IGF1R/vimentin/EMT, one medicine can be combined with IGF1R to inhibit the activity of the medicine, and the medicine combination can be combined with another medicine to synergistically inhibit the activity of the vimentin, so that the EMT is inhibited, and the synergistic anti-tumor effect is achieved. Vimentin is a key intermediate regulatory point for the inhibition of EMT by IGF 1R. When the IGF 1R-targeted drugs are selected for combined drugs, the EMT inhibition induced by the vismentin reduction can be used as a new effect target way for screening the combined drugs.
Description
Technical Field
The invention relates to the technical field of medicines, and relates to application of a beta-elemene and oxitinib medicine composition in preparation of an anti-lung cancer medicine.
Background
Lung cancer is currently the leading cause of cancer death, accounting for nearly 20% of all cancer deaths. The morbidity and mortality of lung cancer in China are higher than those in Western countries. It is expected that by 2030, lung cancer mortality in china may increase by about 40%. Targeted drug epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become a milestone in the treatment of lung cancer. However, more than half of patients are resistant to the first and second generation EGFR-TKIs due to the mutation at the T790M site in EGFR. The newly developed third-generation EGFR-TKI oxitinib can effectively solve the drug resistance generated by mutation of the T790M site, remarkably prolong the progression-free survival time, and is taken as a first-line treatment drug for EGFR mutation positive non-small cell lung cancer. However, like other EGFR-TKI, resistance is inevitably generated due to a new mutation point of EGFR and an increase in the level of a resistance signal pathway. This suggests that targeting EGFR alone would not result in long-term benefit, and there may be other signaling pathways that attenuate the effects of oxitinib and render it resistant. Therefore, reversing the drug resistance of oxitinib by combining other antitumor pathways is an effective strategy for clinical treatment of lung cancer. The traditional Chinese medicine has the advantages of multiple aspects, small toxicity and the like in the aspect of drug resistance, and the unique effect of the traditional Chinese medicine in the comprehensive treatment of the lung cancer is highlighted day by day.
Promoting blood circulation by removing blood stasis is an important principle of the traditional Chinese medicine for treating lung cancer by differentiation of syndromes, and is widely applied to clinic. The traditional Chinese medicine Wen Yu jin for promoting blood circulation and removing blood stasis has high use frequency for treating lung cancer, has bitter and pungent taste and warm nature, enters lung, liver and heart channels, has the efficacies of eliminating mass, dispersing pathogenic accumulation, breaking blood and relieving pain, and is indicated as 'capable of opening the stagnation of lung and golden spirit' in the herbal medicine from Xin. Elemene extracted from Curcuma wenyujin has been successfully developed and used for treating various lung cancers. The function and mechanism of the beta-elemi synergistic with the oxitinib for resisting the lung cancer are not reported. The drug combination has better synergistic anti-lung cancer effect and provides an effective clinical treatment strategy for antagonizing the generation of the drug resistance of the oxitinib.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the application of a beta-elemene and oxitinib medicine composition in preparing an anti-lung cancer medicine, the composition inhibits vimentin through IGF1R so as to inhibit the EMT process, thereby enhancing the anti-tumor curative effect, reducing the using amount of oxitinib, reducing the drug resistance of oxitinib and reducing the tumor metastasis probability.
Preferably, the tumor is lung cancer, more preferably non-small cell lung cancer.
The second purpose of the invention is to provide a pharmaceutical composition, which comprises beta-elemene and oxitinib.
Preferably, the dosage ratio of the beta-elemene to the oxitinib is 100 mu g/ml: 0.2-80 nM; preferably 100. mu.g/ml: 20 nM.
Preferably, the composition also comprises pharmaceutically acceptable auxiliary materials or auxiliary components.
Preferably, the dosage form of the pharmaceutical composition is any one of the medically approved dosage forms.
More preferably, the dosage form of the pharmaceutical composition is tablets, oral liquid, granules, spray, injection, powder or capsules.
The reduction in vimentin is a key downstream event in the inhibition of IGF1R by the combination of β -elemene and ocitinib, inhibiting EMT through the reduction in vimentin.
