CN101049327A - Application of gambogicacid in preparing medication for restraining angiogenesis - Google Patents
Application of gambogicacid in preparing medication for restraining angiogenesis Download PDFInfo
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- CN101049327A CN101049327A CN 200710022230 CN200710022230A CN101049327A CN 101049327 A CN101049327 A CN 101049327A CN 200710022230 CN200710022230 CN 200710022230 CN 200710022230 A CN200710022230 A CN 200710022230A CN 101049327 A CN101049327 A CN 101049327A
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Abstract
An application of garcinolic acid in preparing the medicines for suppressing the angiogenesis of tumor, arthritis, retinopathy, angioma and psoriasis and in turn treating them is disclosed.
Description
Technical field
The present invention relates to the new purposes of gamlogic acid, be specifically related to the application of gamlogic acid in preparation inhibition angiogenesis drug.
Background technology:
Angiogenesis (angiogenesis) is meant that the new capillary vessel that comes from the blood capillary that existed and blood capillary posterior vein generates.Blood vessel is the important channel of delivery of oxygen, nutrient substance and metabolite, does not have the tissue of blood vessel support or organ to be difficult to existence, therefore with body in organ and organize forming process to accompany vascularization can take place.Because tissue or organ are to the needs of oxygen and nutrient substance and the dependence that metabolite is removed, heart and vascular system are the organs that forms the earliest in the embryo development procedure.Physiological angiogenesis only is present in the process of reproductive system and wound healing, and is of short duration and be strictly controlled.
Angiogenesis is a complex process, mainly is made up of successive 10 steps: 1, anoxia is made a response the synthetic angiogenesis factor that discharges of damage or diseased tissue; 2, separately receptors bind on angiogenesis factor and the endotheliocyte; 3, receptors bind activates endotheliocyte; 4, protease discharges, the dissolved matrix film; 5, endotheliocyte moves, rises in value; 6, the adhesion molecule blood vessel that helps to sprout extends forward; 7, (matrixmetalloproteinases MMPs) comes the dissolved cell epimatrix to produce the matrix metal hydrolysising protease; 8, angiogenin and Tie-2 interact and regulate the tubule generation; 9, the EphB-ephrinB system regulates tubular structure connection ring formation; 10, pericyte participates in the stability adjusting of new vessels.
Angiogenesis is one and complicated process, not only has many compositions such as endotheliocyte, smooth muscle fiber to participate in wherein, and it also relates to multiple enzyme that plays an important role and protein.
Tumor-blood-vessel growth is newer field in the tumor research.People are rich in blood vessel with regard to having found that tumor tissues is more normally organized before more than 100 year.1945, Algire at first proposed the notion of " tumor-blood-vessel growth ".1971, it is that blood vessel is dependent that Folkman proposes tumor growth the earliest, but this at that time viewpoint is not accepted by the people, and the foundation of capillary endothelial cell culture technique after these 8 years, the discovery of first angiogenesis inhibitor after 11 years, the finishing of a series of activities such as proteic purification of first angiogenic activity after 13 years then makes this viewpoint be supported by more and more evidences, and makes this field become the focus of tumor research and the New Policy of oncotherapy.
Growth of tumor has two visibly different stages, and promptly being transformed into from avascular slow growth stage has the fast breeding of the blood vessel stage, and angiogenesis makes tumor can obtain enough nutrient substance, is the key link of facilitating above-mentioned transformation.If there is not angiogenesis, the growth of primary tumo(u)r can not surpass 1-2mm
3
Diseases such as arthritis (as rheumatoid arthritis), retinopathy (as diabetic retinopathy, retinal vein occlusion, prematureness retinopathy), hemangioma, psoriasis all need the pathological tissues angiogenesis is controlled.
