CN103202834A - Applications of oridonin in the preparation of antineoplastic drugs - Google Patents
Applications of oridonin in the preparation of antineoplastic drugs Download PDFInfo
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- CN103202834A CN103202834A CN2012100111202A CN201210011120A CN103202834A CN 103202834 A CN103202834 A CN 103202834A CN 2012100111202 A CN2012100111202 A CN 2012100111202A CN 201210011120 A CN201210011120 A CN 201210011120A CN 103202834 A CN103202834 A CN 103202834A
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Abstract
The invention belongs to the fields of chemical and pharmaceutical, relating to applications of oridonin in the preparation of antineoplastic drugs. The present invention provides applications of oridonin in the preparation of antineoplastic drugs; wherein the tumor cells include liver cancer cells, lung adenocarcinoma cells and pancreatic cancer cells. The oridonin is a natural product of low toxicity, high bioavailability and stable nature, and has clinical value. As a new antineoplastic drug or an auxiliary component for antineoplastic drugs for development, the small molecule compound of this invention has an obvious tumor suppression effect and is environment protecting, providing a new way and method for treating and curing tumours.
Description
Technical field
The invention belongs to chemical field and field of medicaments, relate to the application of rubescensine A in the preparation antitumor drug.
Background technology
Rabdosia rubescens, undershrub is the fork mutation of cracking rice of Labiatae Rabdosia plant, because its plant butterfly-shaped ice slush sheet as thin as cicada's wings, that come in every shape that condenses is gained the name.
Rabdosia rubescens is a kind of plant that comprehensive development and utilization is worth that has.The Rabdosia rubescens adaptability is strong, and is not tight to the soil requirement, is chosen in drying, is difficult for the sand of hydrops or gently clay soil plantation.Implantation time was advisable in spring and autumn, and mu is planted about 4000 strains.It is intertill and clean tillage that Rabdosia rubescens is mainly managed, anti-hydrops.NATURAL DISTRIBUTION is in the south, Taihang Mountain.
The medicinal part of Rabdosia rubescens is Herb, and therefore, its output is higher, and general per mu yield Radix Glycyrrhizae is more than 500 kilograms.Do medicinally, before blooming, gather, because the Rabdosia rubescens pharmacological action of this moment is the strongest; Do the Rabdosia rubescens health tea, the whole growth phase all can, bright leaf is directly made tea or is cooperated with Flos Chrysanthemi, Flos Lonicerae etc. and drinks, and also can dry or dry for standby.
Rabdosia rubescens nature and flavor hardship, sweet, be slightly cold.Rabdosia rubescens has good heat clearing away poison, promoting blood circulation and stopping pain, antibacterial, antitumor action, cures mainly laryngopharynx swelling and pain, tonsillitis, headache due to common cold, tracheitis, chronic hepatitis, joint rheumatalgia, snake bite and insect sting.Herb has mitigation to the esophageal carcinoma, breast carcinoma, rectal cancer etc.The decoct of Rabdosia rubescens and pure agent can suppress first type, beta hemolytic streptococcus, staphylococcus aureus etc. effectively, thereby improve the human body resistance, reduce the leukocyte that causes because of inflammation rapidly and increase.Rabdosia rubescens can have potentiation significantly with chemotherapy, other cancer therapy drug partner treatment cancer,
Rubescensine A is the important activity composition in the Rabdosia rubescens, and bioavailability height, stable in properties have clinical use value.Along with people to the going deep into of the chemistry and biology of this compounds research, its molecular mechanism of action will progressively clear and definite, this will further promote chemical constitution modification and the structure activity study of this compounds, and help to improve the medical value of this compounds.
Summary of the invention
The new medicinal usage that the purpose of this invention is to provide rubescensine A.
