CN111265665B - Pharmaceutical composition for treating cervical cancer and pharmaceutical application thereof - Google Patents
Pharmaceutical composition for treating cervical cancer and pharmaceutical application thereof Download PDFInfo
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- CN111265665B CN111265665B CN202010194278.2A CN202010194278A CN111265665B CN 111265665 B CN111265665 B CN 111265665B CN 202010194278 A CN202010194278 A CN 202010194278A CN 111265665 B CN111265665 B CN 111265665B
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- cervical cancer
- pharmaceutical composition
- licochalcone
- pharmaceutical
- apatinib
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- 206010008342 Cervix carcinoma Diseases 0.000 title claims abstract description 43
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 title claims abstract description 43
- 201000010881 cervical cancer Diseases 0.000 title claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 33
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- 230000000694 effects Effects 0.000 claims abstract description 22
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- WBDNTJSRHDSPSR-UHFFFAOYSA-N Licochalcone C Natural products C1=CC(O)=C(CC=C(C)C)C(OC)=C1C=CC(=O)C1=CC=C(O)C=C1 WBDNTJSRHDSPSR-UHFFFAOYSA-N 0.000 claims abstract description 20
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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
- 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
-
- 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
- A61K31/12—Ketones
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition for treating cervical cancer and pharmaceutical application thereof. The pharmaceutical composition of the invention comprises effective dose of licochalcone and VEGFR inhibitor, has synergistic inhibition effect on HeLa S3 cervical cancer cell strain, and has more obvious anticancer effect when the two are combined compared with the single use of one of the active ingredients. In particular, when licochalcone B and apatinib are mixed in a molar ratio of 1:3, the inhibition effect is optimal when the components are mixed, and the treatment effect of the medicine can be obviously improved.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition for treating cervical cancer and pharmaceutical application thereof.
Background
Cervical cancer is one of the malignant tumors that seriously threaten the health of women worldwide. In a global cancer survey of 2018, the incidence and mortality of cervical cancer is located at the 4 th position of all female malignancies. An estimated 53 million new cases per year with 27 million deaths. In China, about 13 thousands of new cases of cervical cancer occur each year, about 5.3 thousands of cases die, and the number of deaths accounts for about 18.4% of deaths of female patients caused by malignant tumors.
The development of cervical cancer is a complex and slow process, and the cervical cancer develops from cervical epitheliosis intratumoral transformation to invasive cervical cancer, and the specific pathogenesis is not clear. It is currently believed that cervical cancer occurs in association with Human Papillomavirus (HPV), that more than 90% of cervical cancer patients have HPV infections, and that almost all cervical cancers are associated with HPV, including cervical squamous cell carcinoma (70%), cervical adenocarcinoma (25%) and mixed histological tumors. HPV is a group of small non-enveloped double-stranded DNA viruses belonging to the papovaviridae family, which are similar to polyomaviruses and consist of about 72 chitosans; the genome of HPV is a circular structure comprising DNA of 7500-8000bp related to histones, compressed into chromatin-like aggregates.
At present, the treatment modes of cervical cancer mainly adopt surgical treatment, external radiation radiotherapy, intracavity radiotherapy and auxiliary chemotherapy. The early cervical cancer is usually treated by an operation, and the operation mode is radical hysterectomy plus pelvic lymph node cleaning, so that the treatment effect is good; radiation therapy can be used when not indicated by surgery, and cervical cancer is generally sensitive to radiation therapy, but has a relatively poor prognosis for advanced and recurrent cervical cancer. Despite advances in surgical and adjuvant therapies, development and recurrence of the disease continues to afflict women with cervical cancer, and finding effective treatments is critical, especially in middle-to-advanced and recurrent patients, where effective chemotherapy is important. Anti-angiogenesis (bevacizumab) targeted therapy has improved the quality of life of patients with recurrent metastatic cervical cancer, while the use of other new molecularly targeted drugs and immune checkpoint inhibitors is actively explored.
Disclosure of Invention
The invention aims to solve the technical problem of the prior art and provides a pharmaceutical composition for treating cervical cancer and pharmaceutical application thereof. The invention combines licochalcone and VEGFR inhibitor to treat cervical cancer, greatly improves the use effect of single medicine. Experiments prove that the licochalcone and VEGFR inhibitor combined drug can obviously inhibit the proliferation of cervical cancer cells.
In order to solve the technical problems, the invention adopts the technical scheme that:
a pharmaceutical composition for treating cervical cancer comprises licochalcone and VEGFR inhibitor with effective dose.
