CN113648291B - Application of benzyl ketene compound in preparing lung cancer chemotherapy sensitization medicine and medicine - Google Patents

Application of benzyl ketene compound in preparing lung cancer chemotherapy sensitization medicine and medicine Download PDF

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CN113648291B
CN113648291B CN202111030392.2A CN202111030392A CN113648291B CN 113648291 B CN113648291 B CN 113648291B CN 202111030392 A CN202111030392 A CN 202111030392A CN 113648291 B CN113648291 B CN 113648291B
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lung cancer
phenylbutenone
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paclitaxel
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CN113648291A (en
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纪建松
严鹏程
方世记
邱熔芳
陈敏江
徐民
赵敏
殳高峰
丁佳怡
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Lishui Central Hospital
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Abstract

The invention provides an application of a phenylbutenone compound in preparing a lung cancer chemotherapy sensitizing medicament. The (E) -4- (3, 4-dihydroxyphenyl) but-3-en-2-one of the phenylbutenone compound can obviously increase the sensitivity of A549 and SK-MES-1 lung cancer cells to the chemotherapeutic drug Paclitaxel (PTX), and obviously improve the proliferation inhibition effect of the paclitaxel. The phenylbutenone is an excellent lung cancer chemotherapy sensitizer, has a synergistic effect when used together with PTX, and has wide application prospects in the aspects of treating lung cancer and solving the problem of drug resistance of the lung cancer. Correspondingly, the invention also provides a lung cancer chemotherapy sensitization drug.

Description

Application of benzyl ketone compound in preparing lung cancer chemotherapy sensitization medicine and medicine
Technical Field
The invention belongs to the field of medicines, and particularly relates to an application of a phenylbutenone compound in preparation of a lung cancer chemotherapy sensitizing medicine.
Background
Lung cancer is one of the most common malignant tumors in the world, and mainly comprises two major types, namely non-small cell lung cancer and small cell lung cancer. Chemotherapy remains one of the main therapeutic approaches, but is often limited in efficacy and prone to drug resistance. Paclitaxel is one of the first-line cytotoxic drugs of advanced lung cancer, and its mechanism of action is to cause apoptosis of lung cancer cells by promoting microtubule polymerization and stabilizing polymerized microtubules. In order to enhance the curative effect and delay the drug resistance phenomenon, several chemotherapy drugs are often used clinically in combination, but the tumor response rate of the combined chemotherapy scheme based on paclitaxel is still low, the clinical benefit is very limited, serious toxic and side effects are inevitably brought, and the 3/4 grade toxic reaction incidence rate is high. Therefore, the search and development of a novel high-efficiency and low-toxicity lung cancer chemosensitizer can improve the treatment effect of paclitaxel and reduce the dose of chemotherapy, and has important practical significance for treating lung cancer and reversing/delaying the drug resistance of lung cancer.
The benzyl ketone compound has few discovered medicinal functions, mainly including tumor cell toxicity, oxidation resistance and alpha-glucosidase inhibition. Until now, no research report on the tumor chemotherapy sensitization function exists.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the application of the phenylbutenone compound in preparing the lung cancer chemotherapy sensitizing medicament.
As the first invention of the invention, the invention provides the application of the benzyl vinyl ketone compound in the preparation of the lung cancer chemotherapy sensitizing drugs, wherein the chemical structure of the benzyl vinyl ketone is shown as the formula (I):
Figure BDA0003244997090000021
furthermore, the combined ratio of the phenylbutenone and the paclitaxel is 50-200.
Further, the combined ratio of the phenylbutenone and the paclitaxel is 100.
As the second aspect of the invention, the invention provides a lung cancer chemotherapy sensitization medicine, which contains active ingredients and pharmaceutic adjuvant; the active ingredient comprises the phenylbutenone as claimed in claim 1, wherein the chemical structure of the phenylbutenone is shown as formula (I):
Figure BDA0003244997090000022
further, the active ingredient also comprises paclitaxel.
