CN101278925A - Application of embellin in preparation of medicament for inhibiting angiogenesis - Google Patents
Application of embellin in preparation of medicament for inhibiting angiogenesis Download PDFInfo
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- CN101278925A CN101278925A CNA2008100381012A CN200810038101A CN101278925A CN 101278925 A CN101278925 A CN 101278925A CN A2008100381012 A CNA2008100381012 A CN A2008100381012A CN 200810038101 A CN200810038101 A CN 200810038101A CN 101278925 A CN101278925 A CN 101278925A
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Abstract
The invention relates to a novel use of Chinese herbal medicine monomer embelin, in particular to an application of the embelin in a preparation of a drug for inhibiting angiogenesis. The embelin is applied in the inhibition of angiogenesis dependent disease such as mammary cancer, colon cancer, lymphoma, acute myelocytic leukemia, rheumatoidarthritis, psoriasis, diabetic syndrome, hemangioma, etc. Experiments show that the embelin has remarkable inhibitory action in proliferation experiment, migration experiment, invasion experiment, cell tabulation experiment, the angiogenesis of chick embryo allantois, etc. in the human microvascular endothelial cells (HMEC-1), thereby being used for preparing the drug for inhibiting the angiogenesis.
Description
Technical field
The present invention relates to the new purposes of a kind of Chinese herbal medicine monomer embellin (Embelin), be specifically related to the application of embellin in the preparation anti-angiogenic drugs.
Background technology
Angiogenesis is the process that produces neovascularity on existing blood vessel basis, comprises five basic processes: 1. basement membrane of blood vessel degraded; 2. endotheliocyte passes basement membrane and moves to substrate around the blood vessel; 3. endothelial cell proliferation, stick mutually and connect; 4. form the tube chamber spline structure; 5. substrate reinvent with smooth muscle cell hold and mutually coincideing of blood vessel forms vasoganglion.
Angiogenesis all has generation under physiology and pathological conditions, the physiological angiogenesis mainly occurs in fetal development and female pathology cycle, and is very crucial for normal growth; Pathological is the major reason that numerous disease takes place, and comprises tumor, cardiovascular disease, diabetes etc., and wherein tumor causes very big threat to human health always, and growth of tumor all depends on new vessels with transfer and provides nutrient for it; Therefore do not have the generation of new vessels, tumor generally can only be grown to 2～3 cubic millimeters, suppresses tumor by angiogenesis inhibiting and other relevant diseases have broad application prospects.
Compare with traditional tumour therapeutic modality (as chemotherapy, radiotherapy etc.), anti-angiogenic rebirth therapy targeting has plurality of advantages such as curative effect is obvious, toxic and side effects is little in the vascular endothelial cell rather than the tumor cell itself of tumor kitchen range.It can also can pass through their effect of inhibition and onset directly by stoping the generation of angiogenesis associated protein, and specific anti-angiogenic drugs becomes effective Therapeutic Method of treatment cancer and other angiogenesis dependence diseases already.Drugs approved by FDA in 2004 first angiogenesis inhibitors be used for the treatment of colon cancer, existing multiple similar formulations is being carried out clinical trial, some Chinese herbal medicine monomers also have been found the effect with anti-angiogenic rebirth.
Embellin (Embelin) is to spend a kind of benzoquinone compound of purifying out in the Fructus embeliae laetae in vain, though existing bibliographical information embellin can have antineoplastic action by directly acting on tumor cell, effects such as antibiotic in addition, antiinflammatory, antifertility, but still there is not the report that embellin can angiogenesis inhibiting, or suppress tumor by angiogenesis inhibiting, there be not the report of embellin as anti-angiogenic drugs yet.
Summary of the invention
The objective of the invention is to develop the pharmacological use of embellin as a kind of new angiogenesis inhibitor.
The invention reside in embellin and preparing the related application that suppresses in the angiogenesis dependence diseases such as breast carcinoma, colon cancer, lymphoma, acute myelogenous leukemia, rheumatoid arthritis, psoriasis, diabetic syndrome, hemangioma at application, the especially embellin that the preparation angiogenesis suppresses in the medicine.
Particularly, the invention provides the application of embellin in the medicine of preparation inhibition neonate tumour blood vessel.Be the application in the medicine of the angiogenesis of inhibition arthritis pathological changes tissue at the preparation anti-angiogenic drugs, described arthritis is rheumatoid arthritis or inflammatory arthritis.