When the beta-elemene and the target drug for treating lung cancer are used together as the drug for preventing and treating non-small cell lung cancer, the synergistic effect can be achieved, and the generation of drug resistance of the oxitinib can be reduced.
The combination of beta-elemene and oxitinib can reduce the migration of lung cancer cells and inhibit the EMT process.
The reduction of lung cancer cell migration and the inhibition of EMT caused by the combination of β -elemene and oxitinib can be reversed by the overexpression of IGF 1R. The combination of beta-elemene and oxitinib can reduce the expression of EMT protein vimentin, P-GSK3b (ser9), and can be reversed by the overexpression of IGF 1R.
The inventor finds that the beta-elemi and the oxitinib have stronger synergistic anti-lung cancer effect when used together, and the beta-elemi of 100 mu g/ml and the oxitinib of 0.2nM, 1nM, 5nM, 20nM and 80nM have good synergistic anti-lung cancer effect. The maximum synergistic effect combination is beta-elemene 100 mu g/ml and oxitinib 20nM, and the combination can obviously increase the apoptosis of lung cancer cells and the expression of apoptosis protein. Therefore, the beta-elemene and the oxitinib can be used together for preparing the anti-lung cancer (especially non-small cell lung cancer) medicament.
In addition, the invention also provides application of the pharmaceutical composition in preparing a drug for resisting the induction of the oxitinib resistance of the IGF1R pathway. Activation of the IGF1R pathway and transformation of epithelial cells into mesenchymal cells (EMT) are important factors in development of drug resistance by ocitinib. The beta-elemene has binding effect with IGF1R protein, and can inhibit IGF 1R. And can also synergistically enhance the inhibition effect on the lung cancer cell EMT and migration. And the inhibition effect of the process can be reversed by the overexpression of IGF1R, which indicates that the inhibition on IGF1R is the key point for inhibiting EMT and migration by combining two medicines. Therefore, the drug beta-elemene based on inhibiting IGF1R mediated EMT combined with oxitinib can be used for resisting the oxitinib drug resistance induced by IGF 1R. Meanwhile, the combination of the beta-elemene and the oxitinib can reduce the expression of the protein vitamin for promoting EMT, and the process can be reversed by IGF1R, which shows that the combination of the beta-elemene and the oxitinib inhibits the vitamin through IGF1R to inhibit the EMT process. Vimentin has not been reported as a direct downstream intervention in EMT for IGF 1R. This result provides a new downstream event regulated after targeting IGF1R drugs, namely reduction of vimentin, and provides a new target approach for development of anti-lung cancer drugs based on IGF1R regulation.
Drawings
FIG. 1 is a graph showing the results of the combination of beta-elemene and oxitinib of example 1 for enhancing the anti-tumor effect; wherein A is an inhibition rate curve of the combination of beta-elemene with high concentration (100 mug/ml) and low concentration (50 mug/ml) and different concentrations of ocitinib on non-small cell lung cancer, labels 1-5 are respectively the combination of low dose elemene with oxitinib 0.2nM, 1nM, 5nM, 20nM and 80nM, and labels 6-10 are respectively the combination of high dose elemene with oxitinib 0.2nM, 1nM, 5nM, 20nM and 80 nM; b is the synergy index of different drug combinations; c is the survival rate of the drug combination (100 mu g/ml elemene is combined with 20nM of ocitinib) with the optimal synergistic index and the single drug after acting on the non-small cell lung cancer; d is the microscopic picture of the drug combination (100 mug/ml elemene combined with 20nM of ocitinib) with the optimal synergistic index and the single drug after the action on the non-small cell lung cancer.
FIG. 2 is a graph showing the binding effect of beta-elemi of example 2 to IGF1R and the inhibition of its expression; wherein, the graph A is a Biacore sensing graph of the combination of beta-elemi and IGF1R protein, and the graph B is an affinity graph of the combination of the beta-elemi and IGF1R protein;
FIG. 3 is a graph of the results of using beta-elemene in combination with oxitinib of example 3 to further increase apoptosis in lung cancer cells; the graph A is a flow type apoptosis graph of the combination of beta-elemene and oxitinib for non-small cell lung cancer, the graph B is the apoptosis rate of the graph A, the graph C is a western blot graph of the change of apoptosis protein after the combination of the beta-elemene and oxitinib for non-small cell lung cancer, and the graph D is a semi-quantitative result of the graph C.
