CN117045639A - Pharmaceutical composition for treating gastric cancer and application thereof - Google Patents
Pharmaceutical composition for treating gastric cancer and application thereof Download PDFInfo
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- CN117045639A CN117045639A CN202311260864.2A CN202311260864A CN117045639A CN 117045639 A CN117045639 A CN 117045639A CN 202311260864 A CN202311260864 A CN 202311260864A CN 117045639 A CN117045639 A CN 117045639A
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- gastric cancer
- wogonin
- baicalein
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- 206010017758 gastric cancer Diseases 0.000 title claims abstract description 50
- 201000011549 stomach cancer Diseases 0.000 title claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 35
- HIMJIPRMECETLJ-UHFFFAOYSA-N Wogonin Natural products COc1cc(O)c(O)c2C(=O)C=C(Oc12)c3ccccc3 HIMJIPRMECETLJ-UHFFFAOYSA-N 0.000 claims abstract description 29
- XLTFNNCXVBYBSX-UHFFFAOYSA-N wogonin Chemical compound COC1=C(O)C=C(O)C(C(C=2)=O)=C1OC=2C1=CC=CC=C1 XLTFNNCXVBYBSX-UHFFFAOYSA-N 0.000 claims abstract description 29
- FXNFHKRTJBSTCS-UHFFFAOYSA-N Baicalein Natural products C=1C(=O)C=2C(O)=C(O)C(O)=CC=2OC=1C1=CC=CC=C1 FXNFHKRTJBSTCS-UHFFFAOYSA-N 0.000 claims abstract description 27
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- 238000013399 early diagnosis Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- -1 flavonoid compound Chemical class 0.000 description 1
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Classifications
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pharmaceutical composition for treating gastric cancer, which consists of baicalein and wogonin, wherein the mass ratio of the baicalein to the wogonin is 1: (0.125-8). The inventor discovers through experimental study that the baicalein and the wogonin are matched in a specific proportion range for use, has obvious combined synergistic effect on the treatment of gastric cancer, is obviously superior to the treatment effect of single use of the baicalein or the wogonin, and has low dosage. Compared with the existing medicines for treating gastric cancer, the medicine composition disclosed by the invention has the advantages of low raw material cost and small toxic and side effects, and has important significance for clinical treatment of gastric cancer.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition for treating gastric cancer and application thereof.
Background
Gastric cancer is a malignant tumor derived from gastric mucosal epithelium, and is one of the most common malignant tumors of the digestive tract. China is a high incidence country of gastric cancer, and about 40 ten thousand new gastric cancer patients exist each year. The onset of gastric cancer tends to be younger due to changes in dietary structure, increased working pressure, infection with helicobacter pylori, and the like. Gastric cancer can occur in any part of the stomach, with more than half occurring in the antrum, the greater curvature, lesser curvature and anterior and posterior walls of the stomach all affected. Most stomach cancer belongs to adenocarcinoma, has no obvious symptoms in early stage, or has nonspecific symptoms such as upper abdomen discomfort, eructation and the like, is often similar to symptoms of chronic gastric diseases such as gastritis, gastric ulcer and the like, and is easy to ignore, so that the early diagnosis rate of stomach cancer in China is still lower. The patients with middle and late gastric cancer have relatively weak bodies, reduced functions of organs, listlessness, reduced immunity and poor capability of immune cells in resisting gastric cancer cell invasion, so that gastric cancer cell diffusion is accelerated, pain of the patients is deepened, and the conditions of liver metastasis, bone metastasis and the like of cancer cells are easy to occur, so that the illness state is rapidly worsened.
Common methods for treating gastric cancer are operation and radiotherapy and chemotherapy, but the loss of the operation treatment to the body of a gastric cancer patient is great, so that the body of the patient who is originally weak is easily weakened, the postoperative recovery is slow, and the residual cancer cells in the body grow more rapidly; while the radiotherapy and chemotherapy treatment kills cancer cells, the radiotherapy and chemotherapy treatment can cause certain harm to normal immunocytes and normal organs of a human body, and has side effects of nausea, vomiting, no appetite, alopecia and the like. At present, most of stomach cancer treatment medicines are western medicines, and have large toxic and side effects.
