CN113350325B - Application of dianthrone compound in preparation of antitumor drugs - Google Patents
Application of dianthrone compound in preparation of antitumor drugs Download PDFInfo
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- CN113350325B CN113350325B CN202110806685.9A CN202110806685A CN113350325B CN 113350325 B CN113350325 B CN 113350325B CN 202110806685 A CN202110806685 A CN 202110806685A CN 113350325 B CN113350325 B CN 113350325B
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- A—HUMAN NECESSITIES
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Abstract
The invention provides an application of dianthrone compounds in preparing anti-liver cancer tumor drugs, belonging to the technical field of biological medicines; the dianthranone compound comprises Trans-emodin dianthranone and/or Cis-emodin dianthranone. The invention provides a new application of dianthrone compounds in the aspect of preventing and/or treating liver cancer. Experiments prove that the dianthrone compound has the following significant activity in pharmacology: inhibiting the growth of liver cancer cells, inducing S-phase arrest, inducing the apoptosis of liver cancer cells, and showing significant anti-liver cancer activity in vivo.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of dianthrone compounds in preparation of anti-tumor medicines.
Background
Liver cancer, i.e., malignant tumor of liver, can be divided into two main categories, primary and secondary. Liver cancer is an important public health problem in the world, and the treatment of liver cancer mainly comprises liver transplantation, liver cancer surgical treatment, radiotherapy and chemotherapy. Surgery is the main treatment mode of liver cancer, but because liver cancer is hidden, most patients are diagnosed at an advanced stage and are easy to be combined with liver cirrhosis, the number of patients who can be treated by the surgery is less than 30%, the resection rate of the surgery is very low, the recurrence rate after the surgery is high, and the prognosis is very poor. Liver transplantation is also an effective treatment means, but the indication requirement for liver transplantation is extremely strict, and a proper liver source is difficult to obtain. Among other two treatment methods, liver cancer has poor sensitivity to radiotherapy and low sensitivity to drug treatment, but the 5-year survival rate of liver cancer patients who cannot be operated is only 5%, and drug treatment is still indispensable to liver cancer.
Cytotoxic drugs in conventional drug therapy such as fluorouracil, doxorubicin, cisplatin and the like have serious toxic and side effects in treating liver cancer, and generally can not significantly alleviate the liver cancer process or prolong the life. At present, only the tyrosine kinase inhibitor sorafenib is proved to be a drug capable of prolonging the life cycle of liver cancer patients, the toxic and side effects are obviously reduced, the curative effect is poor, and the drug resistance phenomenon also exists.
At present, liver cancer treatment medicines far fail to meet clinical requirements, and discovery of new medicines with anti-liver cancer activity is of great significance.
Disclosure of Invention
The invention aims to provide application of dianthrone compounds in preparing anti-tumor medicines and provides new application of the dianthrone compounds in preventing and/or treating liver cancer.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an application of dianthrone compounds in preparing anti-liver cancer tumor drugs;
the dianthranone compound comprises Trans-emodin dianthranone and/or Cis-emodin dianthranone.
Preferably, when the dianthrone compounds comprise Trans-emodin dianthrone and Cis-emodin dianthrone, the molar ratio of Trans-emodin dianthrone to Cis-emodin dianthrone is 1: (0.5-1).
Preferably, the Trans-emodin dianthrone and the Cis-emodin dianthrone are racemates including Trans-emodin dianthrone and Cis-emodin dianthrone.
Preferably, the actual racemization ratio of the racemates of the Trans-emodin dianthrone and the Cis-emodin dianthrone is 56:38.
preferably, the liver cancer tumor is formed by human liver cancer HepG2 cells or mouse H22 liver cancer.
Preferably, the content of dianthrone compounds in the medicine is 0.1-95% by mass.
Preferably, the content of the dianthrone compound in the medicament is 30-90% by mass.
Preferably, the dosage form of the medicament comprises an oral preparation, an external preparation, an injection or a cavity administration preparation.
