CN106727638A - Application of the ginsenoside as heparanase inhibitors in anti-tumor medicine is prepared - Google Patents
Application of the ginsenoside as heparanase inhibitors in anti-tumor medicine is prepared Download PDFInfo
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- CN106727638A CN106727638A CN201611238657.7A CN201611238657A CN106727638A CN 106727638 A CN106727638 A CN 106727638A CN 201611238657 A CN201611238657 A CN 201611238657A CN 106727638 A CN106727638 A CN 106727638A
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
Abstract
The present invention relates to ginsenoside pharmaceutical field application.Specifically related in its application as heparanase inhibitors in anti-tumor medicine is prepared.In experiments it is found that, such compound has security higher under test dose and has good inhibitory action to heparitinase, can be used for the treatment of tumour.
Description
Technical field
The present invention relates to chemical substance field of medicaments purposes.In particular it is ginsenoside as heparitinase
The application of inhibitor, is directed to application of the ginsenoside in anti-tumor medicine is prepared.
Technical background
Heparitinase (Heparanase, HPSE-1) is a kind of beta-glucuronic acid restriction endonuclease of mammal, is so far
The restriction endonuclease that can uniquely cut acetylsulfuric acid heparin (HS) that the present is found, heparitinase is produced from specific site cut-out HS chains
The fragment of about 5-7kD.Heparitinase is by cutting the HS chains on heparan sulfate proteoglycan (HSPG) to promote cell
Migration and impregnation process.Heparitinase is high in the tumour cells such as lung cancer, the cancer of the esophagus, colorectal cancer, cancer of pancreas to express simultaneously
Promote the invasion and attack and transfer of tumour cell.Meanwhile, the angiogenesis such as VEGF, bFGF, HGF that HPSE will can also be combined on HS chains promotees
Enter the vicinity that the factor is discharged into tumour cell, the angiogenesis of induced tumor tissue.Therefore the antagonist of heparitinase can
Suppress the growth and transfer of tumour.
The antagonist of various heparitinases is in development.Antibody and vaccine antagonist complex manufacturing,
Production cost is high, also often causes violent immune response.Existing inhibitor such as hyparinoids from animal organs and sulfated polysaccharides, it is difficult to
Prepare monomer and be often associated with blood coagulation resisting function.PI-88 is the heparanase inhibitors of Australian Progen companies production,
Relative molecular mass is 2300, is the mixture of the mannosan oligosaccharide of height sulphation, is promising antitumor candidate
Medicine, it comes into clinical research as antineoplastic.Micromolecular inhibitor prepares simple, product compared with these materials
Purity is high, drug delivery is convenient, long half time the advantages of, be the focus of modern inhibitor class medicament research and development.
The content of the invention
For existing heparitinase antagonist as the problems of antineoplastic, present invention finds ginseng soap
Glycosides is preparing cancer therapeutics further to it as the application of heparanase inhibitors as heparanase inhibitors
Application in thing.
The tumour includes：Colorectal cancer, cancer of pancreas, the cancer of the esophagus, oophoroma, cervical carcinoma, breast cancer, prostate cancer,
Lung cancer.
The invention also discloses a kind of pharmaceutical composition for tumor cells targeted therapy, it includes ginsenoside and medicine
Acceptable carrier on.
The ginsenoside is selected from and heparan zymoprotein has the ginsenoside for interacting.
Preferably, the ginsenoside be selected from ginsenoside Rk1, (20S)-ginseng saponin Rh 2, ginsenoside Rk_2,
(20R)-ginsenoside PPT, (20S)-ginsenoside PPD, (20S)-ginsenoside PPT, (20R)-ginsenoside PPD, ginseng
Saponin(e Rh3, (20S)-ginsenoside Rh 1, Ginsenoside Rh4.
Most preferably, the ginsenoside is ginsenoside Rk1.
It is used for lung cancer, colorectal cancer, cancer of pancreas, the cancer of the esophagus, oophoroma, cervical carcinoma, breast the invention also discloses one kind
Gland cancer, the pharmaceutical composition of prostate cancer targeting treatment, it includes ginsenoside and pharmaceutically acceptable carrier.