Wogonin is a flavonoid compound contained in roots of the Labiatae plant, namely, the baikal skullcap root and various plants of the same genus, and researches have shown that wogonin has various pharmacological effects including antioxidant effect, anticoagulation effect, antitumor effect, spasmolysis effect, antibacterial effect, antiviral effect, diuretic effect and the like. The Chinese patent of the invention with publication number of CN101062029B discloses application of wogonin in preparing medicines for treating gastric cancer, and has small toxic and side effects, which is beneficial to clinical application, but has weak anti-tumor activity and poor curative effect when being independently used for treating gastric cancer.
Disclosure of Invention
The invention aims to solve the problems of large side effect and poor curative effect of the existing medicines for treating gastric cancer, and provides a medicine composition for treating gastric cancer.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the medicine composition for treating the gastric cancer consists of baicalein and wogonin, wherein the mass ratio of the baicalein to the wogonin is 1: (0.125-8). The inventor researches find that the baicalein and the wogonin are matched in a specific proportion range for use, and the composition has a remarkable curative effect on gastric cancer treatment and is remarkably superior to the effect of single use of the baicalein or the wogonin.
Further, in the pharmaceutical composition, the mass ratio of baicalein to wogonin is 1:0.25 or 1:1.
The application of the pharmaceutical composition in preparing medicines for treating gastric cancer. The dosage of the pharmaceutical composition is 200-400 mg/kg.
A pharmaceutical formulation for treating gastric cancer, the pharmaceutical formulation comprising the pharmaceutical composition described above, and a pharmaceutically acceptable carrier.
The preparation formulation of the pharmaceutical preparation is decoction, tablets, capsules, injection, powder injection, granules or syrup.
The invention has the beneficial effects that:
the invention discloses a pharmaceutical composition for treating gastric cancer, which comprises the following components in percentage by mass: the inventor researches and discovers that the baicalein and the wogonin are matched in a specific proportion range for use, and the baicalein and the wogonin have obvious combined synergistic effect on the treatment of gastric cancer, are obviously superior to the treatment effect of single use of the baicalein or the wogonin and have low dosage.
The pharmaceutical composition has low cost of raw materials and small toxic and side effects, and has important significance for clinical treatment of gastric cancer.
Drawings
Fig. 1 shows the results of the test of the inhibition ability of the pharmaceutical composition of the present invention to human gastric cancer cell MGC 823.
Detailed Description
The technical scheme of the invention is clearly and completely described below with reference to the accompanying drawings and the specific embodiments.
In order to clearly illustrate the technical scheme of the present invention, reagents and materials used in examples, experimental instruments, related detection methods and evaluation methods are described below, but the present invention is not limited thereto.
1. Reagents and materials used
(1) Compounds of formula (I)
Baicalein is provided by tumor generation and intervention laboratory in Jiangsu province of Chinese university of medical science, and is pale yellow powder with purity of more than 95%. Before use, the compound powder is prepared into stock solution with the concentration of 100mg/mL by using dimethyl sulfoxide, and the stock solution is stored at the temperature of-80 ℃. When in use, the corresponding culture medium of the cell culture is adopted to dilute to the required concentration.
Wogonin is provided by tumor generation and intervention laboratory in Jiangsu province of Chinese university of medical science, and is pale yellow powder with purity of more than 95%. Before use, the compound powder is prepared into stock solution with the concentration of 100mg/mL by using dimethyl sulfoxide, and the stock solution is stored at the temperature of-80 ℃. When in use, the corresponding culture medium of the cell culture is adopted to dilute to the required concentration.
Fluorouracil injection, produced by Tianjin obsidian pharmaceutical industry Co., ltd., specification 10mL:0.25g. Before use, the composition is prepared into a concentration of 3mg/mL by normal saline, and the composition is filtered and sterilized by a sterile filter membrane with a pore diameter of 0.22 mu m.
(2) Cell lines
Human gastric cancer cell line MGC823, purchased from Shanghai China academy of sciences.
(3) Cell culture reagent
DMEM medium (GIBCO, carlsbad, CA, USA): 6.74g of DMEM powder and 1.85g of NaHCO are taken 3 Is co-dissolved in 0.5L ddH 2 O.
Filtering with sterile cylinder filter, sterilizing, packaging, and preserving at 4deg.C. Before use, 100U/mL penicillin (Chenxin pharmaceutical Co., ltd.) and 100mg/L streptomycin (Chenxin pharmaceutical Co., ltd.) are added.