Rubescensine A of the present invention,, have another name called Oridonin, structural formula is as follows:
Its relevant nature is as follows:
[another name] rubescensin, isodonin
[English name] Oridonin
[molecular formula] C20H2806
[molecular weight] 364.44
[CAS number] 28957-04-2
[detection mode] high performance liquid chromatography HPLC 〉=98%
[character] this product is faint yellow acicular crystal
[extract source] is the crack rice herb of inferior fork (Rabdosia rubescens) of Labiatae Rabdosia plant.
248 ℃-250 ℃ of [pharmacological properties] fusing points are slightly soluble in water, are dissolved in methanol, ethyl acetate, acetone etc.
Rubescensine A of the present invention is available from source, Shanghai leaf bio tech ltd article No.: 90063 (http://www.biomart.cn/infosupply/4768868.htm).
The invention provides the application of rubescensine A in the preparation antitumor drug.Described tumor can be hepatocarcinoma, adenocarcinoma of lung, breast carcinoma, gastric cancer, cancer of pancreas, cervical cancer or leukemia.
Corresponding antitumor drug can be injection or tablet.
The invention provides a kind of method that suppresses tumor cell in vitro propagation, rubescensine A is added in the culture fluid of tumor cell.Described tumor cell can be hepatoma carcinoma cell, blood cell, cervical cancer cell, breast cancer cell or pancreatic cancer cell.The hepatoma carcinoma cell that adopts in one embodiment of the present of invention is SK-HEP1, Focus and QGY.
Mtt result shows that rubescensine A can obviously suppress cell proliferation, even causes death of neoplastic cells.The cell cycle result shows that rubescensine A can promote apoptosis.
Generally speaking, the final concentration of adding rubescensine A is 0.1-50 μ M.For example, 0.1-5 μ M, 0.1-10 μ M, 0.1-12 μ M, 0.1-20 μ M, 0.1-30 μ M, 0.1-50 μ M, 0.1-2 μ M, 5-10 μ M, 2-50 μ M, 0.5-50 μ M, 0.5-5 μ M, 0.5-10 μ M, 1-12 μ M, 1-20 μ M, 0.5-50 μ M, 15-50 μ M, 0.5-10 μ M, 0.5-12 μ M, 0.5-20 μ M, 0.5-30 μ M, 15-60 μ M, etc.
The present invention also provides a kind of antitumor drug, and the active component of described antitumor drug is rubescensine A.Described tumor can be hepatocarcinoma, adenocarcinoma of lung, breast carcinoma, gastric cancer, cancer of pancreas, cervical cancer or leukemia.
Micromolecular compound of the present invention can adopt the preparation method preparation of various routines.For example, adopt the method for artificial chemosynthesis.
Utilize micromolecular compound of the present invention, by various conventional screening techniques, can filter out with rubescensine A interactional material takes place, as receptor, inhibitor or pick up anti-dose etc.
The present invention and inhibitor thereof, pick up anti-dose etc., when (administration) used in treatment, can provide different effects.Usually, these materials can be formulated in nontoxic, inertia with pharmaceutically acceptable aqueous carrier medium in, wherein pH is about 5-8 usually, preferably pH is about 6-8, pH value can change to some extent with being formulated Substance Properties and disease to be treated.The pharmaceutical composition for preparing can carry out administration by conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, Intradermal or topical.
Be example with rubescensine A of the present invention, can be with itself and suitable pharmaceutically acceptable carrier coupling.This class pharmaceutical composition contains chemical compound and pharmaceutically acceptable carrier or the excipient for the treatment of effective dose.This class carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should be complementary with administering mode.Rubescensine A of the present invention can be made into the injection form, for example is prepared by conventional method with normal saline or the aqueous solution that contains glucose and other adjuvant.Pharmaceutical composition such as tablet and capsule can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule should be made under aseptic condition.The dosage of active component is the treatment effective dose, for example every day about 1 microgram/kg body weight-Yue 5 mg/kg body weight.In addition, rubescensine A of the present invention also can use with the other treatment agent.
