CN114796234B - Application of cholesterol transport inhibitor U18666A as sensitizer in preparation of anti-tumor products - Google Patents
Application of cholesterol transport inhibitor U18666A as sensitizer in preparation of anti-tumor products Download PDFInfo
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- CN114796234B CN114796234B CN202210044410.0A CN202210044410A CN114796234B CN 114796234 B CN114796234 B CN 114796234B CN 202210044410 A CN202210044410 A CN 202210044410A CN 114796234 B CN114796234 B CN 114796234B
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Classifications
-
- 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
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
Abstract
The invention relates to application of cholesterol transport inhibitor U18666A as a sensitizer in preparation of anti-tumor products. The invention discloses an application of GPNA and U18666A combined drug in resisting tumor, wherein U18666A improves the killing effect of GPNA on tumor cells, and provides a novel method for overcoming the reduction of the anti-tumor drug effect of GPNA. The method specifically comprises the following steps: GPNA and U18666A have better anti-tumor effect when being used together; u18666a increased sensitivity of tumor cells to glutamine restriction; GPNA and U18666A are combined to enhance the inhibition effect of GPNA on tumor cell proliferation; the use of gpna in combination with U18666A significantly promotes tumor cell death. Compared with the prior art, the invention has more remarkable anti-tumor effect.
Description
Technical Field
The invention belongs to the technical field of antitumor drugs, and particularly relates to application of cholesterol transport inhibitor U18666A as a sensitizer in preparation of antitumor products, and application of a pharmaceutical composition of U18666A and GPNA in the antitumor products.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Malignant tumors are the main killers of current human health, and are one of the most important diseases seriously threatening human life. Fast growing tumor metabolism is reprogrammed to produce sufficient structural molecules and energy. In normal cells, glutamine (Gln) is a non-essential amino acid. However, tumor cells need to provide nutrients and energy sources for self-proliferation by Gln metabolism and help clear the ROS accumulated in the tumor cells, maintaining tumor cell redox homeostasis. Thus, gln is an "essential amino acid" of a tumor. Limiting Gln is a potential strategy for tumor treatment, and tumor cells can evade or reduce damage to tumor cells caused by Gln deficiency through metabolic remodeling. GPNA (L-gamma-Glutamyl-p-nitroanide) is a potent selective inhibitor of the Gln transporter ASCT2 (SLC 1A 5) and can significantly reduce Gln uptake. It has been found that GPNA alone does not achieve a highly effective inhibition of tumor growth.
Cholesterol metabolic remodeling is critical for the development and progression of tumors. Numerous studies have shown that cholesterol synthesis genes are highly expressed in tumors and down-regulating these key genes can significantly inhibit tumor growth. At the same time, various drugs inhibiting cholesterol synthesis have also been shown to inhibit tumor growth. However, currently, there are few reports of the effect of intracellular cholesterol transport drugs on tumor cells. U18666A is an inhibitor of intracellular cholesterol transport, and reports indicate that it has a remarkable inhibitory effect on infection and transmission of viruses and can cause tumor cell necrosis. On the basis of the medicine, the combination with other antitumor medicines has potential application prospect.
The inventor considers that aiming at the defect of insufficient tumor treatment effect of the Gln transporter inhibitor, corresponding sensitizers are developed, and a combined drug strategy containing the Gln transporter inhibitor is provided, so that effective inhibition of tumor proliferation is expected to be realized.
Disclosure of Invention
Current studies demonstrate that U18666A can inhibit the release of cholesterol from late endosomes and lysosomes, with a significant impact on intracellular cholesterol transport pathways. Based on the inhibition of cholesterol transport by U18666A, the prior art also simulates the loss of functional Niemann-Pick type C protein, providing a corresponding disease model. U18666A then becomes a tool to assess the importance of molecular transport via the lysosomal pathway in other situations (e.g., atherosclerosis, alzheimer's disease and viral infections). Since U18666A can limit cholesterol formation in membranes by inhibiting cholesterol synthesis and intracellular transport, it widely affects the mechanisms of various processes in the body. However, there is no report on the anti-tumor application of U18666A. In the invention, U18666A is independently used for tumor cells in vitro, and the effect of inhibiting tumor proliferation is not obvious.
