CN114028407A - Application of withaferin A in preparation of antitumor drugs - Google Patents
Application of withaferin A in preparation of antitumor drugs Download PDFInfo
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- CN114028407A CN114028407A CN202111028127.0A CN202111028127A CN114028407A CN 114028407 A CN114028407 A CN 114028407A CN 202111028127 A CN202111028127 A CN 202111028127A CN 114028407 A CN114028407 A CN 114028407A
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- YCGBUPXEBUFYFV-UHFFFAOYSA-N withaferin A Natural products CC(C1CC(=C(CO)C(=O)O1)C)C2CCC3C4CC5OC56C(O)C=CC(O)C6(C)C4CCC23C YCGBUPXEBUFYFV-UHFFFAOYSA-N 0.000 title claims abstract description 39
- DBRXOUCRJQVYJQ-CKNDUULBSA-N withaferin A Chemical compound C([C@@H]1[C@H]([C@@H]2[C@]3(CC[C@@H]4[C@@]5(C)C(=O)C=C[C@H](O)[C@@]65O[C@@H]6C[C@H]4[C@@H]3CC2)C)C)C(C)=C(CO)C(=O)O1 DBRXOUCRJQVYJQ-CKNDUULBSA-N 0.000 title claims abstract description 34
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 37
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- 229960001433 erlotinib Drugs 0.000 claims abstract description 14
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims abstract description 14
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- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 1
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- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- 240000004482 Withania somnifera Species 0.000 description 1
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- SASUFNRGCZMRFD-JCUIILOWSA-N withanolide D Chemical compound C1C(C)=C(C)C(=O)O[C@H]1[C@](C)(O)[C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)C(=O)C=C[C@H](O)[C@@]54O[C@@H]5C[C@H]3[C@@H]2CC1 SASUFNRGCZMRFD-JCUIILOWSA-N 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses application of withaferin A in preparation of an anti-tumor medicament, wherein the anti-tumor medicament is used for treating lung cancer. The test result shows that withaferin A can inhibit the proliferation of NSCLC cells, promote the apoptosis of the NSCLC cells and inhibit the migration capacity of the NSCLC cells; meanwhile, the combination of withaferin A and erlotinib or ocitinib can play a strong synergistic role, so that the results of inhibiting NSCLC proliferation and promoting NSCLC apoptosis are achieved.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to application of withaferin A in preparation of an anti-tumor medicine.
Background
Lung cancer is one of the common malignant tumors in clinic at present, and has extremely serious harm to human health. Related reports show that the incidence of lung cancer in various countries has increased by 15-65% on average in recent years, and the lung cancer has become one of the cancers with the highest incidence and fatality rate worldwide. While their 5-year overall survival rates vary from 4% to 17%, and are still lower than most other types of cancer. Among all lung cancers, Non-small cell lung cancer (NSCLC) accounts for 75% to 80%, and is the most clinically common histological type of lung cancer. Since early disease is usually asymptomatic, most patients (61%) are diagnosed as stage III or IV, when surgical opportunities have been lost, chemotherapy becomes one of their standard treatment modalities. However, in recent years, the curative effect of traditional cytotoxic drugs has reached a platform, and even if various comprehensive treatment means are used for assistance, the survival rate of lung cancer cannot be improved remarkably. With the discovery of NSCLC driver genes and the research and application of corresponding targeted drugs, treatment of NSCLC has gone on gene-guided personalized treatment.
Withaferin A (Withaferin A, WA) is one of active ingredients extracted from Withania somnifera, the molecular structural formula of which is shown in figure 1A, and the Withaferin A has been used for hundreds of years for treating various diseases safely and effectively in Ayurvedic medicine.
Disclosure of Invention
The invention provides an application of withaferin A in preparing an anti-tumor medicament, which can be used for treating lung cancer, particularly non-small cell lung cancer.
The application of withaferin A in preparing antineoplastic medicine, said antineoplastic medicine is used for treating lung cancer;
the anti-tumor medicine comprises an active ingredient and an auxiliary material;
the active ingredient comprises withaferin A.