Gamlogic acid (gambogic acid, GA, C
38H
44O
8) be one of effective ingredient in the Chinese medicine Resina garciniae.Resina garciniae is the secreted dry resin of Guttiferae plant Resina garciniae.Experimental result shows that gamlogic acid can suppress the tumor growth of animal-transplanted tumor, in the external growth that can suppress tumor cell.There is not gamlogic acid at present as the report that suppresses the angiogenesis medicine.
Summary of the invention
The purpose of this invention is to provide the application of gamlogic acid in preparation inhibition angiogenesis drug.
Technical scheme of the present invention is the application of application, the especially gamlogic acid of gamlogic acid in preparation inhibition angiogenesis drug in the angiogenesis drug of diseases such as preparation inhibition tumor, arthritis (as rheumatoid arthritis), retinopathy (as diabetic retinopathy, retinal vein occlusion, prematureness retinopathy), hemangioma, psoriasis.
The gamlogic acid of treatment effective dose and any one adjuvant of pharmaceutically permission can be made pharmaceutical composition according to the present invention, also can add the medicine that other and gamlogic acid do not have other angiogenesis inhibitor of antagonism.Its preparation can be any one dosage form that pharmaceutically allows, and includes but not limited to tablet, granule, capsule, pill, oral liquid, injection, liposome etc.The consumption of gamlogic acid can be according to variations such as route of administration, patient age, body weight, body surface area, the disease type of being treated and the orders of severity, and its daily dose can be used by one or many at 1～5mg/Kg weight range.
Useful result of the present invention:
The invention discloses the new purposes of gamlogic acid, i.e. the application of gamlogic acid in preparation inhibition angiogenesis drug.Experiment shows, gamlogic acid all has significant inhibitory effect to chick chorioallantoic membrane angiogenesis, rat artery ring angiogenesis, migration of vascular endothelial cells, the generation of vascular endothelial cell tubule, tumor cell secretion VEGF etc., can be used for preparing the medicine that suppresses angiogenesis.
Description of drawings
Fig. 1: gamlogic acid suppresses chick chorioallantoic membrane angiogenesis photo.Wherein: A, contrast; B, 0.9ng GA; C, 4.5ngGA; D, 22.5ng GA.
Fig. 2: gamlogic acid suppresses the microscope figure of rat artery ring angiogenesis.Wherein: A, contrast; B, 10
-6Mol/LGA; C, 5 * 10
-6Mol/L GA; D, 2.5 * 10
-5Mol/L GA.
Fig. 3: gamlogic acid suppresses the microscope figure of endothelial cell migration.Wherein: A, contrast; B, 0.5 * 10
-6Mol/L GA; C, 1 * 10
-6Mol/L GA; D, 2 * 10
-5Mol/L GA.
Fig. 4: gamlogic acid suppresses the phase contrast microscope figure that the endotheliocyte tubule generates.Wherein: A, contrast; B, 0.5 * 10
-6Mol/L GA; C, 1 * 10
-6Mol/L GA; D, 2 * 10
-5Mol/L GA.
Fig. 5: gamlogic acid suppresses the ELISA testing result figure of lung cell A549 secretion of VEGF.
The specific embodiment
The invention will be further elaborated by the following examples.
Embodiment 1: gamlogic acid suppresses the chick chorioallantoic membrane angiogenesis.
Purpose and principle: the angiogenesis at chick chorioallantoic membrane is early stage, and body immune system is not set up as yet fully, and rejection is taken place various foreign bodies hardly, will contain the medicine carrier and place its surface, can be observed the influence of medicine to angiogenesis.Because it to the anti-angiogenic medicaments sensitivity, still is considered to a kind of comparatively ideal medicaments sifting model at present.