The present invention also provides embellin to suppress the application of the medicine kind of neovascular oculopathy in preparation.Specifically comprise the neovascular keratopathy; Perhaps neovascular retinal diseases; Perhaps angiogenesis inhibiting iris disease; Perhaps make neovascular glaucoma; Perhaps neovascular choroidal diseases; Perhaps neovascular conjunctiva oculopathy; Perhaps generate the vascular type cataract; Perhaps neovascular vitreous body oculopathy; Perhaps neovascular optic nerve disease.Wherein, described neovascular retinal diseases is diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity or retinal arterial obstruction.Described neovascular choroidal diseases is moist old maculopathy.
The present invention also provides the application of embellin in preparation inhibition hemangioma pathological changes tissue blood vessel new life's medicine, and the application in preparation inhibition psoriatic lesions tissue blood vessel new life's medicine, and the application in the medicine of preparation inhibition solid tumor pathological tissues angiogenesis, wherein solid tumor is constitutional or insecondary solid tumor.
The present invention also provides the application of embellin in the angiomatous medicine of preparation inhibition, and wherein hemangioma comprises angiomatosis or hemangioblastoma.Also provide embellin to suppress Kaposi ' s sarcoma pathological changes tissue blood vessel new life's medicine and suppress the medicine of leukemia, lymphoma or myeloma hematologic cancers and suppress application in the medicine of Paget ' s disease in preparation.The present invention also provides the application of embellin on preparation angiogenesis inhibitors compositions.
The embellin 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 anti-angiogenic drugs that other and embellin do not have antagonism.Its preparation can be any one dosage form pharmaceutically, includes but not limited to tablet, granule, capsule, pill, oral liquid, injection, liposome etc.
For implementing method of the present invention, embellin can or pass through the administration of implanted reservoir by oral, parenteral, suction-type spraying." parenteral " comprise in subcutaneous, Intradermal, intravenous, intramuscular, intraarticular, intra-arterial, the synovial cavity, in the breastbone, in the sheath, intralesional and intracranial injection or input technology.
Oral available solid or liquid dosage unit carry out administration as dosage forms such as last agent, powder, tablet, sugar-coat agent, capsule, granule, suspending agent, solution, syrup, drop, sublingual lozenges.
The end agent is The compounds of this invention is worn into suitable fineness and to make.Powder is that The compounds of this invention is worn into suitable fineness, and the pharmaceutical carrier (as carrier, mannitol and so on edibility carbohydrate etc.) with same fineness is mixed and made into then.As required, also can sneak into materials such as correctives, antiseptic, dispersant, coloring agent, spice.
Capsule is to be filled into as in the gelatine capsule shell and make making pulverous last agent and powder as mentioned above or going into the described granular material of tablet part.Also lubricant and fluidizer etc. can be mixed in the powdered substance, in capsule, carry out padding then.If add cosolvent and disintegrating agent etc., as Polyethylene Glycol, sodium carbonate, the drug effect in the time of can improving the capsule picked-up.
The invention discloses the application of embellin in the preparation angiogenesis medicament.Experiment shows that embellin becomes pipe experiment, chick chorioallantoic membrane angiogenesis etc. that the obvious suppression effect is all arranged at proliferation experiment, migration experiment, invasion and attack experiment, the cell of human microvascular endothelial cell (mvec) (HMEC-1), can be used for preparing the medicine of angiogenesis inhibiting.
Description of drawings
Fig. 1: embellin suppresses the propagation of HMEC-1 cell
Fig. 2: embellin suppresses HMEC-1 cells in vitro cut migration photo
Wherein: the A. contrast; B.10 μ M embellin
Fig. 3: embellin suppresses the Boyden cell migration photo of the modification of HMEC-1 cell
Wherein: the A. contrast; B.1 μ M embellin
Fig. 4: embellin suppresses the one-tenth pipe photo of HMEC-1 cell
Wherein: the A. contrast; B.10 μ M embellin
Fig. 5: embellin suppresses the photo that the chick chorioallantoic membrane new vessels forms
Wherein: the A. contrast; B.1 μ g/disc embellin
The specific embodiment
Experimental example 1: embellin suppresses human microvascular endothelial cell (mvec) (HMEC-1) cell proliferation
Purpose and principle: cell proliferation experiment adopts MTS assay.MTS assay is that a kind of colorimetry of using in living cells is determined the assay method of cell proliferation quantity.The NADPH dehydrogenase is transformed into a kind of a kind of coloring matter that is dissolved in tissue culture medium with MTS tetrazolium salts chemical compound, and the living cells number of its shade and cell strain is height correlation within the specific limits.Can estimate the influence of medicine on cell proliferation ability by this model.