Preferably, the anti-tumor medicament is used for treating non-small cell lung cancer.
Preferably, the anti-tumor medicament is used for inhibiting the proliferation of the NSCLC cells, promoting the apoptosis of the NSCLC cells or inhibiting the migration of the NSCLC cells.
Preferably, the active ingredients consist of withaferin A and other compounds for targeted therapy of lung cancer; as a further preference, the other compound for targeted therapy of lung cancer is one or two of erlotinib and ocitinib.
Preferably, the other compound for targeted therapy of lung cancer is erlotinib; preferably, the molar ratio of withaferin A to erlotinib is 0.25-2.5: 0.5-10, wherein the two medicines have a certain synergistic effect; as a further preference, the molar ratio of withaferin a to erlotinib is 1: 0.5-10, wherein CI is less than 0.4, and the two have strong synergistic effect; more preferably, the concentration of withaferin A is 1 μ M, and the concentration of erlotinib is 0.5-10 μ M.
As another preferred, the other compound targeted for treating lung cancer is ocitinib; preferably, the molar ratio of withaferin A to ocitinib is 1-15: 1 to 15. At the moment, the two medicines have a certain synergistic effect; more preferably, the concentration of withaferin A is 1 μ M, the concentration of ocitinib is 1-10 μ M, or the concentration of withaferin A is 2.5 μ M, the concentration of ocitinib is 10 μ M, or the concentration of withaferin A is 5 μ M, the concentration of ocitinib is 5-10 μ M, and CI is less than 0.4, so that the two have strong synergistic effect.
Compared with the prior art, the invention has the beneficial effects that:
(1) the experimental result shows that the withanotin A can inhibit the proliferation of the NSCLC cells, promote the apoptosis of the NSCLC cells and inhibit the migration capacity of the NSCLC cells;
(2) the test result shows that the combination of withaferin A and erlotinib or ocitinib can play a strong synergistic effect to achieve the results of inhibiting NSCLC proliferation and promoting NSCLC apoptosis.
Drawings
FIG. 1 is a graph showing the results of WA inhibiting NSCLC cell proliferation in example 1;
FIG. 2 is the result of WA promoting apoptosis in NSCLC cells in example 2;
FIG. 3 is the result of WA inhibiting the migration ability of NSCLC cells in example 3
FIG. 4 shows the results of the synergistic inhibition of NSCLC proliferation and promotion of NSCLC apoptosis of WA and erlotinib in example 4;
FIG. 5 shows the results of the synergistic effect of WA and ocitinib on the inhibition of NSCLC proliferation and the promotion of NSCLC apoptosis in example 5.
Detailed Description
The invention is further described with reference to specific embodiments and the accompanying drawings.
Example 1
This example examines the antiproliferative effect of WA on three lung cancer cells (H460, H1975 and PC-9) by MTT assay. The specific process is as follows:
tumor cells were plated in 96-well plates at 3000-. The next day, 100. mu.L of fresh complete medium was added, and 1. mu.L/well of the corresponding concentration of drug (0.1-20. mu.M) was added. After 48h, 25. mu.L/well of MTT working solution (5mg/ml) was added under a dark environment. And after 3-4h, removing the supernatant, adding DMSO (150 mu L/well), shaking for 5min to fully dissolve, placing in an enzyme-linked immunosorbent assay (ELISA) instrument, selecting 490nm as the detection wavelength, and determining the absorption value (OD) of each well. As shown in FIG. 1B, the Half inhibitory concentrations (IC 50) of WA in four cells, H460, H1975 and PC-9, were 1.572. mu.M, 2.441. mu.M and 4.980. mu.M, respectively.
