CN112237586A - Application of rhizoma paridis saponin and sorafenib in preparation of anti-tumor combined medicine - Google Patents

Application of rhizoma paridis saponin and sorafenib in preparation of anti-tumor combined medicine Download PDF

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CN112237586A
CN112237586A CN202011096312.9A CN202011096312A CN112237586A CN 112237586 A CN112237586 A CN 112237586A CN 202011096312 A CN202011096312 A CN 202011096312A CN 112237586 A CN112237586 A CN 112237586A
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sorafenib
saponin
liver cancer
paris polyphylla
tumor
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何庆瑜
汪洋
高桂彬
张静
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Jinan University
University of Jinan
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The invention discloses application of paridis saponin and sorafenib in preparation of an anti-tumor combined medicament. According to the invention, the combination of the paris polyphylla saponin and the sorafenib drug is found, and the same drug dosage can achieve a better effect of inhibiting the growth of liver cancer cells. Therefore, the combination of the paris polyphylla saponin and the sorafenib can prepare a medicament for effectively treating liver cancer, and has wide application prospect.

Description

Application of rhizoma paridis saponin and sorafenib in preparation of anti-tumor combined medicine
Technical Field
The invention relates to the technical field of medicines, in particular to application of paris polyphylla saponin and sorafenib in preparation of an anti-tumor combined medicine.
Background
The paris polyphylla is a dried rhizome of paris polyphylla or paris polyphylla, and in recent years, with continuous research on pharmacological evaluation of paris polyphylla, the paris polyphylla is found to have the effects of resisting bacteria and tumors. Rhizome of Paris polyphylla contains many kinds of chemical compoundsThe compound comprises steroid saponin, ion amino acid, sterol-grade flavone, etc., wherein the steroid saponin contains one of the main active ingredients of rhizoma paridis (Polyphyllin D, PD)1The structural formula is shown as formula I:
Figure BDA0002723870740000011
sorafenib (Sorafenib) is a novel multi-targeted oral drug for treating tumors. Sorafenib can inhibit the proliferation of tumor cells, inhibit the formation of new blood vessels, and cut off the nutrient supply of tumor cells to inhibit tumor growth, and is primarily developed for treating gastrointestinal stromal tumors and metastatic renal cells that do not respond to or are intolerant to standard therapies2. The structural formula of sorafenib is shown as formula II:
Figure DEST_PATH_IMAGE001
hepatocellular carcinoma (HCC) is one of the malignant cancers that have recently tended to increase in mortality rates. Liver cancer usually has no obvious sign change in the early stage, and the disease is generally in the late stage when patients find the disease. Liver cancer is mainly treated by surgery, but the treatment of HCC usually faces the problems of postoperative cancer recurrence and metastasis. Therefore, the combination of chemotherapy is needed. There is a clinical need to find more effective drugs for treating HCC.
Related reports show that PD has an inhibitory effect on ovarian cancer3It has effects of inhibiting or inducing apoptosis of hepatocarcinoma cell. Sorafenib is also reported in the literature to inhibit lung cancer cell growth4However, the drug sensitivity is inactivated in the clinical liver cancer treatment process. At present, no report related to the treatment of liver cancer by the combination of the paris polyphylla saponin and the sorafenib is available.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides the application of the paris polyphylla saponin and the sorafenib in preparing an anti-tumor combined medicament.
The invention also aims to provide an anti-tumor medicament.
The purpose of the invention is realized by the following technical scheme: application of rhizoma paridis saponin and Sorafenib in preparing anti-tumor combined medicine is provided.
The tumor is preferably liver cancer.
The liver cancer cell is preferably HepG2 cell or Hep3B cell.
An antitumor drug comprises rhizoma paridis saponin and Sorafenib.
The tumor is preferably liver cancer.
The concentration of the rhizoma paridis saponin is 1.5-6 μ M; preferably 3. mu.M
The concentration of the sorafenib is 5-20 mu M; preferably 10. mu.M.
The anti-tumor medicine contains a pharmaceutically acceptable carrier or auxiliary material.
The carrier is preferably at least one of microcapsule, microsphere, nanoparticle or liposome.
The auxiliary materials are preferably at least one of cosolvent, preservative, wetting agent, emulsifier, surfactant, sustained release agent, disintegrant, excipient and filler.
The antitumor drug is prepared into various dosage forms by adopting a conventional method.
Application of rhizoma paridis saponin and Sorafenib in preparing medicine for inhibiting cell proliferation is provided.
The cells are preferably liver cancer cells.
Compared with the prior art, the invention has the following advantages and effects:
the invention combines the paris polyphylla saponin and the sorafenib, and the same drug dosage can achieve better effect of inhibiting the growth of liver cancer cells. Therefore, the combination of the paris polyphylla saponin and the sorafenib can prepare a medicament for effectively treating liver cancer, and has wide application prospect.
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FIG. 1 is a graph showing the effect of the combination of paridis saponin and Sorafenib on the formation of HepG2 and Hep3B clones of liver cancer cells; wherein, A is a photograph of influence of the paris polyphylla saponin, the sorafenib and the combination thereof on the formation of cloned cells, and B is a statistical chart of the number of the paris polyphylla saponin, the sorafenib and the combined use thereof on the number of the cloned cells.
FIG. 2 is a graph showing the results of cell activity assays of cells treated with different concentrations of Paris saponin and Sorafenib alone; wherein A is rhizoma paridis saponin, and B is sorafenib.
FIG. 3 is a statistical chart of the effect of the combination of the paridis saponin and Sorafenib on the activity of liver cancer cells.
FIG. 4 is a graph showing the effect of Hep3B on the tumorigenicity ability of hepatoma cells in nude mice; wherein, A is a picture of a tumor forming picture of Hep3B of each experimental group, and B is a statistical picture of tumor weight.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Human hepatoma cells HepG2 and Hep3B were purchased from the chinese academy of sciences cell bank.
Example 1