Fetal bovine serum (GIBCO) was stored at-20deg.C, inactivated in a water bath at 56deg.C for 35min before use, and then sub-packaged and stored at 4deg.C for one week. The fetal bovine serum is mixed with the culture medium at a ratio of 1:10 for use.
(4) Relevant index detection kit
MTT solution: in a dark place, 0.05g of MTT (following Saint Biotechnology, shanghai, china) powder was dissolved in 10mL of PBS buffer and sonicated for 20min to prepare a 5mg/mL solution. Filtering with 0.22 μm sterile filter head, packaging, and storing at-80deg.C. The product is dissolved at room temperature.
(5) Experimental animals and cultures
BALB/c nude mice, 18-22 g body weight, male, purchased from Shanghai Bikeside Biotech Co., ltd., license number: SCXK 2018-0006. The administration period is free of feeding and drinking water, 12h of light and 12h of darkness each day, the temperature is 22+/-2 ℃, and the humidity is 55-70%.
2. Experimental apparatus used
YJ-875 medical decontamination station (decontamination plant, su zhou, china); 3111 water jacket type CO 2 Incubator (ThermoFisher Scientific, waltham, MA, USA); 702 ultra-low temperature refrigerator (ThermoFisher Scientific); electronic balance (Sidoris instruments systems Co., beijing, china); syringes, vernier calipers, QIUJING blood cell counter plates (Severe Biochemical reagent instruments, inc., shanghai, china); LD4-2 common centrifuge (medical centrifuge factory, shanghai, china); 5417R bench-top refrigerated high-speed centrifuges (Eppendorf AG, hamburg, germany); research type single-pass adjustable pipettor (Eppendorf AG); THZ-312 bench-type thermostatic oscillator (fine macro test equipment limited, shanghai, china); varioskan full wavelength microplate reader (ThermoFisher Scientific).
3. Detection and analysis method
(1) Cell viability detection: the principle is that MTT can be reduced by intracellular mitochondrial dehydrogenase to generate bluish purple crystal Formazan (Formazan), and Optical Density (OD) values at 570nm wavelength are detected and compared, so that the relative level of cell viability can be reflected. The operation flow is as follows: 100 mu L of cells (5000 cells/well) are uniformly cultured in a 96-well plate, and 100 mu L of baicalein with a certain concentration and 100 mu L of wogonin with a certain concentration are added to enable the two medicines to reach the final action concentration. Cells were incubated at 37℃with 5% CO 2 Culturing in an incubator; after 48h of drug action, 15 μl of MTT solution was added per well. Cultivation methodAfter incubation for 3h in the incubator, the OD value at 570nM was measured using an enzyme-labeled instrument, and cell viability before and after dosing was calculated.
(2) Combined action index (combination index, CI) analysis: the calculation was performed by Compusyn software using the principle of median efficiency (ci= (D) 1/(dχ) 1+ (D) 2/(dχ) 2). Average CI intervals and interaction evaluations are shown in table 1:
TABLE 1 mean CI intervals for compound combinations and interaction assessment
(3) Subcutaneous transplantation tumor model construction and tumor volume measurement calculation
Taking human gastric cancer BGC823 cell strain in logarithmic growth phase, preparing into 2×10 under aseptic condition 7 A0.1 mL aliquot of the cell suspension was inoculated subcutaneously into the right armpit of nude mice. The diameter of the transplanted tumor is measured by a vernier caliper for the transplanted tumor of the nude mice, and the tumor grows to 100-200 mm 3 Animals were then randomly grouped. The antitumor effect of the test object is dynamically observed by using a method for measuring tumor diameters. Tumor diameter was measured 1 time per 3 d. The administration volume was 0.2mL/20g. After 21d, mice were sacrificed and tumor mass was surgically removed and weighed. The calculation formula of Tumor Volume (TV) is:
TV＝1/2×a×b 2
wherein a and b respectively represent length and width.
Based on the measured results, the relative tumor volume (relative tumor volume, RTV) is calculated as: rtv=v t /V 0 . Wherein V is 0 For administration in separate cages (i.e. d 0 ) Measuring the volume of the obtained tumor, V t Tumor volume at each measurement. The evaluation index of the anti-tumor activity is relative tumor proliferation rate T/C (%), and the calculation formula is as follows:
T RTV : treatment group RTV; c (C) RTV : negative control RTV.