Next, we performed cell cloning experiments to examine the effect of WA on colony forming ability of the above several tumor cells, and the cell independent viability is expressed by the cell colony forming rate and the colony forming size. Cells were plated at 500-. The next day, 1mL of fresh complete medium was added, 1. mu.L/well of the corresponding concentration of drug (0, 2.5, 5, 7.5. mu.M) was added, and DMSO was added as a solvent to prepare a suspension, which was then placed in an incubator for further culture. After 6-12h of drug action, 2mL of fresh complete medium without drug was replaced. The medium was then changed every 3 days. After 2 weeks the supernatant was discarded, washed with PBS and fixed with 4% paraformaldehyde for 15 minutes. Then, the cells were washed with PBS and stained with crystal violet staining solution for 20 minutes. Finally, PBS is washed until the bottom of the hole plate is transparent and colorless. Standing for several days, naturally drying, and taking a picture. The colony formation results after drug treatment at different concentrations showed that WA inhibited the clonogenic capacity of lung cancer cell lines and WAs concentration dependent (fig. 1C).
Cell proliferation capacity was measured using EdU: cells were plated at 10 w/well in 6-well plates and allowed to adhere overnight in a 37 ℃ incubator. The next day, 1mL of fresh complete medium was added, 1. mu.L/well of the corresponding concentration of drug (0, 2.5, 5, 7.5mM) was added, and the mixture was prepared in DMSO as a solvent and placed in an incubator for further culture. After 24h of drug action, complete medium (1:1000) containing EdU reagent was added and incubated at 37 ℃ for 2 h. Washing with PBS for 5min, adding 4% paraformaldehyde, fixing at room temperature for 30min, neutralizing with 2mg/mL glycine for 5min, washing with PBS for 5min, adding 0.5% TritonX-100, penetrating for 10min, and washing with PBS for 5 min. Incubation was performed in Apollo staining reaction chamber with light and warm for 30min, and washed with 0.5% TritonX-100 for 10 min. Incubation was performed in 1X Hoechst 33342 reaction solution for 30min in the dark at room temperature, washed with PBS, and imaged under a fluorescence microscope. The results of EdU proliferation experiments also suggested that WA treatment could inhibit cell proliferation activity (fig. 1D). These results indicate that WA can inhibit NSCLC cell proliferation.
Example 2
This example explores the effect of WA on apoptosis in NSCLC cell lines. After treatment of cells with a gradient concentration of WA, cells were double labeled with Annexin V-FITC and PI. The results show that WA treatment can promote apoptosis in H460, PC-9 and H1975 cells (FIG. 2A). The use of Hoechest in combination with live cell DNA distinguishes normal cells from intermediate and early apoptotic cells and shows an increased proportion of intermediate and early apoptosis in the cells after WA treatment. Further detection of apoptotic proteins suggests that WA treatment can induce increased expression of the apoptotic proteins Cl-PARP and Bax, while inhibiting expression of the anti-apoptotic protein Bcl-2. These results indicate that WA promotes apoptosis in NSCLC cells.
Example 3
The effect of WA on cell crawling ability WAs examined using the Transwell migration assay. 500. mu.L/well of the basal medium was placed in a 24-well plate and placed in a chamber with a polycarbonate filter. After cell digestion and centrifugation, the supernatant was discarded, the cells were resuspended in a serum-free basal medium, and the cells were counted and diluted and added to the chamber at about 8000 cells/well. After 24h 500. mu.L/well of fresh complete medium was added to a new 24-well plate, the chamber was transferred to a new plate, 100. mu.L of serum-free basal medium was replaced in the chamber, and 1. mu.L/well of the corresponding concentration of drug (0, 0.25, 0.5, 0.75mM) was added. After 12-24h, fixing with 4% paraformaldehyde for 15min, and dyeing with 1% crystal violet for 15 min. The non-migrated cells inside the chamber were gently wiped with a cotton swab, and the number of migrated cells was observed and counted under an optical microscope. The results show that the number of cells successfully passing through the polycarbonate filter membrane after WA treatment with gradient concentration is obviously reduced, which indicates that the migration capability of the cells is obviously inhibited.