Preferably, the molar ratio of the licochalcone to the VEGFR inhibitor is (1-5) to (5-10).
Preferably, the molar ratio of licochalcone to VEGFR inhibitor is 1: 3.
Preferably, the licochalcone is licochalcone B.
Preferably, the VEGFR inhibitor is selected from one or more of apatinib, imatinib, lapatinib.
Preferably, the VEGFR inhibitor is selected from apatinib.
Preferably, the cervical cancer is cervical squamous cell carcinoma.
Furthermore, the invention also provides a pharmaceutical preparation with the effect of treating cervical cancer, which comprises the pharmaceutical composition and pharmaceutic conventional auxiliary materials.
Preferably, the preparation is selected from one or more of tablets, capsules, granules and injections.
Further, the invention also provides application of the pharmaceutical composition in preparing a medicine for treating cervical cancer.
The chalcone compound molecules can be combined with different biological receptors, and have obvious inhibition effect on tumor cell proliferation, and the action mechanism comprises the following components: inhibition of tubulin polymerization, anti-angiogenesis, induction of apoptosis, anti-estrogen and reversal of multidrug resistance. Research shows that chalcone is an important compound type of a novel antitumor drug or an antitumor auxiliary drug with application prospect. Licochalcone is a newly discovered estrogen flavone, which can be divided into several different types. Licochalcone B (lico B) is a chalcone compound obtained from Glycyrrhiza plants, exists in root and stem of Glycyrrhiza uralensis Fisch of Leguminosae, is yellow needle crystal, and is difficult to dissolve in water. Research reports that Lico B has the effects of resisting inflammation, resisting bacteria (having strong inhibitory activity on gram-positive bacteria), resisting oxidation, resisting Alzheimer disease, protecting liver and the like. Recent studies have reported that Lico B also has significant antitumor activity, which can inhibit the proliferation of tumor cells and induce cell cycle arrest and apoptosis of tumor cells.
Angiogenesis abnormalities are a key factor in the development of a variety of diseases, including tumors, and the process is complex and involves highly regulated interactions of multiple signaling molecules. The angiogenesis promoting signal molecules such as VEGF, VEGFR-2 and the like are highly expressed in various human tumors and play an important role in tumor neovascularization. Because of its important role in tumor development, the vascular system has become one of the targets for tumor therapy. The anti-angiogenesis therapy can normalize the tumor vasculature by preventing the expansion of the tumor vasculature, thereby improving the blood circulation conditions around the tumor, enabling the cytotoxic drug to be uniformly delivered to the tumor tissue core, and enhancing the anti-tumor effect of the drug. In addition, anti-angiogenic therapies can also reduce the chemotherapy resistance of tumor cells by improving hypoxic microenvironment and reducing interstitial pressure. The above studies suggest that targeting multiple molecules in the angiogenic cascade with an angiogenesis inhibitor optimizes inhibition of angiogenesis and may improve clinical therapeutic efficacy in cervical cancer patients. Apatinib is a novel micromolecular VEGFR-2 tyrosine kinase inhibitor independently developed in China, and the main action mechanism of the Apatinib is that the VEGFR-2 tyrosine kinase activity is inhibited, the signal transduction of the combined VEGF and the receptor thereof is blocked, and the tumor angiogenesis is inhibited.
Compared with the prior art, the invention has the beneficial effects that: the inventor unexpectedly finds that the licochalcone and the VEGFR inhibitor have synergistic inhibition effect on a HeLa S3 cell line when being simultaneously administered, and the anticancer effect is more obvious when the licochalcone and the VEGFR inhibitor are used together compared with the anticancer effect when one of the active ingredients is singly used. In particular, when licochalcone B and apatinib are mixed in a molar ratio of 1:3, the inhibition effect is optimal when the components are mixed, and the treatment effect of the medicine can be obviously improved.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1
A pharmaceutical composition for treating cervical cancer comprises an effective amount of licochalcone B and apatinib, wherein the molar ratio of the licochalcone B to the apatinib is 1: 3.
Example 2
A pharmaceutical composition for treating cervical cancer comprises effective amounts of licochalcone B and imatinib, wherein the molar ratio of licochalcone B to imatinib is 1: 3.
Example 3
A pharmaceutical composition for treating cervical cancer comprises effective amounts of licochalcone B and lapatinib, wherein the molar ratio of licochalcone B to lapatinib is 1: 3.
Example 4
A pharmaceutical composition for treating cervical cancer comprises an effective amount of licochalcone B and apatinib, wherein the molar ratio of the licochalcone B to the apatinib is 1: 10.