GPNA is a Gln transporter inhibitor, and the prior study proves that the GPNA can promote apoptosis of pancreatic cancer cells, improve drug resistance of breast cancer tamoxifen and the like. According to the invention, U18666A and GPNA are combined for tumor cell culture and in-vivo mouse tumor models, and researches show that the inhibition effect of the two compounds on tumor cells is obviously improved after the two compounds are combined, and the research results show that the U18666A is hopeful to be used as a sensitizer to improve the anti-tumor effect of the Gln transporter inhibitor.
Based on the research results of the invention, the invention firstly provides the application of the cholesterol transport inhibitor U18666A as a sensitizer in the preparation of anti-tumor products.
The invention further provides a novel treatment strategy of the combined drug of GPNA and U18666A, and particularly provides a form of a pharmaceutical composition which can effectively inhibit proliferation of tumor cells and promote death of the tumor cells.
Based on the medicinal composition, the invention also correspondingly provides an anti-tumor application, in particular to an application in anti-liver cancer aspect.
The beneficial effects of the above technical scheme are:
in one embodiment of the invention, the application of U18666A as a sensitizer in the aspect of resisting tumors is provided, and the composition form of GPNA and U18666A is further provided, so that the tumor inhibition effect of the pharmaceutical composition is remarkably improved, and the pharmaceutical composition is expected to provide a medicament administration mode with simple cost and remarkable curative effect for clinical medicament administration.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a graph showing the in vitro combination of GPNA and U18666A with crystal violet staining;
FIG. 2 is a statistical chart of the in vitro combination crystal violet staining of GPNA and U18666A;
FIG. 3 is a PI fluorescence image of GPNA and U18666A in vitro combination;
FIG. 4 is a graph showing the PI-positive statistics of GPNA and U18666A in vitro combination;
FIG. 5 is a graph showing tumor volume change of GPNA in vivo in combination with U18666A;
FIG. 6 is a graph of the in vivo combination Ki67 of GPNA and U18666A;
FIG. 7 is a statistical plot of the combination Ki67 histology of GPNA and U18666A in vivo.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
As described in the background, selective inhibitors of the Gln transporter ASCT2 (SLC 1A 5) can achieve the effect of inhibiting tumor cell growth by reducing the uptake of Gln in the cell, but the use of such inhibitors alone is not ideal. In order to solve the technical problems, the invention provides application of U18666A as a GPNA sensitizer, and the application can obtain better anti-tumor effect by using the U18666A as a pharmaceutical composition.
In a first aspect, the invention provides an application of cholesterol transport inhibitor U18666A as a sensitizer in preparing an anti-tumor product.
The structural formula of U18666A in the first aspect is C 25 H 42 ClNO 2 CAS number: 3039-71-2.
In a second aspect of the invention, a pharmaceutical composition is provided, which comprises at least one cholesterol transport inhibitor and one Gln transporter inhibitor.
In one embodiment of the pharmaceutical composition of the second aspect, the cholesterol transport inhibitor is U18666A and the Gln transporter inhibitor is GPNA. In the above embodiments, the ratio of the two compounds can be determined according to conventional studies in the art, and viable manners such as MTT and the like. In one possible manner provided by the invention, the mass ratio of GPNA to U18666A is 20:1 to 5; further, the mass is 20:2 to 3; specific mass is 20:2 or 20:2.5 or 20:3.
the dosage form of the pharmaceutical composition according to the second aspect is not particularly limited, and possible formulation forms include solid formulations (tablets, capsules, granules, powders, etc.), liquid formulations (syrups, injections, etc.), and the like; in addition, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, and as the carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials can be used.
Possible carriers in the above solid preparations include excipients, lubricants, binders, disintegrants, etc.;
in liquid formulations, the carrier includes solubilizers, suspending agents, isotonic agents, buffers, soothing agents. Suitably, preservatives, antioxidants, colorants, sweeteners and other formulation additives may also be included.
In a third aspect, the invention provides the use of a pharmaceutical composition according to the second aspect for the preparation of an anti-tumour product.
The application mode includes but is not limited to any one of the following:
(1) The pharmaceutical composition is applied to a medicament for treating and preventing/treating tumors;
(2) The above pharmaceutical composition is used as a model agent for preparing tumor growth inhibition models and the like.
In a fourth aspect, the present invention provides an antitumor drug, wherein the pharmaceutical composition of the first aspect is an active ingredient.
In one embodiment of the antitumor drug according to the fourth aspect, the pharmaceutical composition is the only active ingredient, and in this embodiment, the antitumor drug is composed of the pharmaceutical composition and a pharmaceutical carrier.