Furthermore, the combined ratio of the phenylbutenone and the paclitaxel is 50-200.
Further, the ratio of the combination of the phenylbutenone and the paclitaxel is 100.
Further, the medicine is in the form of one of injection, tablet, capsule, aerosol, dripping pill, controlled release agent, sustained release agent and nano preparation.
Further, the tablet also comprises a pharmaceutic adjuvant which at least comprises a bonding agent, a diluent and a disintegrating agent.
Further, the binder includes at least one of cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone; the diluent comprises at least one of fiber starch, pregelatinized starch, dextrin, sucrose, lactose and mannitol; the disintegrant comprises at least one of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and dry starch.
The invention has the advantages that: the benzyl ketone compound (E) -4- (3, 4-dihydroxyphenyl) but-3-en-2-one with the chemosensitization function can obviously increase the sensitivity of A549 and SK-MES-1 lung cancer cells to the chemo-treatment medicament Paclitaxel (PTX), can be applied to the preparation of the lung cancer chemo-sensitization medicament, and has specific effects shown in specific embodiments and experimental data.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the prior art descriptions will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is within the scope of the present invention for those skilled in the art to obtain other drawings based on the drawings without inventive labor.
FIG. 1 is a diagram showing the effect of a phenylbutenone compound of the present invention on the inhibition of A549 lung cancer cell proliferation;
FIG. 2 shows the effect of the inhibition of the proliferation of A549 lung cancer cells by the combination of a phenylbutenone compound and paclitaxel PTX in the present invention;
fig. 3 is a combination index CI value in a549 lung cancer cells for a combination of a phenylbutenone compound of the present invention with paclitaxel PTX (molar ratio 50.
FIG. 4 combination index CI values of compound (E) -4- (3, 4-dihydroxyphenyl) but-3-en-2-one with paclitaxel PTX (molar ratio 100) in A549 lung cancer cells.
FIG. 5 combination index CI values of compound (E) -4- (3, 4-dihydroxyphenyl) but-3-en-2-one with paclitaxel PTX (molar ratio 200) in A549 lung cancer cells.
FIG. 6 is a graph showing the effect of a phenylbutenone compound of the present invention on the inhibition of SK-MES-1 lung cancer cell proliferation;
FIG. 7 shows the effect of the phenylbutenone compound of the present invention in combination with paclitaxel on the inhibition of SK-MES-1 lung cancer cell proliferation;
FIG. 8 combination index CI values of compound to paclitaxel PTX (molar ratio 50.
Figure 9 association index CI values of compound to paclitaxel PTX (molar ratio 100.
Figure 10 association index CI values of compound to paclitaxel PTX (molar ratio 200.
Detailed Description
To make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
The invention provides an application of a phenylbutenone compound in preparing a lung cancer chemotherapy sensitizing drug, wherein the chemical structure of the phenylbutenone is shown as a formula (I):
Figure BDA0003244997090000041
the combined ratio of the benzyl ketone and the paclitaxel is 50.
The ratio of the combined use of the benzyl crotone and the paclitaxel is 100.
As the second aspect of the invention, the invention provides a lung cancer chemotherapy sensitization medicine, which contains active ingredients and pharmaceutic adjuvant; the active ingredient comprises the phenylbutenone as claimed in claim 1, wherein the chemical structure of the phenylbutenone is shown as formula (I):
Figure BDA0003244997090000042
the active ingredient of (a) further comprises paclitaxel.
The combined ratio of the phenylbutenone and the paclitaxel is 50.
The combined ratio of the benzyl ketone and the paclitaxel is 100.
The medicine is in the form of one of injection, tablet, capsule, aerosol, dripping pill, controlled release agent, sustained release agent and nanometer preparation.
Also comprises pharmaceutic adjuvant which at least comprises an adhesive, a diluent and a disintegrating agent.