(1) In vitro experiments: different drug combinations are used for treating the liver cancer cells, and then the WST-1 and clone formation experiments are used for detecting the cell activity, so as to research the influence of different combinations of the paris polyphylla saponin and the sorafenib on the proliferation of the liver cancer cells.
The cell activity detection experiment comprises the following steps:
1) spreading HepG2 and Hep3B into 96-well plates, 3000 cells per well;
2) dissolving rhizoma paridis saponin (purchased from Shanghai ceramic Biotechnology Co., Ltd.) in DMSO (dimethyl sulfoxide) to prepare stock solution with concentration of 10mM, and diluting the stock solution with DMEM cell culture medium (purchased from Life Technologies, Gaithersburg, Md., USA) to prepare working solution with different concentrations;
3) sorafenib (purchased from Shanghai ceramic Biotechnology Co., Ltd.) is dissolved in DMSO (dimethyl sulfoxide) to prepare stock solution with the concentration of 10mM, and then DMEM cell culture medium (purchased from Life Technologies, Gaithersburg, Md., USA) is used for diluting the stock solution to prepare working solution with different concentrations;
4) after the cells in the step 1) adhere to the wall, respectively adding the working solutions with different concentrations prepared in the steps 2 and 3 to treat the cells: 1. adding the Paris saponin working solutions with different concentrations prepared in the step 2, wherein the concentration gradient in the system is 0 muM, 1.5 muM, 3 muM and 6 muM; 2. adding the Sorafenib working solution with different concentrations prepared in the step (3), wherein the concentration gradient in the system is 0 muM, 5 muM, 10 muM and 20 muM; 3. simultaneously adding the paris polyphylla saponin working solution and the sorafenib working solution prepared in the steps 2 and 3, wherein the concentrations of the paris polyphylla saponin and the sorafenib working solution in the system are respectively 3 mu M and 10 mu M; 4. the blank was supplemented with DMEM (0.1% DMSO) medium. After 24 hours of treatment, the cell activity was detected by using a WST-1 cell proliferation and cytotoxicity detection kit (purchased from Biyuntian biotechnology, Co., Ltd.); the above experimental procedure was performed in 3 biological replicates.
The cloning capacity test was carried out as follows:
1) laying HepG2 and Hep3B into 12-well plates, 500 cells per well, respectively;
2) dissolving rhizoma paridis saponin and Sorafenib in DMSO (dimethyl sulfoxide) to obtain stock solution with concentration of 10mM, and diluting the stock solution with DMEM cell culture medium (purchased from Life Technologies, Gaithersburg, Md., USA) to obtain working solution;
3) after the cells in the step 1) adhere to the wall, adding the paris polyphylla saponin and the sorafenib working solution prepared in the step 2 respectively to treat the cells: 1. simultaneously adding the prepared paris polyphylla saponin and sorafenib working solution, wherein the concentration in the system is 3 mu M and 10 mu M respectively; 2. adding the paris polyphylla saponin working solution until the concentration of the paris polyphylla saponin working solution in the system is 3 mu M; 3. adding Sorafenib working solution until the concentration of the Sorafenib working solution in the system is 10 mu M; 4. the blank was added to DMEM medium containing 0.1% DMSO. After 15 days of treatment, fixing with absolute methanol and detecting the cell clone formation after crystal violet staining; the above experimental procedure was performed in 3 biological replicates.
The results are shown in FIGS. 1 to 3. FIG. 1 shows the results of detecting the clonogenic capacities of hepatoma cells HepG2 and Hep3B, and FIG. 2 shows the results of detecting the activities of cells treated with different concentrations of chiretta saponin and Sorafenib alone. FIG. 3 shows the results of cell activity assays using 3. mu.M Paris Saponin and 10. mu.M Sorafenib alone or in combination. The results show that the activity of the cells HepG2 and Hep3B after the combination of the paris polyphylla saponin and the sorafenib is obviously lower than that of the single drug.
(2) In vivo experiments: 24 female nude mice (balb/c-nu/nu, purchased from Jiangsu Jiziyao Biotech Co., Ltd.) with age of 6 weeks, 6 control groups and 18 experimental groups were selected to construct subcutaneous tumor models: (1) liver cancer cell Hep3B was resuspended in 1 XPBS buffer and mixed with matrigel at a volume ratio of 1:1, and injected subcutaneously 2X 10/nude mouse6Hep3B cells; (2) before the experiment, the nude mouse is anesthetized, the anesthesia degree is evaluated through painless and painful stimulation, and the nude mouse is determined to be in an anesthetic state; (3) taking the resuspended cells by using a microinjector with a 25G needle head to carry out subcutaneous injection on the nude mice; (4) and (3) drug treatment: ten days after subcutaneous injection, administration by intragastric administration was started. In the experiment, 3 medicine combinations are set, wherein the medicine combinations are respectively PD 4mg/kg, Sorafenib 10mg/kg, PD 4mg/kg and Sorafenib 10 mg/kg; each group was 6, administered every two days. The drug was dissolved in edible oil and each mouse was dosed with 100 μ L each time. Tumor size and body weight of nude mice were measured for each dose. After 3 weeks the nude mice were euthanized and the tumors were removed, photographed and weighed.
The experimental result of the nude mouse subcutaneous tumor formation is shown in fig. 4, the size and weight of the tumor show that the nude mouse subcutaneous tumor formation is obviously inhibited after the combination of the paris polyphylla saponin and the sorafenib, and the paris polyphylla saponin and the sorafenib can better inhibit the growth of the liver cancer tumor.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Reference documents:
1. wushan san, Gaoyangyuan, hongquan, Jiawei, Paris polyphylla chemical composition and pharmacological action research progress Chinese herbal medicine 2004(03): 344-.
2.Wilhelm SM,Carter C,Tang L,et al.BAY 43-9006exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.Cancer Res. 2004；64(19):7099-7109.doi:10.1158/0008-5472.CAN-04-1443.
3.Xiao X,Zou J,Bui-Nguyen TM,et al.Paris saponin II of Rhizoma Paridis--a novel inducer of apoptosis in human ovarian cancer cells.Biosci Trends. 2012；6(4):201-211.doi:10.5582/bst.2012.v6.4.201 4.Li M,Yang J,Zhou W,et al. Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer.Br J Cancer.2017；117(7):974-983. doi:10.1038/bjc.2017.292.
4.Wei L,Lee D,Law CT,Zhang MS,Shen J,Chin DW,Zhang A,Tsang FH, Wong CL,Ng IO,Wong CC,Wong CM.Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC.Nat Commun.2019 Oct 15；10(1):4681.doi:10.1038/s41467-019-12606-7.PMID: 31615983；PMCID:PMC6794322。