Example 4
In PC-9 cells, the MTT method measures cell growth activity after 48h treatment with different concentrations of WA and erlotinib in 96-well plates, either alone or in combination, and CompySyn software WAs used to calculate the combination index. The results are shown in FIG. 4A, where the combination treatment significantly reduced cell viability over the treatment alone, and the Combination Index (CI) < 0.8, indicating that the combination had a synergistic effect. The results of colony formation experiments are shown in fig. 4B, and the colony formation rate of the combination group is obviously reduced, and the size and the number of the colonies are smaller than those of the single drug group. Whereas flow apoptosis experiments suggested that the degree of apoptosis in the combination was promoted (fig. 4C). The results show that WA and erlotinib combined application can synergistically inhibit NSCLC proliferation and promote NSCLC apoptosis.
Example 5
In H1975 cells, we used WA and ocitinib at different concentrations, alone or in combination, for 48H, and the results are shown in fig. 5A, with the combination treatment significantly reduced cell viability over the treatment alone, with a combination index CI < 0.8, indicating a synergistic effect of the combination. Colony formation experiments suggested a significant reduction in colony forming ability of the combination group (fig. 5B), and flow apoptosis experiments suggested a promotion of apoptosis in the combination group (fig. 5C). The results show that WA and ocitinib can synergistically inhibit the proliferation of the NSCLC and promote the apoptosis of the NSCLC when being used together.
Claims (10)
1. The application of withaferin A in preparing antineoplastic medicine, characterized by, said antineoplastic medicine is used for treating lung cancer;
the anti-tumor medicine comprises an active ingredient and an auxiliary material;
the active ingredient comprises withaferin A.
2. The use of withaferin a according to claim 1 in the preparation of an anti-tumor medicament for the treatment of non-small cell lung cancer.
3. The use of withaferin a in the preparation of an anti-tumor medicament according to claim 1, wherein the anti-tumor medicament is used for inhibiting NSCLC cell proliferation, promoting NSCLC cell apoptosis or inhibiting NSCLC cell migration.
4. The use of withaferin A in the preparation of anti-tumor drugs according to any one of claims 1 to 3, wherein the active ingredients consist of withaferin A and other compounds for targeted therapy of lung cancer.
5. The use of withaferin A in preparing antineoplastic drugs according to claim 4, wherein the other compounds for targeting lung cancer are one or two of erlotinib and ocitinib.
6. The use of withaferin A in the preparation of anti-tumor drugs according to claim 5, wherein the other compounds for the targeted therapy of lung cancer are erlotinib;
the molar ratio of withaferin A to erlotinib is 0.25-2.5: 0.5 to 10.
7. The application of withaferin A in preparation of antitumor drugs according to claim 6, wherein in the antitumor drugs, the concentration of withaferin A is 1 μ M, and the concentration of erlotinib is 0.5-10 μ M.
8. The withaferin A application in preparing antitumor drugs according to claim 5, wherein the other compounds for targeted therapy of lung cancer are ocitinib;
the molar ratio of withaferin A to ocitinib is 1-15: 1 to 15.
9. The use of withaferin A in the preparation of an antitumor drug according to claim 8, wherein the concentration of withaferin A in the antitumor drug is 1 μ M, and the concentration of ocitinib is 1-10 μ M.
10. The use of withaferin a in the preparation of an anti-tumor medicament according to claim 8, wherein the concentration of withaferin a in the anti-tumor medicament is 2.5 μ M, and the concentration of ocitinib in the anti-tumor medicament is 10 μ M; alternatively, the first and second electrodes may be,
the concentration of withaferin A is 5 mu M, and the concentration of ocitinib is 5-10 mu M.
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Non-Patent Citations (2)
| Title |
|---|
| AL HASSAN KYAKULAGA: "Withaferin A inhibits Epithelial to Mesenchymal Transition in Non- Small Cell Lung Cancer Cells", 《SCIENTIFIC REPORTS》 * |
| 蔡勇: "醉茄素A 对非小细胞肺癌A549 细胞增殖、凋亡及 PI3K/Akt 信号通路的影响", 《临床肿瘤学杂》, vol. 19, no. 2, pages 107 - 111 * |
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