The binder comprises at least one of a cellulose derivative, alginate, gelatin, and polyvinylpyrrolidone; the diluent comprises at least one of fiber starch, pregelatinized starch, dextrin, sucrose, lactose and mannitol; the disintegrant comprises at least one of sodium carboxymethyl starch, crospovidone, and dry starch.
In addition, the term "pharmaceutical excipient" as used herein refers to a pharmaceutical carrier that is conventional in the pharmaceutical field, such as: binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; diluents such as starch, pregelatinized starch, dextrin, sucrose, lactose, mannitol, etc., fillers such as starch, sucrose, etc.; humectants such as glycerol; disintegrants such as sodium carboxymethyl starch, crospovidone, and dry starch; absorption enhancers such as quaternary ammonium compounds; surfactants such as polysorbates, sorbitan fatty acids, and glycerol fatty acid esters; coloring agents such as titanium dioxide, sunset yellow, methylene blue, medicinal iron oxide red, etc.; lubricants such as hydrogenated vegetable oils, talc, polyethylene glycol and the like. Coating materials such as acrylic resin, hypromellose, povidone, cellulose acetate, etc.; other adjuvants such as flavoring agent, sweetener, etc. can also be added into the composition.
Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional production methods in the pharmaceutical field. For example, the active ingredient may be combined with one or more carriers and then brought into the desired dosage form. The preparation forms of the medicine comprise injection, tablets, capsules, aerosol, dripping pills, controlled release or sustained release preparation, nano preparation and the like. The present invention may be administered in the form of a composition to a patient in need of such treatment by gastrointestinal administration, injection administration, respiratory administration, and the like. For oral administration, it can be made into conventional solid preparations such as tablet, powder, granule, capsule, etc., liquid preparations such as aqueous or oil suspension, or other liquid preparations such as syrup, elixir, etc.; for parenteral administration, it can be formulated into solution for injection, aqueous or oily suspension, etc.
The (E) -4- (3, 4-dihydroxyphenyl) but-3-en-2-one with the chemosensitization function can obviously increase the sensitivity of A549 and SK-MES-1 lung cancer cells to the chemo-treatment medicament Paclitaxel (PTX), can be applied to the preparation of the lung cancer chemosensitization medicament, and has the specific effects shown in the following specific examples and experimental data.
In the following examples, the phenylbutenone compound was isolated from Inonotus sanghuang, a genuine product purchased from the institute of agricultural science, lishui, and identified as (E) -4- (3, 4-dihydroxyphenyl) but-3-en-2-one represented by formula (I).
Figure BDA0003244997090000061
Example 1:
example 1 is a determination of inhibitory effect of a phenylbutenone compound on a549 lung cancer cell proliferation.
Taking A549 cells in logarithmic growth phase, inoculating into 96-well culture plate at 3000 cells/well, 200. Mu.L per well of medium, containing 5% CO at 37% 2 Was incubated overnight in the incubator of (1). Test phenylbutenone (0.1, 0.5, 1, 2.5, 5, 10, 25 μ M) and DMSO (negative control) were added to each well and stimulated for 48h. Finally, 20. Mu.L of enhanced CCK-8 solution was added to each well, and the cell culture was incubated for 2 hours in a cell incubator with equal amounts of cell-free medium mixed with enhanced CCK-8 as a blank. The absorbance (A value) was measured at a wavelength of 450nm using an enzyme-linked immunosorbent assay (ELISA) apparatus, and the blank was the B value. Cell viability (experimental group a value/control group B value x 100%) was calculated, and this experiment was repeated three times.
The experimental results are shown in FIG. 1, and the concentration of the phenylbutenone compound (E) -4- (3, 4-dihydroxyphenyl) but-3-en-2-one is shownBelow 2.5. Mu.M, the cytotoxicity is low. At concentrations greater than 5 μ M, the cell viability is significantly reduced, and concentration-dependent, semi-Inhibitory Concentrations (IC) are exhibited 50 ) The concentration of the benzyl ketone is 13.41 mu M, and the benzyl ketone with high concentration has the function of inhibiting the proliferation of A549 lung cancer cells.
