CN102058570A - Application of carnosic acid in preparing medicament for suppressing angiogenesis - Google Patents
Application of carnosic acid in preparing medicament for suppressing angiogenesis Download PDFInfo
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- CN102058570A CN102058570A CN 201110004218 CN201110004218A CN102058570A CN 102058570 A CN102058570 A CN 102058570A CN 201110004218 CN201110004218 CN 201110004218 CN 201110004218 A CN201110004218 A CN 201110004218A CN 102058570 A CN102058570 A CN 102058570A
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Abstract
The invention relates to application of carnosic acid in preparing a medicament for suppressing angiogenesis. The invention has the advantages that: the novel application of the carnosic acid discovers the effect of the carnosic acid in resisting angiogenesis for the first time, and the carnosic acid can effectively suppress proliferation, migration and canaliculization of vascular endothelial cells for the first time, which proves that the carnosic acid has the activity of resisting the angiogenesis, can be used as an angiogenesis suppressant, and can be applied to preparation of angiogenesis medicaments as the angiogenesis suppressant to treat neovascularization dependent and neovascularization related diseases, such as tumors, arthritis, psoriasis, ocular diseases, atherosclerosis, and the like.
Description
Technical field
The present invention relates to the monomeric application of a kind of Chinese herbal medicine, specifically, is the application of a kind of Chinese herbal medicine monomer carnosic acid in preparation inhibition angiogenesis drug.
Background technology
Angiogenesis (angiogenesis) refers to that new vessels is by reinventing and expand the process of formation ripe blood vessels at different levels.The blood vessel that germinating growth makes new advances from already present mature tissue often, or from huge vascular system, divide less filial generation blood vessel.Angiogenesis mainly comprises following process: the degraded of (1) active period basement membrane of blood vessel; (2) activation of vascular endothelial cell, propagation, migration; (3) formation of new capillary vessel official jargon structure; (4) raise pericyte with the stable new capillary network that forms; (5) reinventing and expanding and form sophisticated vasoganglion by primitive vessel.Angiogenesis is being brought into play important effect in fetal development, reproduction, repair in trauma and women's body normal physiological processes such as physiological period.It is partial that pathologic new vessels forms, and the tumor that some diseases such as a variety of causes cause, eye neovascularization, arthritis, dermatopathy, atherosclerosis etc. all have a large amount of blood capillaries to generate in the part.
Malignant tumor is the major disease of serious threat human health, and 1971, it is closely related that Folkman etc. propose angiogenesis and growth of tumor and transfer, and thinks that the process of blocking-up angiogenesis can reach the purpose of effective treatment tumor.Suppress the angiogenesis molecule and promote the intermolecular dynamic equilibrium of angiogenesis to be considered to " switch " that modulating vascular generates.In most cases, both are in balance, and angiogenesis mechanism is closed; And when the balance of the two was destroyed, angiogenesis mechanism was unlocked, thereby caused the generation and the development of disease.In tumor tissues, because inducing of factors such as anoxia or oncogene activation, make and promote the angiogenesis developed by molecule to raise or the downward modulation of inhibition angiogenesis molecule, thereby destroy dynamic equilibrium between the two, tumor vessel begins growth, and, finally cause the quick growth of tumor even shift by new vessels for tumor tissues provides prescribing adequate nutrition composition and oxygen.Therefore, the inhibition angiogenesis is significant for antineoplaston.
Carnosic acid (Carnosic acid) is a kind of plant phenols acid compounds compound, comes from Labiatae Rosmarinus plant rosemary (Rosmarinus officinalis L).Its molecular formula is C
20H
28O
4, molecular weight is 332.43.Carnosic acid possesses multiple pharmacological activity.Studies show that carnosic acid has antioxidation; Migration to the differentiation of Mus 3T3-L1 adipose cell and human artery's smooth muscle cell is inhibited; Can reverse the multidrug resistance of P-glycoprotein mediation; Carnosic acid has anti-tumor activity simultaneously, can suppress 1, the pharmacotoxicological effect of 25-dihydroxy vitamin D and the inductive Leukemia Cell Proliferation of tretinoin.The report that does not also have at present carnosic acid to suppress new vessels formation and use as angiogenesis inhibitor.