In another embodiment, the antitumor agent has an active ingredient in addition to the pharmaceutical composition of the second aspect; such other active ingredients are, but are not limited to, cytotoxic drugs, nucleic acid synthesis, transcription inhibitors, hormonal drugs, monoclonal antibodies, interferons or biological response modifiers and the like.
The tumor is one of brain tumor, oral tumor, lung cancer, gastric cancer, liver cancer, intestinal cancer, uterus tumor, osteosarcoma or glioma; in one possible implementation mode of the verification of the invention, the anti-tumor drug is an anti-liver cancer drug.
In a fifth aspect of the invention, there is provided a method of tumor treatment comprising administering to an individual in need thereof the pharmaceutical composition of the second aspect, or the anti-tumor agent of the fourth aspect.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
The cell lines and animals involved in the following examples are as follows:
the human liver cancer cell strain HepG2 is purchased from Shanghai department of science; mouse hepatoma cell H22 was purchased from Shandong medical institute; SPF BALB/c-nu nude mice, female mice, 10 mice, 6-8 weeks old, weight 18-20g, beijing Veitz Lihua laboratory animal technology Co., ltd, laboratory animal production license code SCXK 2016-0006, in Shandong university laboratory animal center, mice after adaptation to the environment for one week, tumor experiment was performed, laboratory unit use license code SYXK 2019 0005.
The following examples relate to the drugs and the main reagents as follows:
GPNA: selleck Co Ltd
U18666A: MCE Co Ltd
High quality Fetal Bovine Serum (FBS), DMEM medium and pancreatin: thermo Co Ltd
Rabbit anti-Ki67 antibody：Abcam
Goat anti-Rabbit IgG(H+L)HRP：Abways
Grouping pens and DAB color development liquid: china fir gold bridge
Hematoxylin: biological engineering (Shanghai) Co., ltd
Crystal violet reagent: sigma Co Ltd
Propidium Iodide (PI): biyun Tian (a kind of Chinese character)
The main instruments involved in the following examples are as follows:
pipetting: eppendorf Co
Medical centrifuge, available from Shandong Bai Ou medical science and technology Co., ltd
Carbon dioxide cell incubator: panasonic Co Ltd
Biological safety cabinet: thermo Co Ltd
Inverted fluorescence microscope: olympus Co Ltd
Constant temperature water bath: fine macro Co Ltd
Paraffin slicer: thermo Co Ltd
Example 1
1. Cell culture
The human hepatocellular carcinoma HepG2 cell line was cultured in DMEM medium containing 100U/mL streptomycin, 100U/mL penicillin and 10% bovine serum, and placed in 5% CO 2 Sterile culturing in incubator at 37deg.C and saturated humidity.
2. Cell crystal violet staining experiment
HepG2 cells at 1x 10 5 Inoculating the cells/wells into 24-well plates, and culturing overnight at 37 ℃; the following day, the culture medium is sequentially replaced, the control group is not added with medicine, the experimental group is sequentially added with GPNA (0.5 mM), U18666A (1 mu M), GPNA (0.5 mM) and U18666A (1 mu M), and the culture is carried out for 24 hours at 37 ℃; the medium was aspirated and discarded, 500. Mu.L of pre-chilled PBS was added, 500. Mu.L of methanol was added, and the mixture was fixed at room temperature for 10min; methanol was removed by suction, 500. Mu.L of crystal violet staining solution (0.5%) was added and stained at room temperature for 15min; sucking away the staining solution, flushing residual staining solution with tap water, naturally airing, and observing and photographing under a microscope.
3. Effects of drugs on cell proliferation
As can be seen from fig. 1 and fig. 2, compared with the control group, the 0.5mM GPNA treatment has an effect of inhibiting the proliferation of tumor cells by 25%, the 1 mu M U18666A does not substantially affect the proliferation process of tumor cells, and the combination of the two drugs significantly inhibits the proliferation of tumor cells, with an inhibition efficiency of about 2.7 times that of the 0.5mM GPNA treatment alone.
4. Cell PI staining experiment
HepG2 cells at 1x 10 5 Inoculating the cells/wells into 24-well plates, and culturing overnight at 37 ℃; the following day, the culture medium is sequentially replaced, the control group is not added with medicine, the experimental group is sequentially added with GPNA (0.5 mM), U18666A (1 mu M), GPNA (0.5 mM) and U18666A (1 mu M), and the culture is carried out for 24 hours at 37 ℃; PI staining solution (1. Mu.g/mL) was added thereto, and after staining at room temperature for 2 minutes, the resultant was observed under a microscope and photographed.