In described pharmaceutical composition, the ginsenoside is selected from ginsenoside Rk1, (20S)-ginseng saponin Rh 2, ginseng
Saponin(e Rk2, (20R)-ginsenoside PPT, (20S)-ginsenoside PPD, (20S)-ginsenoside PPT, (20R)-ginsenoside
PPD, ginsenoside Rh 3, (20S)-ginsenoside Rh 1, Ginsenoside Rh4.
In the present invention,
Ginsenoside Rk1, chemical name is 3 β, 6 α, 12 β-trihydroxydammar-20 (21), 24-diene-6-O- β-
D-glucopyranoside, molecular formula C42H70O12, the odorless of molecular weight 767.0, white powder.Methyl alcohol, ethanol are dissolved in, it is micro-
Molten and ethyl acetate, it is water-soluble poor, insoluble in chloroform, ether, No. CAS：494753-69-4, structural formula is：
(20S)-ginseng saponin Rh 2, chemical name is 3-O- β-D-glucopyranosyl-20 (S)-protopa
Naxadiol, molecular formula：C36H62O8, molecular weight：622.4, odorless, white powder.Dissolve in methyl alcohol, ethanol, slightly soluble and second
Acetoacetic ester, it is water-soluble poor, insoluble in chloroform, ether, No. CAS：78214-33-2, structural formula is：
Ginsenoside Rk_2, chemical name is 3-O- β-D-glucopyranosyl-20 (- H2O)-cis-protopa
Naxadio, molecular formula：C36H60O7, molecular weight：604.4, odorless, white powder.Dissolve in methyl alcohol, ethanol, slightly soluble and acetic acid
Ethyl ester, it is water-soluble poor, insoluble in chloroform, ether, No. CAS：364779-14-6, structural formula is：
(20R)-ginsenoside PPT, chemical name is 20 (R)-protopanaxatriol, molecular formula：C30H52O4, molecule
Amount：476.7, odorless, white powder.Methyl alcohol, ethanol, slightly soluble and ethyl acetate are dissolved in, it is water-soluble poor, insoluble in trichlorine
Methane, ether, No. CAS：1453-93-6, structural formula is：
(20S)-ginsenoside PPD, chemical name is 20 (S)-protopanaxadiol, molecular formula：C30H52O3, molecular weight：
460.7, odorless, white powder.Methyl alcohol, ethanol, slightly soluble and ethyl acetate are dissolved in, it is water-soluble poor, insoluble in three chloromethanes
Alkane, ether, No. CAS：30636-90-9, structural formula is：
(20S)-ginsenoside PPT, chemical name is 20 (S)-protopanaxatriol, molecular formula：C30H52O4, molecule
Amount：476.7, odorless, white powder.Methyl alcohol, ethanol, slightly soluble and ethyl acetate are dissolved in, it is water-soluble poor, insoluble in trichlorine
Methane, ether, No. CAS：34080-08-5, structural formula is：
(20R)-ginsenoside PPD, chemical name is 20 (R)-protopanaxadiol, molecular formula：C30H52O3, molecular weight：
460.7, odorless, white powder.Methyl alcohol, ethanol, slightly soluble and ethyl acetate are dissolved in, it is water-soluble poor, insoluble in three chloromethanes
Alkane, ether, No. CAS：7755-01-3, structural formula is：
Ginsenoside Rh 3, and chemical name is 3-O- β-D-glucopyranosyl-20 (- H2O)-cis-protopa
Naxadiol, molecular formula：C36H60O7, molecular weight：604.4, odorless, white powder.Dissolve in methyl alcohol, ethanol, slightly soluble and second
Acetoacetic ester, it is water-soluble poor, insoluble in chloroform, ether, No. CAS：105558-26-7, structural formula is：
(20S)-ginsenoside Rh 1, chemical name is 6-O- β-D-glucopyranosyl-20 (S)-protopa
Naxatriol, molecular formula：C36H62O9, molecular weight：638.4, odorless, white powder.Dissolve in methyl alcohol, ethanol, slightly soluble and second
Acetoacetic ester, it is water-soluble poor, insoluble in chloroform, ether, No. CAS：63223-86-9, structural formula is：
Ginsenoside Rh4, chemical name is β-D-Glucopyranoside, (3 β, 6 α, 12 β, 20E) -3,12-
Dihydroxydammara-20 (22), 24-dien-6-yl, molecular formula：C36H60O8, molecular weight：620.87, odorless, white powder
Last shape.Methyl alcohol, ethanol, slightly soluble and ethyl acetate are dissolved in, it is water-soluble poor, insoluble in chloroform, ether, No. CAS：