Chinese patent literature CN:100577180C discloses the application of a kind of gamlogic acid in preparation inhibition angiogenesis drug.This invention provides the gamlogic acid application in preparation inhibition angiogenesis drug, the particularly application in the medicine of the pathological tissues angiogenesis for preparing diseases such as suppressing tumor, arthritis, retinopathy, hemangioma, psoriasis.Chinese patent literature CN:1511531A discloses homoharringtonine and the application of harringtonine in suppressing angiogenesis.This disclosure of the Invention homoharringtonine and the harringtonine new purposes in suppressing angiogenesis, studies show that, homoharringtonine and harringtonine have the effect that suppresses angiogenesis, have specificity simultaneously, dosage is little, curative effect is high, side effect is little and advantage such as difficult generation drug resistance.Chinese patent literature CN:1600303A discloses the application of carnosic acid in pharmacy, this disclosure of the Invention carnosic acid suppress the activity of Coxsackie virus, the new purposes of the Sa Qi of section B3 type virus activity particularly, this material can be used for suppressing the activity of Coxsackie virus, particularly the medicine of preparation treatment Coxsackie virus infection disease.But the application in suppressing angiogenesis yet there are no report about carnosic acid.
Summary of the invention
The objective of the invention is at deficiency of the prior art, the application of a kind of carnosic acid in preparation inhibition angiogenesis drug is provided.
For achieving the above object, the technical scheme taked of the present invention is: carnosic acid suppresses application in the angiogenesis drug in preparation.
Described carnosic acid constitutes compositions suppresses angiogenesis with preparation medicine as single component or with other pharmaceutically acceptable compositions.
Described other pharmaceutically acceptable compositions can be the medicines that does not have antagonism with carnosic acid, also can be any or multiple adjuvants that pharmaceutically allows.
The pharmaceutical dosage form of described inhibition angiogenesis is capsule, tablet, oral formulations, microcapsule formulation, injection, suppository, spray or ointment.
The administering mode of the medicine of described inhibition angiogenesis is injection, oral, parenteral, suction-type spraying or transdermal administration.
Described inhibition angiogenesis drug is for suppressing the medicine of neonate tumour blood vessel.
Described angiogenesis is the angiogenesis of neoplastic lesion tissue and the angiogenesis that tumor causes.
Described tumor is an entity tumor.
Described entity tumor is constitutional or Secondary cases entity tumor.
Described neonate tumour blood vessel comprises the angiogenesis of leukemia, lymphoma and myeloma hematologic cancers.
Described inhibition angiogenesis drug is for suppressing psoriatic lesions tissue blood vessel new life's medicine.
Described inhibition angiogenesis drug is for suppressing the medicine of Paget ' s disease angiogenesis.
Described inhibition angiogenesis drug is the medicine of the angiogenesis of the optimum blood vessel hyperplasia disease of inhibition.
Described inhibition angiogenesis drug is the medicine of the angiogenesis of inhibition arthritis pathological changes tissue.
Described inhibition angiogenesis drug is the medicine of the angiogenesis at inhibition atherosclerotic lesion place.
Described inhibition angiogenesis drug is the medicine of the angiogenesis of inhibition neovascular oculopathy.
Described neovascular oculopathy is constitutional or Secondary cases neovascular oculopathy.
The invention has the advantages that:
The invention provides the new purposes of carnosic acid, find the carnosic acid blood vessel formation against function first, find that first carnosic acid can effectively suppress the propagation and the tubule formation of vascular endothelial cell, illustrate that carnosic acid has anti-angiogenesis activity, can be used as angiogenesis inhibitor and use, the preparation that can be applied to angiogenesis drug as angiogenesis inhibitor is diseases related with new vessels dependency such as treatment tumor, arthritis, psoriasis, ophthalmic diseases, atherosclerosis and new vessels.