5. Effects of drugs on cell death
It can be seen from FIGS. 3 and 4 that the total number of cells varies in accordance with the results of FIGS. 1 and 2. In addition, the 0.5mM GPNA treatment has the effect of promoting the death of tumor cells compared with the control group, and the PI positive rate of the GPNA treatment group is 12 times higher than that of the control group; meanwhile, the treatment of 1 mu M U18666A has low toxicity to tumor cells and has no obvious effect on cell proliferation and death; when 0.5mM GPNA was used in combination with 1. Mu. M U18666A, tumor cell mortality was 33-fold higher than in the control group, approximately 21-fold higher than in the 0.5mM GPNA alone, indicating that U18666A significantly enhanced the tumor-inhibiting effect of GPNA. Thus, 1 μ M U18666A in combination with 0.5mM GPNA is a preferred anti-tumor strategy.
Example 2
1. Animal model building and grouping
Recovering H22 cells from ascites of mice, and taking 0.1mL/5x10 under aseptic condition 5 Subcutaneous injections were given to the left and right sides of the back of mice, and after successful tumor modeling, the mice were randomized into four groups, including a placebo group, a GPNA-treated group, a U18666A-treated group, and a GPNA-and U18666A-combined treated group.
The modes and routes of administration of the different administration groups are shown in Table 1, and the blank group is given an equal amount of PBS.
Table 1 modes and routes of administration for different experimental groups
Note that: i.p.: intraperitoneal injection, intraperitoneal injection; qd: quadue die, once a day 2, tumor volume determination
The major (L) and minor (W) diameters of the tumor nodules of each group of animals were measured with vernier calipers, the tumor volumes were calculated according to an elliptic volume formula (v=lxw2/2) and the average values of each group were calculated, and the relative proliferation rates of the tumor volumes of each group were compared, relative proliferation rates=day n/Day1.
3. Effect of drug on tumor volume
After preparing the H22 subcutaneous tumor model, tumor volumes were determined by using GPNA alone, U18666A alone, and GPNA in combination with U18666A. As shown in fig. 5, U18666A alone treated tumor growth slowed down but was not statistically significant compared to the control group; GPNA alone significantly inhibited tumor growth compared to controls; the combined use of GPNA and U18666A can significantly inhibit tumor growth compared with the control or any single administration, and the special emphasis is that the use of U188666A significantly improves the tumor inhibition efficiency of GPNA. Thus, the above results indicate that U18666A increases the sensitivity of tumor tissue to glutamine restriction.
4. Preparation of tissue embedding and paraffin sections
(1) Placing the tissue to be embedded into a 5mL centrifuge tube containing 4% paraformaldehyde, and fixing for 24h;
(2) Taking out the tissue, placing the tissue into an embedding box, moving the embedding box into a dehydrator, and dehydrating and hardening the tissue according to the procedure shown in the table 2;
TABLE 2 dehydration hardening procedure
(3) After the above steps are completed, the tissue is placed in an embedding iron box and immersed in melted paraffin, the embedding box is covered and placed on ice until it solidifies.
(4) After the tissue wax block is solidified, the tissue wax block is taken down from the iron box and fixed on a paraffin slicer, the tissue wax block is modified with the thickness of 20 mu m until the tissue is exposed after the blade is arranged, then the wax block with the tissue is cut off with the thickness of 3 mu m, the wax block is placed in water with the temperature of 45 ℃, after the wax block is stretched, the wax block is gently fished up by a glass slide to be covered on the glass slide smoothly, and then the wax block is placed on a gridiron frame with the temperature of 65 ℃ for baking for 2 hours and then is collected in the glass slide box for subsequent experiment use.
5. Immunohistochemical staining of Paraffin sections
Placing the tumor tissue slices in a 65 ℃ oven for baking for 2 hours;
gradient dewaxing hydration:
xylene (2 times, 15 min/time); 100% ethanol (2 times, 5 min/time); 90% ethanol (1 time, 5 min/time); 70% ethanol (1 time, 5 min/time); distilled water (1 time, 5 min/time);
antigen retrieval was performed using EDTA antigen retrieval liquid (EDTA antigen retrieval liquid stock solution: distilled water=1:50);
600mL of antigen retrieval liquid is taken to be placed in a 1000mL glass beaker, the glass beaker is placed in a slide frame, the glass beaker is placed in a microwave oven, high fire is used for heating for 8min until the liquid boils, then medium and high fire is used for continuously heating for 10min, and the beaker is taken out of a fume hood for cooling to room temperature after the heating is finished.