The invention provides application of dianthrone compounds in preparing anti-hepatoma tumor medicines; the dianthranone compound comprises Cis-emodin dianthranone and/or Trans-emodin dianthranone. The invention provides a new application of the dianthrone compound in preparing a medicament for preventing and/or treating liver cancer. Experiments prove that the dianthrone compound has the following significant activity in pharmacology: inhibiting the growth of liver cancer cells, inducing S-phase arrest, inducing the apoptosis of liver cancer cells, and showing significant anti-liver cancer activity in vivo.
Drawings
Figure 1 growth inhibitory activity on human liver cancer HepG2 cells (n = 4);
FIG. 2 effect on the cell cycle of human hepatoma HepG 2;
FIG. 3 shows the result of counting the number of human hepatoma HepG2 cells in the S phase;
FIG. 4 shows the effect of promoting human hepatoma HepG2 apoptosis.
Detailed Description
The invention provides an application of dianthrone compounds in preparing anti-liver cancer tumor drugs;
the dianthranone compound comprises Trans-emodin dianthranone and/or Cis-emodin dianthranone.
In the present invention, when the dianthrones include Trans-emodin dianthrone and Cis-emodin dianthrone, the molar ratio of Trans-emodin dianthrone to Cis-emodin dianthrone is preferably 1: (0.5-1).
In the invention, the chemical structural formula of the Trans-emodin dianthrone (HSW-W-25) is shown as a formula I; the chemical structural formula of the Cis-emodin dianthrone (HSW-W-26) is shown as a formula II;
the sources of Cis-emodin dianthrone and Trans-emodin dianthrone are not particularly limited in the present invention and are derived from conventional commercial sources or prepared according to methods well known in the art.
In the invention, the Trans-emodin dianthrone and the Cis-emodin dianthrone are preferably racemates comprising Trans-emodin dianthrone and Cis-emodin dianthrone, and the actual racemization ratio is preferably 56:38.
in the present invention, the liver cancer tumor is preferably formed of HepG2 cells or H22 cells.
In the present invention, the content of dianthrone compounds in the drug is preferably 0.1% to 95% by mass, more preferably 30% to 90% by mass, and most preferably 50% to 80% by mass.
In the present invention, the administration route of the drug includes enteral administration or parenteral administration; the enteral administration comprises oral administration or rectal administration; the parenteral administration comprises: intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin or vagina.
In the present invention, the dosage form of the drug preferably includes an oral preparation, a topical preparation, an injection or a preparation for cavity administration.
In the present invention, the oral formulation preferably includes tablets, capsules, pills, granules, oral liquids or suspensions; in the invention, the tablet is preferably included in the invention, and the injection preferably comprises water injection, powder injection and infusion solution.
In the present invention, the dosage form of the drug includes a gaseous dosage form, a liquid dosage form, a solid dosage form or a semisolid dosage form.
In the present invention, the gaseous dosage form preferably comprises an aerosol or spray.
In the present invention, the liquid dosage form includes a solution, an emulsion, a suspension, an injection, an eye drop, a nasal drop, a lotion or a liniment; the solution comprises a true solution or a colloidal solution; the emulsion comprises o/w type and w/o type living compound emulsion; the injection comprises water injection, powder injection or infusion solution.
In the invention, the solid dosage form preferably comprises tablets, capsules, granules, powder, pellets, dripping pills, suppositories, films, patches or powder aerosols; in the present invention, the tablet preferably includes a plain tablet, an enteric coated tablet, a buccal tablet, a dispersible tablet, a chewable tablet, an effervescent tablet or an orally disintegrating tablet; in the present invention, the capsule preferably includes a hard capsule, a soft capsule or an enteric capsule.
In the present invention, the semisolid dosage form preferably includes an ointment, a gel, or a paste.
In the present invention, the dosage form of the drug preferably includes a general formulation, a sustained release formulation, a controlled release formulation, a targeted formulation or a microparticle delivery system.