Description of drawings
Accompanying drawing 1 is the photo that carnosic acid suppresses the propagation of HUVEC.
Accompanying drawing 2 is photos that carnosic acid suppresses the migration of HUVEC Transwell cell.
Accompanying drawing 3 is that carnosic acid suppresses the photo that the HUVEC tubule forms.
The specific embodiment
Below in conjunction with accompanying drawing the specific embodiment provided by the invention is elaborated.
Embodiment 1 carnosic acid suppresses Human umbilical vein endothelial cells (HUVEC) proliferation experiment
Adopt the CCK-8 method to detect the propagation of HUVEC.Contain WST – 8(2-(2-methoxyl group-4-nitrobenzophenone)-3-(4-nitrobenzophenone)-5-(2 in the CCK-8 reagent, 4-disulfonic acid benzene)-2H-tetrazolium list sodium salt), it is in electron carrier 1-Methoxy PMS(1-methoxyl group-5-toluphenazine dimethyl sulfate) effect under be reduced to yellow Jia Za (Formazan) product by the dehydrogenase in the cell mitochondrial with high water soluble.The quantity that generates De Jia Za thing is directly proportional with the quantity of living cells.Measure its absorbance value with enzyme-linked immunosorbent assay instrument at 450 nm wavelength places, can reflect living cells quantity indirectly.Can estimate the influence of medicine by this method to HUVCE propagation.
Method: the HUVEC cell inoculation is cultivated in 96 orifice plates.After treating that the cell growth reaches 80% fusion, carnosic acid is added in the hand-hole by following concentration 1,3,10,30,100 μ M, every Kong Jiayu hole inner volume is than being the CCK-8 solution of 1:10 volume after acting on 48 h, place 37 ℃ of incubators to continue to hatch 2 h, decline the hole microplate reader in 450 nm places detection OD value with wavelengthtunable.With the hole that do not add carnosic acid in contrast.To contain cell culture fluid and CCK-8 solution but not celliferous hole as blank.Be calculated as follows cell viability:
Cell viability (%)=(OD
Sample-OD
Blank)/(OD
Control-OD
Blank) * 100%
Result and conclusion: please refer to accompanying drawing 1, accompanying drawing 1 is the photo that carnosic acid suppresses the propagation of HUVEC.Shown in Fig. 1, carnosic acid is dose-dependence to the inhibited proliferation of HUVEC.When the concentration of carnosic acid was 10 μ M, the propagation that cell viability was reduced to the HUVEC of 20%, 30 μ M concentration when above when the cell viability of HUVEC was 81%, 30 μ M was suppressed fully, and cell viability is 0.
*: compare with matched group (concentration of carnosic acid is 0 μ M) and to have utmost point significant difference (P＜0.01).
Embodiment 2 carnosic acid suppress Human umbilical vein endothelial cells (HUVEC) migration experiment
The Transwell method detects the HUVEC migration.Transwell is a kind of experimental technique, the main material of this technology is Transwell cell (chamber), the bottom of cell has the film of one deck permeability, and (that general commonly used is polycarbonate membrane (polycarbonate membrane), this tunic has the micropore of pore size 0.1-12.0 μ m, cell places on the cell in the experiment, under the chemotactic factor that under cell, contains or the effect of somatomedin, cell sees through polycarbonate membrane, thereby carries out many-sided researchs such as common cultivation, cell chemotaxis, cell migration, cell invasion.
Method: following chamber adds the VEGF that 600 μ L contain 20 ng/ml
165The HUVEC culture fluid.Adding the HUVEC(cell density that contains the variable concentrations carnosic acid in the last chamber is 2 * 10
5/ ml), place CO
2Cultivate 8 h in the cell culture incubator.The group that does not add carnosic acid is contrast.Behind 8 h, take out culture plate, discard culture fluid in the hole from incubator, add 600 μ l, 1% glutaraldehyde room temperature and fix 15 min, wipe the cell that does not move the chamber gently with cotton swab, add 200 μ l, 0.1% violet staining then, rinse unnecessary crystal violet dyestuff with PBS at last.Take pictures just putting under the microscope (Olympus) to observe.