Example 2:
example 2 is a determination of inhibition of a549 lung cancer cell proliferation by the combination of a phenylbutenone compound and paclitaxel PTX.
Taking A549 cells in logarithmic growth phase, inoculating into 96-well culture plate at 3000 cells/well, 200. Mu.L per well of medium, containing 5% CO at 37% 2 Was incubated overnight in the incubator of (1). PTX (1, 5, 10, 25, 50, 100, 250 nM) and DMSO (negative control) were added per well, and after fixing the PTX concentration three concentration ratios (50, 1, 100, 1, 200) of compound and paclitaxel were set, i.e. 50: 1. 250; 100; 200:1. 1000, 2000; and (5) stimulating for 48h. Finally, 20. Mu.L of enhanced CCK-8 solution was added to each well, and the cell culture was incubated for 2 hours in a cell incubator with equal amounts of cell-free medium mixed with enhanced CCK-8 as a blank. The absorbance (A value) was measured at 450nm using an enzyme-linked immunosorbent assay, and the blank was the B value. Cell survival (experimental group a value/control group B value × 100%) was calculated, drug Combination Index (CI) was calculated using Calcusyn 2.0 software, and the experiment was repeated three times.
The results of the experiment are shown in FIG. 2, IC for PTX 50 42.68nM; PTX ratio of phenylbutenone to PTX of 50 50 16.33nM; IC of PTX at a ratio of 100 50 7.42nM; IC of PTX at a ratio of 200 50 It was 1.32nM. At a ratio of 50. The synergistic effect was more pronounced at a ratio of 100. At a ratio of 200, 5 drug concentrations (1000, 2000, 10, 500010000, 20000 nm) from 0.1 to 0.7, the synergistic effect is more significant, but the phenylbutynone in 3 high concentrations has a significant cytotoxic effect (fig. 5). Therefore, the sensitivity of A549 lung cancer cells to PTX can be remarkably improved by the phenylbutenone, and the optimal combination ratio is phenylbutenone to PTX = 100.
Example 3:
example 3 is a measurement of inhibitory effect of a phenylbutenone compound on the proliferation of SK-MES-1 lung cancer cells.
SK-MES-1 cells were seeded at 3000 cells/well in 96-well plates in logarithmic growth phase, and the experimental procedure and procedure were as described in example 1.
As shown in FIG. 6, the cytotoxicity of the phenylbutenone compound (E) -4- (3, 4-dihydroxyphenyl) but-3-en-2-one is low when the concentration is less than 2.5. Mu.M. At concentrations greater than 5 μ M, the cell viability is significantly reduced, and concentration-dependent, semi-Inhibitory Concentrations (IC) are exhibited 50 ) 16.95 mu M, and high concentration of phenylbutenone has the effect of inhibiting SK-MES-1 lung cancer cell proliferation.
Example 4:
example 4 is a measurement of inhibitory effect of a phenylbutenone compound on the proliferation of SK-MES-1 lung cancer cells in combination with paclitaxel PTX.
SK-MES-1 cells were seeded at 3000 cells/well in 96-well plates in logarithmic growth phase, and the experimental procedure and operation were as described in example 2.
The results of the experiment are shown in FIG. 7, IC of PTX 50 40.12nM; PTX ratio of phenylbutenone to PTX of 50 50 21.05nM; IC of PTX at a ratio of 100 50 9.32nM; IC of PTX at a ratio of 200 50 At 5.55nM. At a ratio of 50. The CI index for 5 drug concentrations (500, 1000, 10, 2500. The CI index of 5 drug concentrations (1000, 2000, 10, 5000,the synergistic effect was significant, but the 3 high concentrations of phenylbutenone had a significant cytotoxic effect (fig. 10). Therefore, the combined use of the phenylbutenone and the PTX can obviously improve the inhibition effect of the PTX on SK-MES-1 lung cancer cells, and the optimal combined proportion is phenylbutenone to PTX = 100.