Example 5
A pharmaceutical composition for treating cervical cancer comprises an effective amount of licochalcone B and apatinib, wherein the molar ratio of the licochalcone B to the apatinib is 1: 1.
Comparative example 1
A pharmaceutical composition for treating cervical cancer comprises licochalcone B with effective dose.
Comparative example 2
A pharmaceutical composition for treating cervical cancer comprises an effective amount of apatinib.
Comparative example 3
A pharmaceutical composition for treating cervical cancer comprises an effective amount of licochalcone B and apatinib, wherein the molar ratio of the licochalcone B to the apatinib is 2: 1.
In vitro cell experiments
1. Experimental materials:
HeLa S3 (human cervical cancer cell line)
2. The experimental method comprises the following steps:
cell lines grown in log phase were quantified (about 10 per well)3Individual cells) were added to a 96-well culture plate, and after 24 hours of complete cell adhesion, the pharmaceutical compositions of examples 1-5 and comparative examples 1-3 (0.125. mu.g/ml, 0.25. mu.g/ml, 0.50. mu.g/ml, 1.00. mu.g/ml, 2.00. mu.g/ml, 4.00. mu.g/ml, 8.00. mu.g/ml, 16.00. mu.g/ml, 32.00. mu.g/ml, 64.00. mu.g/ml) were added at different concentrations, with 4 duplicate wells being set for each concentration. The negative control group was added with complete medium. Culturing in an incubator at 37 ℃ for 48h, adding 10 mu l of MTT solution with the concentration of 5mg/ml into each hole, continuously culturing for 4h, removing supernatant, adding 150 mu l of DMSO into each hole, fully shaking for dissolution, and rapidly determining the OD value of absorbance under the condition of 570nm by using a microplate reader.
3. The calculation method comprises the following steps:
growth Inhibition (GI) × 1- (drug group OD value/negative control group OD value) × 100%. Calculating IC of 48 hours of drug action by SPSS (logit method) according to inhibition rate of each experimental group and negative control group50. The results of the experiment are shown in table 1.
TABLE 1 in vitro IC of pharmaceutical compositions50Measurement of (2)
| Group of | IC50(μg/ml) |
| Example 1 | 6.32±0.37 |
| Example 2 | 8.29±0.52 |
| Example 3 | 8.38±0.59 |
| Example 4 | 7.11±0.68 |
| Example 5 | 7.36±0.62 |
| Comparative example 1 | 17.37±1.77 |
| Comparative example 2 | 48.11±2.78 |
| Comparative example 3 | 8.52±0.60 |
The experimental results in table 1 show that the pharmaceutical composition of the present invention has a strong inhibitory effect on human cervical cancer cell line HeLa S3. Compared with the single use of licochalcone (comparative example 1) or VEGFR inhibitor (comparative example 2), the combined use of the licochalcone and the VEGFR inhibitor (examples 1-5) has more obvious effect of inhibiting the growth of tumor cells and has synergistic inhibition effect on HeLa S3 cell strain. Specifically, when the VEGFR inhibitor in the pharmaceutical composition is apatinib (example 1), its inhibitory effect is superior to that of imatinib (example 2) and lapatinib (example 3), IC50The value can be as low as 6.32. mu.g/ml. In addition, suitable molar ratios between licochalcone and VEGFR inhibitors were also investigated (examples 1,4,5 and comparative example 3), and it was found that when licochalcone B and apatinib were present in a molar ratio of 1:3 when the components are mixed, the growth inhibition effect of the tumor cells is optimal, and the treatment effect of the medicine can be obviously improved.
Inhibition effect of pharmaceutical composition on HeLa S3 (human cervical carcinoma cell) rat transplantation tumor
1. Selection of animals and cell lines:
90 SPF-grade female SD rats (30. + -. 3 g) of 5 weeks old were selected. The cages were housed in 9 cages, 10 per cage. The temperature of the breeding environment is 16-18 deg.C, and the relative humidity is 35-40%. HeLa S3 (human cervical carcinoma cells) was purchased from the cell bank of Chinese academy of sciences.
2. Establishing a model:
suspending and precipitating HeLa S3 cell serum-free culture medium in logarithmic growth phase, counting under microscope, and adjusting cell suspension concentration to (1.5-2) × 108And each/ml, the number of living cells is observed to be more than 90% by staining, 0.2ml of HeLa S3 cell suspension is injected under the skin of the thigh root of a rat in a sterile environment, and a rat model of human cervical carcinoma HeLa S3 cells is established.