174721-08-5, structural formula is：
Therefore, tumor cells target therapeutic agent, existing excellent economic benefit and society are developed based on native compound
Benefit, the also application conversion to native compound has progradation.Ginseng is from ancient times the good medicine that qi-restoratives adjusts god,《Sheng Nong's herbal classic》
Record ginseng " main tonifying five zang organs, soothe the nerves determine soul, stop palpitate with fear, the happy intelligence development of remove pathogenic factor ... ... ".Ginsenoside Rk1 is fresh people
Join when red ginseng is processed into, by a kind of precious secondary glucoside generated after some glycol saponins degradations, in red ginseng
Content is very low, but it is one of effective active composition of ginseng, there is pharmacological activity stronger extensively.At present, for ginsenoside
Rk1 and other species ginsenosides (including protopanoxadiol saponin(e and Protopanaxatriol's saponin(e) there is no as heparitinase
The report of inhibitor application, the present invention will be used to be significant in the treatment of cancer in heparanase inhibitors.
Brief description of the drawings
Fig. 1 is the block diagram of heparitinase maturation body content after ginsenoside Rk1 treatment cells；
Cells survival rate block diagram when Fig. 2 is ginsenoside Rk1 killing tumor cells；
Fig. 3 is the invasive ability experimental result picture that ginsenoside Rk1 effectively reduces people source lung cell A549.
Specific embodiment
The safety evaluatio of embodiment 1
The result of study of nonphosphorylated neurofilament H of the invention is as follows：
1st, Mouse oral acute toxicity test
In maximum administration concentration and maximum administration capacity conditions, Mouse oral gavage gives ginsenoside Rk1 12g/kg
Wt., Continuous Observation 14 days, animal has no dead and undue toxicity reaction.Show the maximum tolerance of ginsenoside Rk1 mouse stomaches
It is 12g/kg wt. to measure.
2nd, Beagle dogs Oral Acute Toxicity experiment
In maximum administration concentration and maximum administration capacity conditions, Beagle dog oral administration gavages give ginsenoside Rk12g/kg
Wt., Continuous Observation 14 days, animal has no dead and undue toxicity reaction.Show the maximum of ginsenoside Rk1Beagle dog gavages
Dosis tolerata is 2g/kg wt..
3rd, the long term toxicity of rat oral gavage administration
Ginsenoside Rk1 (100mg/kg wt., 300mg/kg wt. and 500mg/kg wt.) SD rats continuous oral is filled
Stomach is discontinued after three months and recovers surrounding long term toxicity test.Result shows：1. ordinary circumstance：During administration and recovery, ingest
Drinking-water is normal, and increased weight, animal skin is smooth, and behavioral activity is normal；2. hematology and blood biochemical analysis index：Tied in administration
Beam and after convalescence, animal hematology and each index of blood biochemical analysis fluctuate in normal range (NR), show no obvious abnormalities；3. bone
Marrow and routine urinalysis index：Terminate in administration and after convalescence, marrow and each index of routine urinalysis show no obvious abnormalities；4. organize
Pathological hallmarks：Terminate in administration and after convalescence, each internal organs of animal naked eyes show no obvious abnormalities, organ weights and organ coefficient
Significant difference is had no compared with control group, each internal organs pathology shows no obvious abnormalities change.Result shows, SD rat long term administration people
Ginseng saponin(e Rk1 has no that overt toxicity reacts.