The tumor inhibition rate calculation formula is as follows:
T weight : average tumor weight in treatment group; c (C) weight : average tumor weight of the negative control group.
Example 1
Test of inhibition ability of pharmaceutical composition of the invention to human gastric cancer cells: the baicalein and the wogonin are respectively formed into a pharmaceutical composition according to the mass ratio of (1:0.125, 1:0.25, 1:0.5, 1:1, 1:2, 1:4 and 1:8), the pharmaceutical composition acts on human gastric cancer cells MGC823 at the same time, and the activity inhibition effect of the pharmaceutical composition on MGC823 cells under 48 hours is measured through MTT experiments and compared with single use of the baicalein and the wogonin.
The test result of the inhibition capability of the pharmaceutical composition of the invention to the human gastric cancer cell MGC823 is shown in figure 1, and the combined action index analysis to the human gastric cancer cell MGC823 is shown in table 2:
TABLE 2 Combined action index analysis of baicalein and wogonin on human gastric cancer cell MGC823
| Baicalein (mu g/mL) | Wogonin (μg/mL) | Mass ratio | CI | Synergistic effect |
| 5.0 | 2.5 | 1:0.5 | 0.85118 | The synergistic effect is slight |
| 10.0 | 2.5 | 1:0.25 | 0.39550 | Has stronger synergistic effect |
| 20.0 | 2.5 | 1:0.125 | 0.53716 | Has stronger synergistic effect |
| 5.0 | 5.0 | 1:1 | 0.60206 | Has stronger synergistic effect |
| 10.0 | 5.0 | 1:0.5 | 0.46366 | Has stronger synergistic effect |
| 20.0 | 5.0 | 1:0.25 | 0.55598 | Has stronger synergistic effect |
| 5.0 | 10.0 | 1:2 | 0.94695 | Additive effect |
| 10.0 | 10.0 | 1:1 | 0.48039 | Has stronger synergistic effect |
| 20.0 | 10.0 | 1:0.5 | 0.38120 | Has stronger synergistic effect |
| 5.0 | 20.0 | 1:4 | 0.67245 | Has stronger synergistic effect |
| 10.0 | 20.0 | 1:2 | 0.71125 | Synergistic effect is moderate |
| 20.0 | 20.0 | 1:1 | 0.37682 | Has stronger synergistic effect |
| 5.0 | 40.0 | 1:8 | 0.69374 | Has stronger synergistic effect |
| 10.0 | 40.0 | 1:4 | 0.73520 | Synergistic effect is moderate |
| 20.0 | 40.0 | 1:2 | 0.44939 | Has stronger synergistic effect |
As can be seen from fig. 1 and table 2, under the action of 5, 10, 20 μg/mL baicalein combined with 2.5, 5, 10, 20, 40 μg/mL wogonin, the stomach cancer cells: the wogonin has a strong synergistic effect within the mass ratio of 1:0.125-1:8. The combined use of baicalein and wogonin can achieve the tumor inhibition effect which is not achieved by single drug, namely the total baicalein has the application advantage of being superior to the single component.