When rubescensine A of the present invention is used as medicine, the rubescensine A for the treatment of effective dose can be applied to mammal, wherein should treat effective dose usually at least about 10 micrograms/kg body weight, and in most of the cases be no more than about 8 mg/kg body weight, preferably this dosage is about 10 micrograms/kg body weight-Yue 1 mg/kg body weight.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
The invention provides the application of rubescensine A in the preparation antitumor drug.Rubescensine A is natural product, can obviously suppress the propagation of tumor cell.Micromolecular compound of the present invention is developed as new antitumor drug or its auxiliary element, and tumor killing effect is obvious, environmental protection, and will and cure tumor for treatment provides a kind of new approach and means.
The specific embodiment
Experimental technique:
1. cell recovery
1) from liquid nitrogen container, takes out frozen pipe, directly drop in 37 ℃ of warm water, and shake frequently and make it melt as early as possible.
2) from 37 ℃ of water-baths, take out frozen pipe, with suction pipe sucking-off cell suspension, inject centrifuge tube and add culture fluid more than 10 times, mix the back low-speed centrifugal, abandon supernatant, repeat again to wash once with culture fluid.
3) with after the suitable dilution of culture fluid, the inoculated and cultured bottle is placed on 37 ℃ of incubators and leaves standstill cultivation, changes culture fluid next day, continues to cultivate.Go down to posterity when being cultured to finite concentration.The PANC-1 cell culture is in containing the DMEM high glucose medium of 10%Gibico hyclone, and SK-HEP1 and QGY cell culture contain 100U/ml penicillin and 100 μ g/ml streptomycins in the culture medium in containing the DMEM high glucose medium of 10% hyclone.
2. passage is cultivated
The situation of observation of cell growth every day goes down to posterity when converging when cell grows to about 90% in culture bottle, goes down to posterity once every 2-4 days approximately.One bottle goes down to posterity into three bottles, or a 25cm
2Go down to posterity in a 75cm
2Culture bottle in.Method:
1) with 1 * phosphate buffer washed cell once.
2) add the digestion of 2-3ml trypsinization liquid, place 37 ℃ of incubator numbers minute.Pat Tissue Culture Flask with hands, make cell separation.
3) suitable culture medium with the Gibico hyclone that contains 10-15% stops trypsinization.Cell is sub-packed in the new culture bottle, continues to cultivate.
3. cell cryopreservation
1) get the cell tryptase protease digestion that is cultured to exponential phase, be collected in the centrifuge tube and counting, centrifugal.
2) reject trypsin and old culture fluid add the frozen culture fluid (containing 10%DMSO, 40%DMEM and 50%Gibico hyclone) that configures, and the ultimate density of cell is 0.5-1 * 10 in the cryopreserving liquid
7/ ml.Blow and beat gently with suction pipe and to make cell even, divide in the aseptic frozen pipe of packing into then, every pipe adds 1-1.5ml.
3) frozen pipe is put into freezing storing box and put-80 ℃ of quick-freezings, move in the liquid nitrogen container after 5 hours and preserve.
4. medicine is prepared:
Rubescensine A is dissolved in DMSO (dimethyl sulfoxide), and the mother solution that is mixed with 100mM or 50mM is standby.
Embodiment 1MTS method is measured rubescensine A to the growth inhibited effect of hepatoma carcinoma cell
SK-HEP1 cell (available from Chinese Academy of Sciences's cell bank) 3 * 10
3/ hole is seeded to 96 orifice plates, cultivates to make it adherent back adding rubescensine A (available from Shanghai Pharmaceutical Inst., Chinese Academy of Sciences) in 24 hours, establishes 6 Concentraton gradient, and each concentration is established 3 multiple holes.Cell is at 37 ℃, 5%CO
2Cultivate after 72 hours under the condition, outwell culture fluid, measure cell survival rate with MTS test kit (Promega company).