Method: the fertilization Embryo Gallus domesticus places incubator hatching 9 days (the air chamber end upwards).Then Embryo Gallus domesticus was left standstill 15 minutes after with alcohol wipe, window is cut with the shears mill in the position of windowing of standardized 2 * 2cm size above Embryo Gallus domesticus, blow away the dust that mill is cut on the eggshell, throw off the eggshell at the place of windowing, reuse iris shears is broken shell membrane, exposes allantocherion.(A: matched group does not add gamlogic acid with not commensurability gamlogic acid by grouping; B: gamlogic acid low dose group, 0.9ng GA; C: dosage group in the gamlogic acid, 4.5ng GA; D: gamlogic acid high dose group, 22.5ng GA) is added on high pressure went out the Whatman filter paper of 0.5 * 0.5cm size of bacterium, then filter paper is placed on the no blood vessel position between two trunks of allantocherion, with sterile transparent adhesive tape envelope window.
Result and evaluation: Embryo Gallus domesticus is put into incubator hatching two days, throws off the adhesive tape of envelope window, takes pictures, and the results are shown in Figure 1.With matched group relatively, give gamlogic acid after, angiogenesis is suppressed, big blood vessel is less, illustrates that gamlogic acid can suppress the chick chorioallantoic membrane angiogenesis, and is dose dependent.
Embodiment 2: gamlogic acid suppresses the rat artery ring angiogenesis of In vitro culture.
Purpose and principle: the rat aorta ring is embedded in the gel-type vehicle, observes endotheliocyte and sprout and form the blood capillary spline structure from tunica intima.
Method: one of the male Wistar rat of body weight 100～120g, dislocation method is put to death, and gets thoracic aorta, removes peripheral connective tissue and fatty tissue, is cut into the arterial ring that is about 1mm, with the rinsing of M199 serum-free medium.The rat aorta section is embedded in the Fibrin Glue in 24 orifice plates, carries out In vitro culture, changed liquid 1 time in per 2 to 3 days with M199 culture fluid (matched group does not contain gamlogic acid) and the culture fluid that contains the gamlogic acid of variable concentrations.
Result and evaluation: to outgrowth, formation has branched blood capillary spline structure to endotheliocyte from the artery segment incision.After 7 days near observation arterial ring under the inverted microscope generation situation of endotheliocyte and new vessels and taking pictures.(wherein A is a matched group to the results are shown in Figure 2; B is 10
-6Mol/L GA group; C is 5 * 10
-6Mol/L GA group; D is 2.5 * 10
-5The mol/LGA group).With matched group relatively, give gamlogic acid after, the blood capillary spline structure of arterial ring generates and reduces, and gamlogic acid inhibition rat artery ring angiogenesis be described, and be dose dependent.
Embodiment 3: gamlogic acid suppresses endothelial cell migration.
Purpose and principle: the endothelial cell migration experiment adopts transwell cell culture cell to carry out.The aperture is that the poly carbonate filter membrane of 8 μ m is separated into cell two-layer up and down.Under factors stimulated growth, endotheliocyte passes the filter opening of 8 μ m by ameboid motion, attached to the back side of filter membrane.Utilize this model can estimate the influence of medicine to the endotheliocyte transfer ability.
Method: endotheliocyte is contained the 1640 culture medium effects 30 minutes of variable concentrations gamlogic acid, then with 2.5 * 10
5The cell suspension 400 μ l of individual/ml HUVEC join the chamber, and following chamber adds the RPMI-1640 that 600 μ l contain stimulating factor and variable concentrations, in 5%CO
2Cultivated 4 hours in 37 ℃ of the incubators.
Result and evaluation: take out filter membrane, scrape on the striping not migrating cell, with the fixing filter membrane of 100% methanol, and dye with hematoxylin-Yihong, the glycerol mounting utilizes microscopic examination at last and takes pictures, and (wherein A is a matched group to the results are shown in Figure 3; B is 0.5 * 10
-6Mol/L GA group; C is 1 * 10
-6Mol/L GA group; D is 2 * 10
-5Mol/L GA group).Compare with matched group, give gamlogic acid after, the transfer ability of endotheliocyte is suppressed, and illustrates that gamlogic acid can suppress the motion of endotheliocyte, and is dose dependent.
Embodiment 4: gamlogic acid suppresses the endotheliocyte tubule and generates.