In the present invention, the medicament preferably further comprises pharmaceutically acceptable excipients. In the present invention, when the dosage form of the medicament is a tablet, the auxiliary material preferably includes one or more of a diluent, a binder, a wetting agent, a disintegrant, a lubricant and a glidant.
In the present invention, the diluent preferably comprises one or more of starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate and calcium carbonate; the wetting agent preferably comprises one or more of water, ethanol and isopropanol; the binder preferably comprises one or more of starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone and polyethylene glycol; the disintegrant preferably comprises one or more of dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate, citric acid, polyoxyethylene sorbitol fatty acid ester and sodium dodecyl sulfate; the lubricant and the glidant independently and preferably comprise one or more of talcum powder, silicon dioxide, stearate, tartaric acid, liquid paraffin and polyethylene glycol.
In the present invention, the tablet is preferably prepared into a coated tablet, and the coated tablet preferably comprises a sugar-coated tablet, a film-coated tablet or an enteric-coated tablet; in the present invention, the tablet preferably comprises a single layer tablet or a multi-layer tablet.
In the present invention, when the dosage form of the medicament is a capsule, the auxiliary materials preferably include one or more of diluents, glidants, wetting agents, binders and disintegrants.
In the invention, when the dosage form of the medicament is injection, the injection is one or more of water, ethanol, isopropanol and propylene glycol; the auxiliary materials preferably comprise one or more of solubilizer, cosolvent, pH regulator and osmotic pressure regulator; the solubilizer and the cosolvent independently and preferably comprise one or more of poloxamer, lecithin and hydroxypropyl-beta-cyclodextrin; the pH regulator preferably comprises one or more of phosphate, acetate, hydrochloric acid and sodium hydroxide; the osmotic pressure regulator preferably comprises one or more of sodium chloride, mannitol, glucose, phosphate and acetate.
In the invention, when the dosage form of the medicament is preferably a freeze-dried powder injection, the auxiliary material preferably comprises a propping agent; the proppant preferably comprises mannitol and/or glucose.
In the invention, the auxiliary materials of the medicine preferably also comprise one or more of a coloring agent, a preservative, a spice and a flavoring agent.
The method of administration of the drug is not particularly limited in the present invention, and a method known in the art may be used.
In the present invention, the daily dose of the drug is preferably 0.001 to 150mg/kg body weight, more preferably 0.1 to 100mg/kg body weight, still more preferably 1 to 60mg/kg body weight, and most preferably 2 to 30mg/kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The medicine of the invention can be taken alone or combined with other therapeutic medicines or symptomatic medicines. When the medicament of the invention has synergistic effect with other therapeutic drugs, the dosage of the medicament is adjusted according to actual conditions.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It should be apparent that the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
The following examples and pharmacological activity experiments are intended to further illustrate the invention, but are not intended to limit the invention in any way. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, the full names or corresponding Chinese names of the partial substances are as follows:
and (3) DHS: emodin and its preparation method
MTT: thiazole blue
DMEM: culture medium containing various amino acids and glucose
DMSO, DMSO: dimethyl sulfoxide
PI: propidium Iodide
AnnexinV/FITC: apoptosis detection reagent
The room temperature described in the examples below is as conventional in the art and is typically 15 to 25 ℃.
Experimental example 1 growth inhibitory Activity of HSW-W-25 and HSW-W-26 against human liver cancer HepG2 cell
The experimental method comprises the following steps:
taking human liver cancer HepG2 cells in logarithmic growth phase, and mixing 5X 10 4 Each cell/ml was inoculated into a 96-well plate at 100. Mu.l per well, and after 24 hours of culture, cells were affected by addition of HSW-W-25 (10. Mu.M, 20. Mu.M), HSW-W-26 (10. Mu.M, 20. Mu.M), and DHS (25. Mu.g/ml), for 48 hours. After removing the supernatant, 100. Mu.l of MTT (0.5 mg/ml, prepared by serum-free DMEM medium) was added to each well, and the mixture was cultured in a cell culture chamber for 4 hours, 150. Mu.l of DMSO was added to each well, and the mixture was placed in a microplate reader at 570nm to measure absorbance, and the cell survival rate was calculated.