4th, to the long term toxicity test of Beagle dog gastric infusions
Ginsenoside Rk1 (50mg/kg wt., 100mg/kg wt. and 150mg/kg wt.) Beagle dogs continuous oral is filled
Stomach is discontinued after three months and recovers surrounding long term toxicity test.Result shows：1. ordinary circumstance：During administration and recovery, ingest,
Drinking-water and body temperature are normal, and increased weight, animal skin is smooth, and behavioral activity is normal；2. hematology and blood biochemical analysis index：
Administration terminates and after convalescence, animal hematology and each index of blood biochemical analysis fluctuate in normal range (NR), has no substantially different
Often；3. Electrocardiograph index：Terminate in administration and after convalescence, each index of animal electrocardiogram fluctuates in normal range (NR), has no
It is substantially abnormal；4. marrow and eye examination：Terminate in administration and after convalescence, marrow cell and each classification cell have no different
Often；Eye examination each group animal eyes bottom blood vessel lines clearly oozes out without bleeding, and depending on nipple without oedema, arteriovenous caliber is than normal；
5. immunology and urine excrement Testing index：Terminate in administration and after convalescence, animal immunology and urine excrement detect each index just
Fluctuation in normal scope, shows no obvious abnormalities；6. histopathological indications：Terminate in administration and after convalescence, each internal organs meat of animal
Eye shows no obvious abnormalities, and organ weights and organ coefficient have no significant difference compared with control group, and each internal organs pathology has no obvious
Abnormal change.Result shows that Beagle dog long term administration ginsenosides Rk1 has no that overt toxicity reacts.
5th, general pharmacology experiment
Anesthesia Beagle dog oral administration gavage ginsenosides Rk1 (25mg/kg wt., 50mg/kg wt., 100mg/kg wt.)
Afterwards, the blood pressure (diastolic pressure, systolic pressure) of Beagle dogs, heart rate have no significant effect, phase between phase, PR between P ripples, T ripples, R ripples and QRS,
Phase, respiratory rate and amplitude of respiration also have no significant effect between Q-T.Ginsenoside Rk1 (150mg/kg wt., 300mg/kg
Wt. with 500mg/kg wt.) scoring of mouse Irwin ' s behavior tests and pole-jump test scoring are had no significant effect.Show people
Ginseng saponin(e Rk1 does not influence central nervous system, cardiovascular system and the respiratory system of animal under test conditions.
6th, mutagenicity test
Mammalian culture cell (CHL) chromosomal aberration test, Salmonella reversion test and mouse microkernel test show, ginseng soap
Glycosides Rk1 is without mutagenesis.
The pharmacodynamics of embodiment 2
Result of study of the invention is as follows：
1st, ginsenoside Rk1 lowers heparitinase maturation body content
Material：People source lung cell A549, heparitinase specific antibody (Santa Cruz), ginsenoside Rk1 is (big
Lian Meilun Bioisystech Co., Ltd, purity>99%), denaturing polyacrylamide gel electrophoresis system (BioRad).
Method：
People's source lung cell A549 is cultivated to exponential phase, with 2.0 × 106Individual/plate is passed in 100mm cell culture
Plate, 37 DEG C, 5%CO224h is cultivated in environment, ginsenoside Rk1 ethanol solutions to the end of ginsenoside Rk1 are added in culture medium
Concentration is respectively 1,2,3,4,5 μ g/mL (storing liquid is the ginsenoside Rk1 ethanol solutions of 1mg/mL), 37 DEG C, 5%CO2Environment
It is middle to continue to cultivate 4h, cell is collected, by denaturing polyacrylamide gel electrophoresis --- immunoblotting analysis are detected, as a result such as Fig. 1 institutes
Show, with the increasing of ginsenoside Rk1 concentration, the content of heparitinase maturation body is reduced in the mode of concentration dependant.
2nd, various ginsenosides can combine heparitinase
Various ginsenosides are analyzed with the binding ability of heparan zymoprotein by molecular simulation show various
Ginsenoside can with heparitinase protein binding (molecule simulation method be based on Lamarckian Genetic
Algorithm (Scripps Research Institute, La Jolla, CA, USA) is completed in AutoDock, with reference to certainly
By that can be generated by work station with dissociation constant), the results are shown in Table 1.