Purpose and principle: matrigel is a rat ESH sarcoma cell epimatrix extract, is rich in the IV Collagen Type VI, and its composition and basement membrane are quite similar, can replace natural basement membrane.Can utilize endotheliocyte on matrigel, to creep, merge the formation tubule and come of the influence of observational study medicine angiogenesis.
Method: matrigel is taped against on 96 orifice plates, and 80 μ l/ holes, are placed 30min it are solidified by 37 ℃.Endotheliocyte is contained the culture medium effect 30 minutes of variable concentrations gamlogic acid respectively, and every then hole adds 1 * 10
5Individual/ml endotheliocyte suspension 100 μ l.In 5%CO
237 ℃ of cultivations of incubator are observed tubule generation situation and are taken pictures under phase contrast microscope (* 400) after 8 hours, five different parts are selected in every hole, count the tubule growing amount and also carry out statistical analysis.
Result and evaluation: after endotheliocyte was grown 8 hours in matrigel, cell can become spindle shape by original polygon, and in gel-type vehicle elongation growth, be linear array and form tubular structure, a plurality of tubules are interconnected to form tridimensional network.(wherein A is a matched group to the results are shown in Figure 4; B is 0.5 * 10
-6Mol/L GA group; C is 1 * 10
-6The mol/LGA group; D is 2 * 10
-5Mol/L GA group).Compare with matched group, give gamlogic acid after the endotheliocyte network-like structure be damaged, illustrate that gamlogic acid can suppress the endotheliocyte tubule and generate, and be dose dependent.
Embodiment 5: gamlogic acid suppresses tumor cell secretion VEGF (VEGF).
Purpose and principle: by the enzyme linked immunological principle, the influence of detection of drugs pair cell secretion of VEGF.
Method: lung cell A549 (3 * 10
5/ hole) receive six well culture plates, treat cell attachment after, give variable concentrations gamlogic acid (being respectively 0,0.5 μ M, 1 μ M, 2 μ M), collecting cell supernatant behind the 12h uses the ELISA test kit, measures the content of vegf protein.
Result and evaluation: concentration/cell number of the VEGF that records as estimating the index of medicine to VEGF secretion influence, be the results are shown in Figure 5.Compare with matched group (being that GA is 0), gamlogic acid can suppress tumor cell secretion VEGF, and is dose dependent.
Claims (8)
1, the application of gamlogic acid in preparation inhibition angiogenesis drug.
2, application according to claim 1 is characterized in that suppressing angiogenesis drug for suppressing the medicine of tumor-blood-vessel growth.
3, application according to claim 1 is characterized in that suppressing the medicine of angiogenesis drug for the angiogenesis of inhibition arthritis pathological changes tissue.
4, application according to claim 3 is characterized in that arthritis is rheumatoid arthritis.
5, application according to claim 1 is characterized in that suppressing the medicine of angiogenesis drug for the angiogenesis of inhibition retinopathy pathological tissues.
6, application according to claim 5 is characterized in that retinopathy is diabetic retinopathy, retinal vein occlusion or prematureness retinopathy.
7, application according to claim 1 is characterized in that suppressing the medicine of angiogenesis drug for the angiogenesis of inhibition hemangioma pathological changes tissue.
8, application according to claim 1 is characterized in that suppressing the medicine of angiogenesis drug for the angiogenesis of inhibition psoriatic lesions tissue.
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| CN100577180C CN100577180C (en) | 2010-01-06 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112315955A (en) * | 2020-11-04 | 2021-02-05 | 温州医科大学 | S100A8/A9 protein inhibitor gambogic acid and application thereof |
-
2007
- 2007-05-10 CN CN200710022230A patent/CN100577180C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112315955A (en) * | 2020-11-04 | 2021-02-05 | 温州医科大学 | S100A8/A9 protein inhibitor gambogic acid and application thereof |
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| CN100577180C (en) | 2010-01-06 |
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