Result and conclusion: the displaing amaranth after violet staining of the cell after the migration.Please refer to accompanying drawing 2, accompanying drawing 2 is photos that carnosic acid suppresses the migration of HUVEC Transwell cell.By shown in Figure 2, compare with matched group, when the concentration of carnosic acid was 30 μ M, the cell of migration reduced, and the transfer ability of HUVEC is significantly suppressed.
Embodiment 3 carnosic acid suppress the little tube formation assay of HUVEC
Utilization Matrigel glue detects the tubule formation effect of HUVEC.Artificial basement membrane Matrigel glue is the basement membrane composition that extracts from mice EHS sarcoma, can the gelatinous artificial basement membrane of spontaneous formation under 37 ℃, have the biological action of natural basement membrane.Human umbilical vein endothelial cells can adhere to into pipe on Matrigel glue, thereby can be used for studying the influence of medicine to endotheliocyte tubule formation effect.
Method: get 50 μ l Matrigel sol solutions and join in 96 well culture plates of pre-cooling, be positioned over 37 ℃ of incubators then and hatch 1 h, make adhesive curing.The HUVEC(cell density that will contain the variable concentrations carnosic acid is 1 * 105/ml) to add respectively and be covered with in 96 orifice plates of Matrigel, places CO
2Cultivate 10 h in the cell culture incubator.The group that does not add carnosic acid is contrast.Under the inversion optical microscope, observe vascularization behind 10 h.
Result and conclusion: Human umbilical vein endothelial cells can be on matrigel elongation growth in a tubular form and interconnect, form tridimensional network.Please refer to accompanying drawing 2, accompanying drawing 2 is that carnosic acid suppresses the photo that the HUVEC tubule forms.By shown in Figure 2, compare with matched group, the tubule formation ability of HUVEC was subjected to remarkable inhibition when the concentration of carnosic acid was 3 μ M, and when concentration increased to 30 μ M, cell was dispersed in existence, did not see that tubule forms, and the tubule of HUVEC forms ability to be suppressed fully.
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the inventive method; can also make some improvement and replenish, these improvement and replenish and also should be considered as protection scope of the present invention.
Claims (17)
1. the application of carnosic acid in preparation inhibition angiogenesis drug.
2. application according to claim 1 is characterized in that, described carnosic acid constitutes compositions suppresses angiogenesis with preparation medicine as single component or with other pharmaceutically acceptable compositions.
3. application according to claim 2 is characterized in that, described other pharmaceutically acceptable compositions can be the medicines that does not have antagonism with carnosic acid, also can be any or multiple adjuvant that pharmaceutically allows.
4. application according to claim 1 is characterized in that, the pharmaceutical dosage form of described inhibition angiogenesis is capsule, tablet, oral formulations, microcapsule formulation, injection, suppository, spray or ointment.
5. application according to claim 1 is characterized in that, the administering mode of the medicine of described inhibition angiogenesis is injection, oral, parenteral, suction-type spraying or transdermal administration.
6. application according to claim 1 is characterized in that, described inhibition angiogenesis drug is for suppressing the medicine of neonate tumour blood vessel.
7. application according to claim 6 is characterized in that, described angiogenesis is the angiogenesis of neoplastic lesion tissue and the angiogenesis that tumor causes.
8. application according to claim 6 is characterized in that, described tumor is an entity tumor.
9. application according to claim 8 is characterized in that, described entity tumor is constitutional or Secondary cases entity tumor.
10. application according to claim 6 is characterized in that, described neonate tumour blood vessel comprises the angiogenesis of leukemia, lymphoma and myeloma hematologic cancers.
11. application according to claim 1 is characterized in that, described inhibition angiogenesis drug is for suppressing psoriatic lesions tissue blood vessel new life's medicine.