FIG. 4 is a schematic representation of the EMT inhibition of beta-elemene in example 4 in combination with oxitinib;
FIG. 5 is a graph showing the results of using beta-elemene and oxitinib of example 5 to further reduce the migration ability of lung cancer cells;
FIG. 6 is a graph showing the results of IGF1R of example 6 reversing the inhibition of lung cancer cell migration by the combination of beta-elemene and ocitinib;
FIG. 7 is a graph showing the results of example 7 IGF1R reversing the inhibition of lung cancer cell EMT by the combination of beta-elemene and ocitinib;
in FIGS. 1-7, ELE is beta-elemi and Osimertinib (OSI) is oxitinib.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1: the combined use of beta-elemene and oxitinib can enhance the anti-tumor effect
1. Cell culture
Culturing human non-small cell lung adenocarcinoma cell NCI-H1975 in 1640 culture medium containing 10% fetal calf serum, penicillin 100U/ml, gentamicin 100ug/ml, at 37 deg.C and 5% CO 2 。
2. Cytotoxicity assays
NCI-H1975 cells were plated in 96-well plates at a cell density of about 3X 10 per well 3 And (3) after 24 hours of cell adherence, giving beta-elemene and oxitinib with different concentrations, adding MTT for staining after 48 hours, abandoning the original culture solution after staining for 4 hours, adding DMSO for dissolving, putting into an enzyme-labeling instrument, and measuring absorbance by using a detection wavelength of 570 nm.
By analyzing the pharmacodynamic dose curve of beta-elemene and ocitinib acting on NCI-H1975 cells by computer simulation software, elemene with drug concentration of 50 and 100 mu g/ml is respectively selected to be used in combination with oxitinib of 0.2nM, 1nM, 5nM, 20nM and 80nM, and the effect of each pair of drug combination on oxitinib sensitization is observed. The elemene 100 mug/ml and the oxitinib 20nM have the strongest synergistic effect (figure 1A, C) through the cell proliferation experiment, and the synergistic index is less than 0.4 (figure 1B). Observed under a microscope, the combination of 100 mu g/ml elemene and 20nM of oxitinib can obviously increase the growth inhibition effect of oxitinib on drug-resistant cells (figure 1D).
Example 2: beta-elemi has binding effect with IGF1R, and its expression is inhibited
By searching elemene target protein by using surface plasmon resonance, the elemene is found to have a binding effect on IGF1R, and as the concentration of the elemene is increased, the binding signal is gradually increased, and the dose dependency is shown. While the protein expression of IGF1R did not change significantly after elemene administration to NCIH197548h, the phosphorylation level of IGF1R decreased significantly, suggesting that elemene has a regulatory effect on the activity of IGF1R (fig. 2).
Example 3: beta-elemene and oxitinib are used together to further increase lung cancer cell apoptosis
After the NCI-H1975 cell plates are attached, the medicinal combination with the best synergistic effect is selected for administration (beta-elemi 100 mu g/ml + Oxitinib 20 nM). After 48 hours of dosing, the medium was discarded, washed twice with PBS, cells were collected by digestion, resuspended in a binding buffer, then stained with PI and Annexin V, and detected by flow cytometry at excitation wavelengths of 561nm and 488nm (fig. 3A and 3B). The apoptosis-related protein is detected by using the same drug combination concentration. After administration, cells were collected together with the supernatant, added with cell lysate, shaken for 15min, centrifuged at 12000rcf for 10min, and the pellet was discarded. Protein concentration was determined by Coomassie Brilliant blue method and then denatured after dilution to the same concentration. The western blot method was used to determine the apoptosis-related proteins clear PARP, clear-caspase 7 (FIGS. 3C and 3D). When the elemene and the oxitinib are used together, the induced apoptosis rate is obviously increased compared with that of the single use (figure 2A, B), and the apoptosis marker proteins cl-PARP and cl-C7 are also obviously increased (figure 2C, D).