Claims (10)

1. The application of the combination of the paris polyphylla saponin and the sorafenib in preparing the antitumor drug.
2. The use of claim 1, wherein the tumor is liver cancer.
3. The use of claim 2, wherein the liver cancer cell is HepG2 cell or Hep3B cell.
4. An antitumor drug is characterized by comprising paris polyphylla saponin and sorafenib.
5. The antitumor agent as claimed in claim 4, wherein the tumor is liver cancer.
6. The antitumor drug as claimed in claim 5, wherein the concentration of the said polyphyllin is 1.5-6 μ M; the concentration of the sorafenib is 5-20 mu M.
7. The antitumor drug as claimed in claim 6, wherein the concentration of the said polyphyllin is 3 μ M; the concentration of the sorafenib is 10 mu M.
8. The antitumor agent as claimed in any one of claims 4 to 7, wherein said antitumor agent comprises a pharmaceutically acceptable carrier or excipient.
9. The antitumor agent as claimed in claim 8,
the carrier is at least one of a microcapsule, a microsphere, a nanoparticle or a liposome;
the auxiliary materials are at least one of cosolvent, preservative, wetting agent, emulsifier, surfactant, sustained release agent, disintegrant, excipient and filler.
10. The application of the paris polyphylla saponin and sorafenib in preparing the medicine for inhibiting cell proliferation is characterized in that the cell is a liver cancer cell.
CN202011096312.9A 2020-10-14 2020-10-14 Application of rhizoma paridis saponin and sorafenib in preparation of anti-tumor combined medicine Pending CN112237586A (en)

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WO2022078223A1 (en) * 2020-10-14 2022-04-21 暨南大学 Uses of polyphyllin and sorafenib in the preparation of antitumor drug combination

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CN101536986B (en) * 2009-04-16 2011-05-04 北京圣医耀科技发展有限责任公司 Sodium alginate targeted sustained release microsphere vascular occlusive agent containing Sorafenib as well as preparation and application thereof
CN112237586A (en) * 2020-10-14 2021-01-19 暨南大学 Application of rhizoma paridis saponin and sorafenib in preparation of anti-tumor combined medicine

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倪博然等: "重楼皂苷Ⅵ对肝癌HepG2细胞凋亡的作用", 《中华中医药杂志》 *

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WO2022078223A1 (en) * 2020-10-14 2022-04-21 暨南大学 Uses of polyphyllin and sorafenib in the preparation of antitumor drug combination

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Application publication date: 20210119