12. application according to claim 1 is characterized in that, described inhibition angiogenesis drug is for suppressing the medicine of Paget ' s disease angiogenesis.
13. application according to claim 1 is characterized in that, described inhibition angiogenesis drug is the medicine of the angiogenesis of the optimum blood vessel hyperplasia disease of inhibition.
14. application according to claim 1 is characterized in that, described inhibition angiogenesis drug is the medicine of the angiogenesis of inhibition arthritis pathological changes tissue.
15. application according to claim 1 is characterized in that, described inhibition angiogenesis drug is for suppressing the medicine of atherosclerotic lesion place angiogenesis.
16. application according to claim 1 is characterized in that, described inhibition angiogenesis drug is the medicine of the angiogenesis of inhibition neovascular oculopathy.
17. application according to claim 16 is characterized in that, described neovascular oculopathy is constitutional or Secondary cases neovascular oculopathy.
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| CN 201110004218 CN102058570A (en) | 2011-01-11 | 2011-01-11 | Application of carnosic acid in preparing medicament for suppressing angiogenesis |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176932A (en) * | 2016-08-31 | 2016-12-07 | 山东万安药业有限公司 | A kind of antineoplastic pharmaceutical compositions containing Radix Salviae Miltiorrhizae extract |
| CN110200956A (en) * | 2019-07-17 | 2019-09-06 | 吴广森 | A kind of ophthalmic external use medicine compositions |
| CN110559304A (en) * | 2019-09-23 | 2019-12-13 | 佳木斯大学 | A pharmaceutical composition for treating suppurative arthritis |
| CN114796176A (en) * | 2022-06-09 | 2022-07-29 | 中南大学湘雅医院 | A pharmaceutical composition for treating dermatoses, and its preparation method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1649574A (en) * | 2002-02-15 | 2005-08-03 | Dsmip资产公司 | Compositions comprising lycopene for the treatment and prevention of angiogenesis associated pathologies |
| JP2010090036A (en) * | 2008-10-03 | 2010-04-22 | Hiroshima Univ | Vascularization inhibitor |
| CN101851158A (en) * | 2010-05-27 | 2010-10-06 | 东北林业大学 | Method for preparing high-purity carnosic acid by continuous medium pressure column chromatography |
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2011
- 2011-01-11 CN CN 201110004218 patent/CN102058570A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1649574A (en) * | 2002-02-15 | 2005-08-03 | Dsmip资产公司 | Compositions comprising lycopene for the treatment and prevention of angiogenesis associated pathologies |
| JP2010090036A (en) * | 2008-10-03 | 2010-04-22 | Hiroshima Univ | Vascularization inhibitor |
| CN101851158A (en) * | 2010-05-27 | 2010-10-06 | 东北林业大学 | Method for preparing high-purity carnosic acid by continuous medium pressure column chromatography |
Non-Patent Citations (1)
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| 《中国煤炭工业医学杂志》 20071130 安慧萍 鼠尾草酸对HL-60细胞生长及分化作用的研究 第1324-1325页 1-17 第10卷, 第11期 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176932A (en) * | 2016-08-31 | 2016-12-07 | 山东万安药业有限公司 | A kind of antineoplastic pharmaceutical compositions containing Radix Salviae Miltiorrhizae extract |
| CN110200956A (en) * | 2019-07-17 | 2019-09-06 | 吴广森 | A kind of ophthalmic external use medicine compositions |
| CN110200956B (en) * | 2019-07-17 | 2021-07-27 | 吴广森 | Ophthalmic external medicine composition |
| CN110559304A (en) * | 2019-09-23 | 2019-12-13 | 佳木斯大学 | A pharmaceutical composition for treating suppurative arthritis |
| CN110559304B (en) * | 2019-09-23 | 2020-05-12 | 佳木斯大学 | A pharmaceutical composition for treating suppurative arthritis |
| CN114796176A (en) * | 2022-06-09 | 2022-07-29 | 中南大学湘雅医院 | A pharmaceutical composition for treating dermatoses, and its preparation method |
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Application publication date: 20110518 |