Example 4: combination of beta-elemene and oxitinib for inhibiting EMT
After the NCI-H1975 cell plates were attached, beta-elemene (100. mu.g/ml) and oxitinib (20nM) were given. And (3) collecting cell lysis denaturation, and determining EMT key regulatory protein by using a western blot method. The results show that the epithelial cell marker E-cadherin is obviously increased after combined use, the mesenchymal cell marker N-cadherin is obviously reduced, and the EMT positive regulatory protein vimentin is also obviously reduced (figure 4), and the results show that the beta-elemene and the oxitinib have certain inhibiting effect on the EMT process of the lung cancer cells after combined use.
Example 5: the combination of beta-elemene and oxitinib further reduces the migration capacity of lung cancer cells
EMT is an important positive regulatory factor for cell migration. The inhibition of EMT by elemene in combination with oxitinib may inhibit lung cancer cell migration. This effect was observed using cell migration experiments. NCI-H1975 cells were seeded in transwell chambers, beta-elemene (100. mu.g/ml) and oxitinib (20nM) and the culture medium was changed before dosing. After adding the drug for 48 hours, the culture solution in the upper chamber is sucked out and discarded, and after the membrane is air-dried, the membrane is dyed by 0.1 percent crystal violet and observed and counted under a microscope. The results show that the migration inhibition ability of the lung cancer cells is weak when the elemene is 100 mu g/ml and the oxitinib is singly administered at 20 nM. However, elemene combined with oxitinib almost completely inhibited cell migration, with a significantly greater inhibitory potency than the single use group (fig. 5).
Example 6: IGF1R reverses inhibition of lung cancer cell migration by beta-elemene and combined use with oxitinib
NCI-H1975 cells were seeded in a transwell chamber, transfected with the empty plasmid M35 and IGF1R, respectively, followed by β -elemene (100 μ g/ml) and oxitinib (20 nM). After adding the drug for 48 hours, the culture solution in the upper chamber is sucked out and discarded, and after the membrane is air-dried, the membrane is stained with 0.1 percent crystal violet and observed and counted under a microscope. The results show that the combination of beta-elemene and ocitinib can significantly reduce the cell migration capacity after transfection of the unloaded plasmid M35. In cells transfected with IGF1R, the number of cells migrated was significantly increased compared to M35 transfected cells after administration of the combination of β -elemene and oxitinib. The results show that IGF1R can remarkably reverse the inhibition of lung cancer cell migration by the beta-elemene and the oxitinib combined drug after being shown in the table, and IGF1R plays a key regulation role in the process (figure 6).
Example 7: after the IGF1R reversed the inhibition of beta-elemene combined with oxitinib on lung cancer cell EMT key regulatory protein NCI-H1975 cell plates to adhere to the cell plates, the cells were transfected with unloaded plasmid M35 and IGF1R, respectively, and then beta-elemene (100. mu.g/ml) and oxitinib (20nM) were administered. After cell lysis and denaturation, changes of EMT key regulatory protein vimentin and P-GSK3b (ser9) are measured by a western blot method. The results show that in cells transfected with M35, β -elemene in combination with oxitinib reduced the expression of the EMT-promoting protein vimentin and P-GSK3b (ser 9). The reduction in the above protein was reversed after overexpression of IGF 1R. This result demonstrates that IGF1R has an upstream regulatory effect on beta-elemene and oxitinib-induced reductions in EMT vitamins and P-GSK3b (ser 9).
Example 8
Mixing beta-elemi and oxitinib in a ratio (mass ratio is 100: 1), emulsifying by using soybean lecithin and cholesterol, and preparing into oral emulsion.
Example 9
Dissolving and mixing beta-elemene and oxitinib in a ratio (mass ratio is 100: 1) with soybean lecithin, cholesterol and DSPE-mPEG, and preparing the beta-elemene and oxitinib liposome double-drug-loading injection by adopting a film hydration method for resisting non-small cell lung cancer.