Method of testing is: cell is washed one time with serum-free medium, added the MTS chromophoric solution (adding 2ml solution 1 and 100 μ l solution 2 in the 10ml serum-free medium, fully mixings) for preparing in advance according to the amount of 100 μ l/well.Do not have the hole of cell to be made as this bottom outlet with one, absorb in order to the bias light of calibration solution.Cell is put into cell culture incubator to be continued to cultivate 2～4 hours, read absorbance value (reference wavelength 630-700nm with microplate reader then, measure wavelength 490nm), calculate cell survival rate, to measure hole absorbance value/control wells absorbance value as the numerical value of cell survival rate.According to cell survival rate, calculate rubescensine A to the IC50 value of Sk-hep1 cell.
IC50 refers to be suppressed the concentration of a half inhibitor.Here be the SK-HEP1 cell quantity and be the concentration of a half rubescensine A of contrast.The calculating of IC50 generally need be measured the dosage effect more than 5, obtains function calculation by curve fitting again and gets.
The result: rubescensine A is 4.50 μ M to the IC50 value of Sk-hep1 cell.
Use the same method and test QGY cell (available from Chinese Academy of Sciences's cell bank), rubescensine A is about 23.10 μ M to the IC50 value of QGY cell as a result; IC50 value to the Focus cell is about 2.90 μ M, is about 11.00 μ M to the IC50 value of hep-G2 cell, is about 9.37 μ M to the IC50 value of SMMC-7721 cell.
Embodiment 2 rubescensine A are to human leukemia cell's growth inhibited effect
Utilize cck-8 test kit (Japanese colleague's chemistry institute) to detect.
Step:
1) K562 cell (available from Chinese Academy of Sciences's cell bank) is planted in 96 orifice plates uniformly, every porocyte number is 10
4Individual.
2) treat adherent, the back dosing of spending the night, dosing (rubescensine A concentration is respectively 50,16.67,5.56,1.85,0.62 μ M), each concentration has 3 multiple holes.
3) cultivate 48 hours, complete medium is replaced to the mixture (10:1) of serum-free medium and CCK8, hatched 2 hours in 37 ℃ of incubators.
4) being to measure wavelength with 450nm, is the contrast wavelength with 650nm, measures reading on microplate reader.
The result: rubescensine A is 2.49 μ M to the IC50 value of K562 cell.
Embodiment 3 rubescensine A are to the growth inhibited effect of human pancreatic cancer cell
Method according to embodiment 2 detects rubescensine A to the growth inhibited effect of human pancreatic cancer cell.
The result shows that rubescensine A is 1.83 μ M to the IC50 value of human pancreatic cancer cell PANC-1.
Embodiment 4 rubescensine A are to the growth inhibited effect of human lung adenocarcinoma cell
Method according to embodiment 2 detects rubescensine A to the growth inhibited effect of human lung adenocarcinoma cell.
The result shows that rubescensine A is 5.67 μ M to the IC50 value of human lung adenocarcinoma cell A549.
Embodiment 5 rubescensine A are to the growth inhibited effect of gastric carcinoma cells
Method according to embodiment 2 detects rubescensine A to the growth inhibited effect of gastric carcinoma cells.
The result shows that rubescensine A is 2.86 μ M to the IC50 value of HGC cell.
Embodiment 6 rubescensine A are to the growth inhibited effect of human breast cancer cell
Method according to embodiment 2 detects rubescensine A to the growth inhibited effect of human breast cancer cell.
The result shows that rubescensine A is 3.36 μ M to the IC50 value of human breast cancer cell MCF-7.
Embodiment 7 rubescensine A are to the growth inhibited effect of human cervical carcinoma cell
Method according to embodiment 2 detects rubescensine A to the growth inhibited effect of human cervical carcinoma cell.
The result shows that rubescensine A is 4.41 μ M to the IC50 value of human cervical carcinoma cell cervix uteri.