It can be seen from examples 1-4 that the phenylbutenone compound (E) -4- (3, 4-dihydroxyphenyl) but-3-en-2-one shown in formula (I) can significantly increase the sensitivity of A549 and SK-MES-1 lung cancer cells to the chemotherapeutic drug paclitaxel PTX at low cytotoxic concentration, effectively improve the proliferation inhibition effect of PTX, i.e., has a synergistic effect when used in combination with PTX, is an excellent anti-lung cancer chemotherapeutic sensitizer, and can be used for treating lung cancer and solving the problem of drug resistance of lung cancer. The optimal combined ratio of benzophenones to PTX is 100.
While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

Claims (5)

1. The application of the phenylbutenone compound in preparing the lung cancer chemotherapy sensitization drugs is characterized in that the chemical structure of the phenylbutenone is shown as the formula (I):
Figure FDA0003924996230000011
the combined ratio of the phenylbutenone and the paclitaxel is 100.
2. A lung cancer chemotherapy sensitization medicine is characterized in that the medicine contains active ingredients and pharmaceutic adjuvant; the active ingredient comprises the phenylbutenone as claimed in claim 1, wherein the chemical structure of the phenylbutenone is shown as formula (I):
Figure FDA0003924996230000012
the active ingredient also comprises paclitaxel; the combined ratio of the phenylbutenone and the paclitaxel is 100.
3. The lung cancer chemosensitizer drug according to claim 2, wherein: the medicine is in the form of one of injection, tablet, capsule, aerosol, dripping pill, controlled release agent, sustained release agent and nanometer preparation.
4. The lung cancer chemosensitization medicine according to claim 2, characterized by further comprising pharmaceutic adjuvants, wherein the pharmaceutic adjuvants at least comprise a binder, a diluent and a disintegrant.
5. The lung cancer chemosensitising drug according to claim 4, wherein the binder comprises at least one of a cellulose derivative, alginate, gelatin and polyvinylpyrrolidone; the diluent comprises at least one of fiber starch, pregelatinized starch, dextrin, sucrose, lactose and mannitol; the disintegrant comprises at least one of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and dry starch.
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Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
3,4-Dihydroxybenzalactone Suppresses Human Non-Small Cell Lung Carcinoma Cells Metastasis via Suppression of Epithelial to Mesenchymal Transition, ROS-Mediated PI3K/AKT/MAPK/MMP and NFκB Signaling Pathways;Wei Chao等;《Molecules》;20170328;第22卷(第4期);第1-14页 *
Bokyung Sung等.Identification of a novel blocker of IκBα kinase activation that enhances apoptosis and inhibits proliferation and invasion by suppressing nuclear factor-κb.《Mol Cancer Ther》.2008,第7卷(第1期),第191-201页. *
Cancer Cell Cytotoxicity of Extracts and Small Phenolic Compounds from Chaga [Inonotus obliquus (persoon) Pilat];Yuki Nakajima等;《JOURNAL OF MEDICINAL FOOD》;20091231;第12卷(第3期);第501-507页 *
Identification of a novel blocker of IκBα kinase activation that enhances apoptosis and inhibits proliferation and invasion by suppressing nuclear factor-κb;Bokyung Sung等;《Mol Cancer Ther》;20080131;第7卷(第1期);第191-201页 *
Recent Advances in Elucidating Paclitaxel Resistance Mechanisms in Non-small Cell Lung Cancer and Strategies to Overcome Drug Resistance;Hongmei Cui等;《Current Medicinal Chemistry》;20201231;第27卷(第39期);第6573-6595页 *
The Fire Within: NF-kB Involvement in Non-Small Cell;Foteinos-Ioannis D. Dimitrakopoulos等;《Cancer Res》;20201001;第80卷(第19期);第4025-4036页 *
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