Example 10
The preparation method comprises the steps of adopting L-a-phosphatidylcholine as a liposome membrane material, loading beta-elemene and oxitinib into a liposome according to a ratio (mass ratio is 100: 1), filling the liposome into an aluminum hall bottle, pressing a cover, filling a certain amount of dichlorodifluoromethane through covering a valve body, and preparing the spray as a medicine for preventing and treating non-small cell lung cancer.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is specific and detailed, but not to be understood as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent should be subject to the appended claims.
Claims (10)
1. A pharmaceutical composition characterized by comprising beta-elemene and oxitinib.
2. The pharmaceutical composition as claimed in claim 1, wherein the β -elemene and oxitinib are present in a ratio of 100 μ g/ml: 0.2-80 nM.
3. A pharmaceutical composition as claimed in claim 2, wherein the ratio of β -elemene to oxitinib is 100 μ g/ml: 20 nM.
4. A pharmaceutical composition according to any one of claims 1 to 3, further comprising pharmaceutically acceptable excipients or auxiliary ingredients.
5. A pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is in any one of the pharmaceutically acceptable dosage forms.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is in the form of tablet, oral liquid, granule, spray, injection, powder for injection, powder or capsule.
7. Use of a pharmaceutical composition according to any one of claims 1 to 6 for the preparation of an anti-tumor medicament.
8. Use according to claim 7, characterized in that said tumor is lung cancer.
9. The use according to claim 8, wherein said tumor is non-small cell lung cancer.
10. The use as claimed in any one of claims 7 to 9, wherein the combination of β -elemene and ocitinib inhibits the reduction of a vimentin, a critical downstream event of IGF1R, and by the reduction of vimentin inhibits EMT.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210593323.0A CN114917231A (en) | 2022-05-27 | 2022-05-27 | Application of beta-elemene and oxitinib medicine composition in preparing anti-lung cancer medicine |
| PCT/CN2023/096562 WO2023227112A1 (en) | 2022-05-27 | 2023-05-26 | USE OF PHARMACEUTICAL COMBINATION OF β-ELEMENE AND OSIMERTINIB IN PREPARATION OF ANTI-LUNG CANCER MEDICAMENT |
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| WO2023227112A1 (en) * | 2022-05-27 | 2023-11-30 | 杭州师范大学 | USE OF PHARMACEUTICAL COMBINATION OF β-ELEMENE AND OSIMERTINIB IN PREPARATION OF ANTI-LUNG CANCER MEDICAMENT |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20200368231A1 (en) * | 2018-02-12 | 2020-11-26 | Astrazeneca Ab | Osimertinib for use in the treatment of non-small cell lung cancer |
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| FR3065878A1 (en) * | 2017-05-08 | 2018-11-09 | Guy Faustin Monkam Nitcheu | PHARMACEUTICAL COMPOSITION, CHARACTERIZED IN THAT IT INCLUDES, AS ACTIVE INGREDIENT, A COMBINATION OF BETA-ELEMENE, LUPEOL, ACEMANNANE AND AN AGENT |
| CN114917231A (en) * | 2022-05-27 | 2022-08-19 | 杭州师范大学 | Application of beta-elemene and oxitinib medicine composition in preparing anti-lung cancer medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20200368231A1 (en) * | 2018-02-12 | 2020-11-26 | Astrazeneca Ab | Osimertinib for use in the treatment of non-small cell lung cancer |
Non-Patent Citations (2)
| Title |
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| 丁荣楣: "应用两种国际生存量表评价榄香稀注射液对非小细胞肺癌患者生存质量的影响", 临床肺科杂志, vol. 20, no. 2, pages 230 - 233 * |
| 张清华: "吉非替尼联合榄香烯注射液对EGFR 突变阳性的晚期肺腺癌患者的疗效观察", 中国医学前沿杂志(电子版), vol. 8, no. 110, pages 113 - 116 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023227112A1 (en) * | 2022-05-27 | 2023-11-30 | 杭州师范大学 | USE OF PHARMACEUTICAL COMBINATION OF β-ELEMENE AND OSIMERTINIB IN PREPARATION OF ANTI-LUNG CANCER MEDICAMENT |
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