Example 2
Constructing a mouse subcutaneous transplantation tumor model, preparing baicalein and wogonin into a pharmaceutical composition according to the mass ratio of 1:0.25, and verifying the anti-tumor efficacy of the pharmaceutical composition on the mouse stomach cancer subcutaneous transplantation tumor. The experiments were performed in a high dose experimental group, a low dose experimental group, a negative control group and a positive control group. The high-dose experimental group and the low-dose experimental group adopt pharmaceutical compositions, and are respectively administrated by lavage at doses of 400mg/kg and 200mg/kg, which are administrated 1 time a day and 10 times in total; the negative control group was given the same condition as the high-dose experimental group with the high-dose experimental group equivalent solvent without the pharmaceutical composition; the positive control group was fluorouracil (5-FU), and the dose of 30mg/kg was administered by tail vein injection once every two days for 7 times. After 21d, mice were sacrificed, weights were tested and tumor mass removed by surgery and weighed, and tumor suppression rate was calculated. The test results of the inhibition effect of the pharmaceutical composition on the growth of the subcutaneous transplantation tumor of the gastric cancer of the mice are shown in table 3, and the test results of the influence of the pharmaceutical composition on the weight of the mice are shown in table 4:
TABLE 3 inhibition of growth of gastric cancer subcutaneous transplantable tumor in mice by pharmaceutical composition
| Group of | Dosage (mg/kg) | Animal number (only) | Tumor weight (g) | Tumor inhibition rate (%) |
| Negative control group | / | 12 | 1.45±0.28 | - |
| High dose experimental group | 400 | 6 | 0.74±0.12 | 49.12** |
| Low dose experimental group | 200 | 6 | 0.89±0.10 | 38.58** |
| Positive control group | 30 | 6 | 0.41±0.09 | 71.70** |
Remarks: * P <0.01, compared to negative control group
TABLE 4 influence of baicalein on mouse body weight
| Group of | Dosage (mg/kg) | Animal number (only) | Weight of the terminal |
| Negative control group | / | 12 | 25.06±0.81 |
| High dose experimental group | 400 | 6 | 24.58±0.89 |
| Low dose experimental group | 200 | 6 | 25.22±0.46 |
| Positive control group | 30 | 6 | 17.78±0.77** |
Remarks: * P <0.01, compared to negative control group
As can be seen from the test results in table 3, the tumor inhibition rates of the high-dose experimental group and the low-dose experimental group using the pharmaceutical composition (the mass ratio of baicalein to wogonin is 1:0.25) of the invention on human gastric cancer BGC823 cell nude mice transplanted tumors reach 49.12% and 38.58%, respectively, and the tumor inhibition rate of the positive control group on human gastric cancer BGC823 cells reaches 71.70% after 7 times of administration, but the positive control group has very significant inhibition effect (P < 0.01) on the weight of the mice, and the pharmaceutical composition of the invention has almost no influence on the weight of the experimental mice.
Claims (6)
1. The pharmaceutical composition for treating the gastric cancer is characterized by comprising baicalein and wogonin, wherein the mass ratio of the baicalein to the wogonin is 1: (0.125-8).
2. The pharmaceutical composition for treating gastric cancer according to claim 1, wherein the mass ratio of baicalein to wogonin is 1:0.25 or 1:1.
3. Use of a pharmaceutical composition according to claim 1 or 2 for the preparation of a medicament for the treatment of gastric cancer.
4. The use according to claim 3, wherein the dosage of the pharmaceutical composition is 200-400 mg/kg.
5. A pharmaceutical formulation for treating gastric cancer, comprising the pharmaceutical composition of claim 1 or 2, and a pharmaceutically acceptable carrier.
6. The pharmaceutical formulation for treating gastric cancer according to claim 5, wherein the formulation of the pharmaceutical formulation is a decoction, a tablet, a capsule, an injection, a powder injection, a granule or a syrup.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101062029A (en) * | 2007-05-21 | 2007-10-31 | 中国药科大学 | Application of wogonin in the preparing of medicine for treating gastric cancer |
| CN114831980A (en) * | 2022-05-13 | 2022-08-02 | 中国药科大学 | A composition containing wogonin and baicalein and its application in preparing medicine for treating colorectal cancer |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101062029A (en) * | 2007-05-21 | 2007-10-31 | 中国药科大学 | Application of wogonin in the preparing of medicine for treating gastric cancer |
| CN114831980A (en) * | 2022-05-13 | 2022-08-02 | 中国药科大学 | A composition containing wogonin and baicalein and its application in preparing medicine for treating colorectal cancer |
Non-Patent Citations (4)
| Title |
|---|
| KISHORE BANIK 等: "Wogonin and its analogs for the prevention and treatment of cancer: A systematic review.", PHYTOTHERAPY RESEARCH, vol. 36, pages 1854 - 1883 * |
| 戴金芬 等: "汉黄芩素通过调控上皮间质转化抑制胃癌细胞的侵袭转移", 现代生物医学进展, vol. 20, no. 6, pages 1022 - 1027 * |
| 曹慧娟 等: "黄芩素诱导肿瘤细胞凋亡的研究进展", 中华中医药学刊, vol. 35, no. 4, pages 946 - 948 * |
| 王丽娇: "黄芩素-汉黄芩素复合物对Hela 细胞凋亡作用及机制的研究", 中国优秀硕士学位论文全文数据库 医药卫生科技辑, no. 03, pages 057 - 271 * |
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