The ginsenoside of table 1 and heparitinase protein binding free energy and dissociation constant
| Ginsenoside | Conjugated free energy (kcal/mol) | Dissociation constant (μM) |
| Ginsenoside Rk1 | -7.96 | 2.13 |
| (20S)-ginsenoside PPD | -7.71 | 4.91 |
| (20R)-ginsenoside PPT | -7.62 | 6.28 |
| (20S)-ginsenoside PPT | -6.97 | 9.15 |
| (20R)-ginsenoside PPD | -6.92 | 12.55 |
| Ginsenoside Rh 3 | -6.62 | 22.91 |
| (20S)-ginsenoside Rh 1 | -6.56 | 26.09 |
| Ginsenoside Rh4 | -6.52 | 41.51 |
| (20S)-ginseng saponin Rh 2 | -5.91 | 51.05 |
| Ginsenoside Rk_2 | -5.71 | 57.62 |
3rd, ginsenoside Rk1 inducing death of neoplastic cells
Material：People source lung cancer cell line A549, Human cervical cancer cell lines HeLa, human hepatoma cell line HepG2, human colon carcinoma
Cell line SW480, human heparanase specific antibody (Santa Cruz), CCK8 kits (Sigma), ginsenoside Rk1
(Dalian U.S. logical sequence Technology Co., Ltd., purity>99%).
Method：
By 4 kinds of tumor cell cultures to logarithmic phase, 8000/hole is passed in 96 empty culture plates, 37 DEG C, 5%CO2Environment
Middle culture 24h, add ginsenoside Rk1 ethanol solutions to the final concentration of ginsenoside Rk1 to be respectively 1 in culture medium, 2,5,10,
15th, 25,50 μ g/mL (storing liquid is the ginsenoside Rk1 ethanol solutions of 1mg/mL), continues to cultivate 48h, uses CCK8 kits
Tumour cell is counted.Result is as shown in Fig. 2 ginsenoside Rk1 is respectively provided with lethal effect to kinds of tumor cells.
4th, ginsenoside Rk1 suppresses tumor cell invasion transfer
Material：People source lung cancer cell line A549, matrigel matrigel (BD), transwell cells (corning), people
Ginseng saponin(e Rk1 (Dalian U.S. logical sequence Technology Co., Ltd., purity>99%).
Method：
1 is pressed using DMEM culture mediums：5 (v/v) dilute matrgel matrigels, and 100 μ L add transwell cells per hole
Upper chamber, 37 DEG C, 5%CO2Stand overnight.The A549 cell dissociations to logarithmic phase will be cultivated, be diluted to cell concentration 5 × 105Individual/
ML, 100 μ L add transwell cells upper chamber per hole, and DMEMs of the 500 μ L containing 10% hyclone (v/v) is added in lower room
Culture medium.Experimental group adds ginsenoside Rk1 ethanol solutions, and to the μ g/mL of final concentration 5, (storing liquid is the ginsenoside of 1mg/mL
Rk1 ethanol solutions), negative control group adds isometric ethanol, 37 DEG C, 5%CO2Culture 48h.Remove upper chamber in cell and
Matrigel, the cell in lower room is carried out methyl alcohol fix, violet staining, light Microscopic observation.Test result indicate that, 5 μ g/mL people
Ginseng saponin(e Rk1 effectively reduces the invasive ability (Fig. 3) of people source lung cell A549.
5th, expression of the heparitinase in tumor tissues
Human tumour organization chip is bought in Shanghai Xinchao Biotech Co., Ltd., Shanghai (hepatocellular carcinoma：
HLivH180Su06；Stomach cancer：HStmA180Su09；Colorectal cancer：HColA180Su11；Cancer of pancreas：PanA150CS02；Food
Pipe cancer：HEsoS180Su06；Oophoroma：HUteA060CS01；Breast cancer：HBreD145Su01；Cervical carcinoma：
HUteA060CS01；Prostate cancer：HProA180PG03), and using Immunohistochemical detection heparitinase in tumor group
Expression in knitting.And (primary antibody, secondary antibody are immuning tissue of Santa Cruz companies using heparitinase specific antibody
Chemical use antibody), histotomy is dyeed using AEC Color Appearance Systems (sigma).Microscope high power field (×
200) positive cell percentage, positive cell, are counted<5% be 0 point, 6%~25% be 1 point, 26%~50% be 2 points, 51%~
75% is 3 points,>76% is 4 points.It is divided into 0~3 point by staining power again, the result that both are multiplied scores tumor tissues,
0~1 for-, 2~4 for+, 5~8 are ++, 9~12 are +++.Heparitinase is as shown in table 2 in the expression of tumor tissues.