Cell survival (%) =100 (blank OD value-administered OD value)/blank OD value.
The experimental results are as follows:
HSW-W-25 (10 μ M, 20 μ M) and HSW-W-26 (10 μ M, 20 μ M) act on HepG2 cells of human liver cancer for 48h, and show significant inhibitory activity on the growth of liver cancer cells, as shown in FIG. 1.
Experimental example 2 HSW-W-25 and HSW-W-26 Induction of HepG2 cell cycle arrest assay for human hepatoma
The experimental method comprises the following steps:
taking human liver cancer HepG2 cells in logarithmic growth phase, and mixing 1.5 × 10 5 Inoculating 1ml of each cell in six-well plate, culturing for 24 hrHSW-W-25 (10. Mu.M, 20. Mu.M), HSW-W-26 (10. Mu.M, 20. Mu.M), DHS (25. Mu.g/ml) were added and the cells were allowed to act for a further 48h. Centrifuging at 1000rpm for 3min, collecting cells, washing the cells once with 4 ℃ precooled PBS, adding 1mL of DNA staining solution and 10 mul of permeabilization solution, vortexing and shaking for 5-10 seconds, mixing uniformly, incubating for 30min at room temperature in a dark place, and performing cell cycle analysis by flow cytometry (FACS).
The experimental results show that: HSW-W-25 (10 mu M and 20 mu M) and HSW-W-26 (10 mu M and 20 mu M) act on HepG2 cells of human liver cancer for 48h, the cell cycle dynamics is obviously changed, the proportion of cells in S phase is obviously increased (figure 2 and figure 3), and the results show that the inhibition of liver cancer cell proliferation by HSW-W-25 and HSW-W-26 is related to the induction of S phase block.
Experimental example 3 HSW-W-25 and HSW-W-26 Induction of human hepatoma HepG2 apoptosis test
The experimental method comprises the following steps:
taking human liver cancer HepG2 cells in logarithmic growth phase, and mixing 1.5 × 10 5 Each/ml cell is inoculated in a six-well plate, 1ml of each well, after 24h of culture, HSW-W-25 (10 MuM, 20 MuM), HSW-W-26 (10 MuM, 20 MuM), DHS (25 Mug/ml) are added to act on the cell 48h, the cell is centrifuged at 1000rpm for 3min, the cell is collected, the cell is washed twice by PBS precooled at 4 ℃,500 Mu l of binding buffer solution is used for resuspending the cell again, 5 Mu l of annexin V/FITC solution and 10 Mu l of PI solution are added, after uniform mixing, the cell is incubated for 5min at room temperature in the dark, and the apoptosis is analyzed by flow cytometry (FACS).
The experimental results show that: HSW-W-25 (10 muM and 20 muM) and HSW-W-26 (10 muM and 20 muM) act on the HepG2 cell of the human liver cancer for 48h, can obviously induce the apoptosis of the liver cancer cell, and the apoptosis cell rate is obviously increased compared with a blank control group (figure 4).
Experimental example 4 test of antitumor Activity of HSW-W-25 and HSW-W-26 against H22-bearing liver cancer mouse
The experimental method comprises the following steps:
0.2ml of H22 hepatoma liquid is inoculated in the anterior axilla of Kunming strain mice, and the mice are randomly grouped the next day, wherein the positive control drug is 5-FU 40mg/kg group, the HSW-25/26 20mg/kg group and the blank control group are respectively provided with 10 mice. The administration is carried out by HSW-25/26 intragastric administration for ten days continuously and 5-FU intraperitoneal injection once every three days for three times in total. Mice were sacrificed 24h after the last dose, terminal body weight and tumor weight were recorded, and tumor inhibition rate was calculated. Tumor inhibition (%) =100 × (tumor weight of placebo-tumor weight of administered group)/tumor weight of placebo.