3. Grouping and medicine intervention:
successfully modeled rats were randomly divided into 9 groups on day 15, model group + examples 1-5+ comparative examples 1-3, 10 per group. Each administration group is injected into the abdominal cavity, and the model group is injected into the abdominal cavity with the same amount of normal saline for 1 time/day and is continuously administered for 14 days. Wherein the daily dose of each administration group is 50mg/kg, and the daily dose of the VEGFR inhibitor can be converted by a molar ratio between the two.
4. Detection of tumor inhibition effect:
after 14 days, the drug is stopped for 24 hours, the rat is killed by removing the neck, the tumor tissue is completely stripped, the tumor mass condition and the infiltration of peripheral tissues of each group are observed, the ascites and the metastasis of other organs are observed, the tumor mass is measured, and the tumor inhibition rate is calculated. The results of the experiment are shown in table 2.
TABLE 2 inhibitory Effect of the pharmaceutical compositions on HeLa S3 rat transplantable tumors
| Grouping | Mass of tumor before treatment (g) | Tumor mass (g) after treatment | Tumor inhibition Rate (%) |
| Model set | 1.75±0.16 | 1.98±0.18 | - |
| Example 1 | 1.72±0.11 | 0.62±0.15 | 64.0％ |
| Example 2 | 1.74±0.12 | 0.92±0.13 | 47.1％ |
| Example 3 | 1.73±0.17 | 0.87±0.09 | 49.7％ |
| Example 4 | 1.70±0.20 | 0.73±0.16 | 57.1％ |
| Example 5 | 1.77±0.21 | 0.71±0.06 | 59.9％ |
| Comparative example 1 | 1.76±0.19 | 1.08±0.24 | 38.3％ |
| Comparative example 2 | 1.74±0.18 | 1.53±0.22 | 12.1％ |
| Comparative example 3 | 1.71±0.14 | 0.90±0.07 | 47.4％ |
As can be seen from the experimental results in table 2, when licochalcone (comparative example 1) or VEGFR inhibitor (comparative example 2) was used in combination (examples 1 to 5), the effect of resisting cervical cancer was more significant, and the synergistic inhibitory effect was exhibited on HeLa S3 cell line, as compared to when licochalcone alone (comparative example 1) or VEGFR inhibitor alone (comparative example 2). Specifically, when the VEGFR inhibitor in the pharmaceutical composition is apatinib (example 1), its anticancer effect is superior to that of imatinib (example 2) and lapatinib (example 3). In addition, suitable molar ratios between licochalcone and VEGFR inhibitors were also investigated (examples 1,4,5 and comparative example 3), and it was found that when licochalcone B and apatinib were present in a molar ratio of 1:3, the inhibition effect is optimal when the components are mixed, and the treatment effect of the medicine can be obviously improved.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications or equivalents may be made to the technical solution without departing from the principle of the present invention, and these modifications or equivalents should also be regarded as the protection scope of the present invention.
Claims (10)
1. A pharmaceutical composition for treating cervical cancer, which is characterized by comprising an effective amount of licochalcone and a VEGFR inhibitor.
2. The pharmaceutical composition of claim 1, wherein the molar ratio of licochalcone and VEGFR inhibitor is (1-5) to (5-10).
3. The pharmaceutical composition of claim 2, wherein the molar ratio of licochalcone to VEGFR inhibitor is 1: 3.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the licochalcone is licochalcone B.
5. The pharmaceutical composition of any of claims 1-3, wherein the VEGFR inhibitor is selected from one or more of apatinib, imatinib, and lapatinib.
6. The pharmaceutical composition of claim 5, wherein the VEGFR inhibitor is selected from apatinib.
7. The pharmaceutical composition of any one of claims 1-3, wherein the cervical cancer is cervical squamous cell carcinoma.
8. A pharmaceutical preparation having an effect of treating cervical cancer, comprising the pharmaceutical composition of any one of claims 1 to 7 and pharmaceutically conventional excipients.
9. The pharmaceutical preparation according to claim 8, wherein the preparation is selected from one or more of tablets, capsules, granules and injections.
10. Use of a pharmaceutical composition according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of cervical cancer.
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| CN108698999A (en) * | 2015-11-20 | 2018-10-23 | 李镐允 | Quinolone chalcone compound and application thereof |
| CN109893654A (en) * | 2017-12-11 | 2019-06-18 | 江苏恒瑞医药股份有限公司 | The method of VEGFR inhibitor for treating tumour |
| CN108187055A (en) * | 2018-03-06 | 2018-06-22 | 北京大学 | A kind of anti-cancer composition with synergistic function |
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