Heparitinase high level expression in presentation in tumor tissues, the tumour includes：Colorectal cancer, cancer of pancreas, the cancer of the esophagus,
Oophoroma, cervical carcinoma, breast cancer, prostate cancer, lung cancer.
Expression of the heparitinase of table 2 in tumor tissues
Claims (8)
1. ginsenoside as heparanase inhibitors application.
2. application of the ginsenoside as heparanase inhibitors in anti-tumor medicine is prepared.
3. application according to claim 2, the tumour includes：Lung cancer, colorectal cancer, cancer of pancreas, the cancer of the esophagus, ovary
Cancer, cervical carcinoma, breast cancer, prostate cancer.
4. the application according to any one of claim 1-3, it is characterised in that：The ginsenoside is selected to heparan
Enzyme has the ginsenoside of antagonism.
5. application according to claim 4, it is characterised in that：The ginsenoside is selected from ginsenoside Rk1, (20S)-people
Ginseng saponin(e Rh2, ginsenoside Rk_2, (20R)-ginsenoside PPT, (20S)-ginsenoside PPD, (20S)-ginsenoside PPT,
(20R)-ginsenoside PPD, ginsenoside Rh 3, (20S)-ginsenoside Rh 1, Ginsenoside Rh4.
6. application according to claim 5, it is characterised in that：The ginsenoside is ginsenoside Rk1.
7. it is a kind of to be used for lung cancer, colorectal cancer, cancer of pancreas, the cancer of the esophagus, oophoroma, cervical carcinoma, breast cancer, prostate cancer targeting
The pharmaceutical composition for the treatment of, it includes ginsenoside and pharmaceutically acceptable carrier.
8. pharmaceutical composition according to claim 7, it is characterised in that：The ginsenoside be selected from ginsenoside Rk1,
(20S)-ginseng saponin Rh 2, ginsenoside Rk_2, (20R)-ginsenoside PPT, (20S)-ginsenoside PPD, (20S)-ginseng
Saponin(e PPT, (20R)-ginsenoside PPD, ginsenoside Rh 3, (20S)-ginsenoside Rh 1, Ginsenoside Rh4.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107929296A (en) * | 2017-11-17 | 2018-04-20 | 中国科学院天津工业生物技术研究所 | A kind of preparation method and application of non-natural ginsenoside |
| CN108578702A (en) * | 2018-05-24 | 2018-09-28 | 深圳以诺生物制药有限公司 | A kind of mixture of rare ginsenoside and its application |
| CN111265536A (en) * | 2020-03-31 | 2020-06-12 | 陕西巨子生物技术有限公司 | Antitumor composition containing rare ginsenoside Rk2, CK and PPT |
| CN111467358A (en) * | 2020-03-31 | 2020-07-31 | 陕西巨子生物技术有限公司 | Pharmaceutical composition containing ginsenoside Rh3, PPD and Rh2 |
| CN111467358B (en) * | 2020-03-31 | 2021-05-14 | 陕西巨子生物技术有限公司 | Pharmaceutical composition containing ginsenoside Rh3, PPD and Rh2 |
| WO2022012635A1 (en) * | 2020-07-17 | 2022-01-20 | 陕西巨子生物技术有限公司 | Pharmaceutical composition and use thereof |
| CN116098911A (en) * | 2023-02-23 | 2023-05-12 | 大连医科大学 | Application of ginsenoside Rg6 in preparation of cisplatin-resistant ovarian cancer medicine |
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Application publication date: 20170531 |