The detection of embodiment 8 cell cycles
Get SMMC-7721 cell 3 * 105 cells and be inoculated in the 60mm Tissue Culture Dish.After the gradient drug treating, 37 ℃ of C02 incubators are cultivated 24h.Cell culture fluid and cell harvesting are gone in the centrifuge tube, and the centrifugal 10min of 1000rpm abandons supernatant.Cell is washed 1 time with 1 * PBS of 2ml pre-cooling, and the centrifugal 10min of 1000rpm abandons supernatant.With 4 ℃ of 70% precooled ethanol fixedly 2h or longer time.The centrifugal 10min of 1000rpm carefully sops up supernatant.Resuspended with 500 μ l PI dye liquors, dyeing 20min in room temperature dark place detects the cell cycle situation of change with flow cytometer behind the membrane filtration.
The result shows that rubescensine A has significantly short apoptosis effect.
Claims (10)
1. the application of rubescensine A in the preparation antitumor drug.
2. application as claimed in claim 1 is characterized in that, described tumor is hepatocarcinoma, adenocarcinoma of lung, breast carcinoma, gastric cancer, cancer of pancreas, cervical cancer or leukemia.
3. application as claimed in claim 1 is characterized in that, described antitumor drug is medicines resistant to liver cancer.
4. application as claimed in claim 1 is characterized in that, described antitumor drug is anti-cancer of pancreas medicine.
5. application as claimed in claim 1 is characterized in that, described antitumor drug is Antilung gland cancer medicine.
6. a method that suppresses tumor cell in vitro propagation is characterized in that, rubescensine A is added in the culture fluid of tumor cell.
7. method as claimed in claim 6 is characterized in that, described tumor cell is hepatoma carcinoma cell, breast cancer cell, stomach cancer cell, pancreatic cancer cell, cervical cancer cell, lung adenocarcinoma cell or pancreatic cancer cell.
8. method as claimed in claim 6 is characterized in that, the final concentration that adds rubescensine A is 0.1-50 μ M.
9. an antitumor drug is characterized in that, the active component of described antitumor drug is rubescensine A.
10. antitumor drug as claimed in claim 9 is characterized in that, described tumor is hepatocarcinoma, adenocarcinoma of lung, breast carcinoma, gastric cancer, cancer of pancreas, cervical cancer or leukemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100111202A CN103202834A (en) | 2012-01-13 | 2012-01-13 | Applications of oridonin in the preparation of antineoplastic drugs |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012100111202A CN103202834A (en) | 2012-01-13 | 2012-01-13 | Applications of oridonin in the preparation of antineoplastic drugs |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105267201A (en) * | 2014-07-02 | 2016-01-27 | 复旦大学 | Application of oridonin in preparing medicine for treating tumour |
| CN106234409A (en) * | 2016-07-28 | 2016-12-21 | 石鸿娟 | A kind of high specific environmental protection acaricide |
| CN110151749A (en) * | 2018-02-13 | 2019-08-23 | 中国科学技术大学 | Application of the Oridonin in the drug of preparation prevention or treatment NLRP3 inflammation corpusculum related disease |
| CN114272235A (en) * | 2022-02-16 | 2022-04-05 | 广西国际壮医医院 | Application of oridonin in preparing medicine for treating liver cancer |
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| CN101244054A (en) * | 2008-03-11 | 2008-08-20 | 山东大学 | Application of oridonin in preparing medicaments for promoting surrounding vascellum tunica interna incrassation |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105267201A (en) * | 2014-07-02 | 2016-01-27 | 复旦大学 | Application of oridonin in preparing medicine for treating tumour |
| CN106234409A (en) * | 2016-07-28 | 2016-12-21 | 石鸿娟 | A kind of high specific environmental protection acaricide |
| CN110151749A (en) * | 2018-02-13 | 2019-08-23 | 中国科学技术大学 | Application of the Oridonin in the drug of preparation prevention or treatment NLRP3 inflammation corpusculum related disease |
| CN110151749B (en) * | 2018-02-13 | 2022-04-19 | 中国科学技术大学 | Application of oridonin in preparing medicine for preventing or treating NLRP3 inflammation body related diseases |
| CN114272235A (en) * | 2022-02-16 | 2022-04-05 | 广西国际壮医医院 | Application of oridonin in preparing medicine for treating liver cancer |
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Application publication date: 20130717 |