Placing the slices into a wet box, circling the tissues by using a histochemical pen, dripping a diluted primary antibody solution with a certain proportion, and incubating for 2 hours at room temperature.
Rinse 3 times with 1XPBST solution (containing 0.1% Tween 20) for 5min on a shaker.
And dripping the diluted secondary antibody solution in a certain proportion, and incubating for 30min at room temperature.
1XPBST was rinsed 3 times for 5min each.
According to the solution B: and (3) preparing DAB color development liquid according to the ratio of C liquid=50:1, dripping the DAB color development liquid onto tissues, and putting the tissues into tap water to terminate the dyeing after positive dyeing is found under a mirror, wherein DAB dyeing time of the same tissue slice is kept consistent.
Hematoxylin staining was performed for 2-5min, and tap water was used to terminate staining.
Rinsing with 1% hydrochloric acid for 1s, and stopping running water.
Gradient alcohol elution: 70% ethanol (5 min), 90% ethanol (5 min), 100% ethanol (5 min), xylene (10 min).
And (3) after the dyed slice is dried, dropwise adding neutral gum, and sealing the slice with a cover glass.
6. Drug for inhibiting proliferation of tumor cells
Referring to fig. 6 and 7, by performing Ki67 histochemical staining on tumor tissues, it was found that the Ki67 positive rate is higher in tumor tissues of the group which is not treated with the drug, the Ki67 positive rate is reduced after the GPNA treatment, the inhibition effect of the U18666A alone on tumor proliferation is not remarkable, but the Ki67 positive rate can be remarkably reduced when the U18666A is combined with the GPNA, which indicates that the U18666A can remarkably enhance the sensitivity of the tumor to the GPNA drug, and the GPNA and the U18666A are suggested to be a better in vivo anti-tumor strategy when the combination is used.
7. Statistical analysis
Statistical treatment was performed using GraphPrism software, and the data measured in mean±sd, and more than two sets of data were compared using one-way ANOVA, and the comparison between sets was performed using t-test, with pvlue style GP 0.1234 (ns), 0.0332 (x), 0.0021 (x), 0.0002 (x), and <0.0001 (x). The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A pharmaceutical composition comprising at least one cholesterol transport inhibitor and one Gln protein transport inhibitor;
the cholesterol transport inhibitor is U18666A, and the Gln protein transport inhibitor is GPNA;
the structural formula of the U18666A is C 25 H 42 ClNO 2 CAS number: 3039-71-2;
the mass ratio of GPNA to U18666A is 20:2 or 20:2.5 or 20:3.
2. the pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of a solid formulation or a liquid formulation; also comprises a pharmaceutically acceptable carrier; also comprises preservative, antioxidant, colorant and sweetener;
the carrier of the solid preparation comprises a lubricant, a binder or a disintegrating agent;
the carrier of the liquid preparation comprises solubilizer, suspending agent, isotonic agent, buffer and relieving agent.
3. Use of a pharmaceutical composition according to any one of claims 1-2 for the preparation of an anti-tumor product, wherein the anti-tumor is anti-liver cancer.
4. Use of a pharmaceutical composition according to claim 3 for the preparation of an anti-tumour product in any of the following ways:
(1) The pharmaceutical composition is applied to a medicament for treating and preventing/treating tumors;
(2) The pharmaceutical composition is used as a model medicament for preparing a tumor growth inhibition model.
5. An antitumor drug characterized in that the pharmaceutical composition according to any one of claims 1 to 2 is used as an active ingredient in the drug.
6. The anti-tumor drug according to claim 5, wherein the anti-tumor drug is composed of a pharmaceutical composition and a pharmaceutical carrier;
or, the antitumor drug also comprises other active ingredients; the other active ingredients are cytotoxic drugs, nucleic acid synthesis inhibitors, transcription inhibitors, hormonal drugs, monoclonal antibodies and interferon;
the antitumor drug is an anti-liver cancer drug.
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| US20210154162A1 (en) * | 2018-03-02 | 2021-05-27 | Institute Of Basic Medical Sciences Chinese Academy Of Medical Sciences | Drug and pharmaceutical composition containing transport protein inhibitor, and use |
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