See table 1 for experimental results:
the racemate HSW-W-25/26 of HSW-W-26 is HSW-W-25/26, 20mg/kg of the drug is continuously applied for 10 days, the drug has obvious tumor inhibition activity on H22 liver cancer, the tumor weight is obviously reduced compared with a blank control group, and meanwhile, the animal weight is not obviously reduced, which indicates that the animal has good tolerance on HSW-W-25/26 (Table 1).
TABLE 1 antitumor Activity on H22 hepatoma bearing mice (n = 10)
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
1. The application of dianthrone compounds in preparing anti-liver cancer and anti-tumor drugs;
the dianthranone compounds are Trans-emodin dianthranone and Cis-emodin dianthranone; the molar ratio of the Trans-emodin dianthrone to the Cis-emodin dianthrone is 1:1; the Trans-emodin dianthrone and the Cis-emodin dianthrone are racemates of the Trans-emodin dianthrone and the Cis-emodin dianthrone.
2. The use according to claim 1, wherein the actual racemization ratio of racemates of Trans-emodin dianthrone and Cis-emodin dianthrone is 56:38.
3. the use of claim 1 or 2, wherein the liver cancer tumor is formed by human liver cancer HepG2 cells or mouse H22 liver cancer.
4. The use according to claim 1 or 2, wherein the content of dianthrone compounds in the medicament is 0.1-95% by mass.
5. The use according to claim 4, wherein the content of dianthrone compounds in the medicament is 30-90% by mass.
6. The use according to any one of claims 1, 2 and 5, wherein the medicament is in a dosage form selected from the group consisting of oral, topical, injectable and transluminal.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110806685.9A CN113350325B (en) | 2021-07-16 | 2021-07-16 | Application of dianthrone compound in preparation of antitumor drugs |
| NL2031225A NL2031225A (en) | 2021-07-16 | 2022-03-09 | Use of dianthrone compound in preparation of anti-tumor drug |
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| CN202110806685.9A CN113350325B (en) | 2021-07-16 | 2021-07-16 | Application of dianthrone compound in preparation of antitumor drugs |
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| CN113350325B true CN113350325B (en) | 2022-11-08 |
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| CN113662931B (en) * | 2021-09-14 | 2023-03-14 | 中国食品药品检定研究院 | Application of dianthrone compound in preparation of anti-inflammatory and liver-protecting drugs |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443537A (en) * | 2003-04-22 | 2003-09-24 | 中国医学科学院医药生物技术研究所 | Application of emodin analog EMD-31 for curing tumor |
| CN103356515A (en) * | 2013-07-16 | 2013-10-23 | 山西大学 | Application of emodin anthraquinone derivative in preparation of anti-hepatocellular carcinoma drugs |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443537A (en) * | 2003-04-22 | 2003-09-24 | 中国医学科学院医药生物技术研究所 | Application of emodin analog EMD-31 for curing tumor |
| CN103356515A (en) * | 2013-07-16 | 2013-10-23 | 山西大学 | Application of emodin anthraquinone derivative in preparation of anti-hepatocellular carcinoma drugs |
Non-Patent Citations (3)
| Title |
|---|
| "Cytotoxicity of Rhamnosylanthraquinones and Rhamnosylanthrones from Rhamnus nepalensis";Le Phuong Mai，et.al.;《Journal of Natural Products》;20010830;第64卷(第9期);1162-1168 * |
| "Polygonumnolides A1–B3, minor dianthrone derivatives";Jianbo Yang，et al.;《Archives Pharmacal Research》;20170705;1-8 * |
| "大黄素抑制人肝癌HepG2细胞血管生成作用及其机制研究";高俊霞，等;《中华肿瘤防治杂志》;20160229;第23卷(第3期);164-170 * |
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| CN113350325A (en) | 2021-09-07 |
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