Method: with HMEC-1 cell suspension inoculation in 96 orifice plates (5000 cells in every hole), add the culture medium effect 48～72 hours contain the variable concentrations embellin respectively, every then hole adds 20 μ l developers, hatched 1～4 hour, the reuse microplate reader is read the absorbance value in each hole at the 490nm place.
Result and evaluation: compare with matched group, behind the adding embellin, the multiplication capacity of endotheliocyte is suppressed, and illustrates that embellin can suppress the propagation of endotheliocyte.
Embodiment 2: embellin suppresses HMEC-1 cells in vitro cut migration experiment
Purpose and principle: external scratch experiment is in the cell migration experiment again.This experiment is examined under a microscope by make cut on the monolayer endothelial cell that covers with in culture plate, and notes the situation of cut border cell towards the migration of cut position, estimates the influence of medicine to the endotheliocyte transfer ability.
Method: with 8 * 10
4Individual/ml cell inoculation treats that cell grows to more than 90% in 6 orifice plates, use suction nozzle standardized line in every hole of the 1ml of micropipettor.With PBS cell debris is cleaned, added again and contain VEGF
165And the culture medium that contains different pharmaceutical concentration, in 5%CO
2Incubator was cultivated about about 24 hours for 37 ℃, until VEGF
165Group leader is full.
Result and evaluation: examine under a microscope and take pictures, the result is: wherein A is a matched group, and B is 10 μ M embellins; Compare with matched group, give embellin after, the migration of endotheliocyte is suppressed, and illustrates that embellin can suppress the travel motion of endotheliocyte.
Embodiment 3: embellin suppresses the Boyden cell migration experiment of HMEC-1 cell modification
Purpose and principle: Millicell (Millopore) cell is adopted in the Boyden cell migration experiment that endotheliocyte is modified, this is the culture dish that a class can be inserted Tissue Culture Plate, it is the poly carbonate filter membrane of 8 μ m that bottom has the aperture, the side that cell can see through film under the inducing of somatomedin adhere to the opposite side that contains the high concentration growth factor, and this experiment can detection of drugs has the influence of resistance transfer ability to endotheliocyte.
Method: in 24 orifice plates, add 1% gelatin and hatched 30 minutes in 37 ℃, discard gelatin, give a baby a bath on the third day after its birth time with PBS.Add 600 μ l in outer 24 orifice plates of cell and contain VEGF
165The endotheliocyte culture medium.Insert 20,000 cells in the cell, add the embellin medicine of 50 μ L variable concentrations afterwards again, in 37 ℃ of 5%CO
2Hatched in the incubator four hours.
Result and evaluation: after four hours, the suction of the cell culture fluid inside and outside the cell is gone, the cell of lower floor's cell migration is fixed 20 minutes with 4% paraformaldehyde, with PBS give a baby a bath on the third day after its birth all over and blot, used hematoxylin eosin stain afterwards 20 minutes, reuse PBS is with background excess dyestuff flush away, and room temperature is dried.The OLYMPUS microscopically counting statistics data of taking pictures.The result is: wherein A is a matched group, and B is 1 μ M embellin group; With the matched group ratio, give embellin after, the endothelial cell migration ability is affected, and illustrates that embellin can suppress the ability of the resistant migration of endotheliocyte.
Embodiment 4: embellin suppresses the HMEC-1 cell and becomes the pipe experiment
Purpose and principle: Matrigel (matrigel) is the basement membrane extract of the solubility that extracting obtains from EHS (Engelbreth-Holm-Swarm) murine sarcoma.This kind sarcoma is rich in extracellular matrix protein, its Main Ingredients and Appearance is a laminin, also have collagen iv, entactin, heparin sulfate glycoprotein, it also contains TGF-β, fiber mother cell growth factor, tissue plasminogen activator (tPA) and other some somatomedin.At room temperature, this Matrigel can be grouped to a kind of host material of biologically active, and effect is similar with the mammalian cell basement membrane, for the adhesion and the differentiation of cell the effect effect is arranged.Endotheliocyte can merge on Matrigel and form microtubule, can utilize this specific character of endotheliocyte to study medicine to angiopoietic influence.
Method: Matrigel is taped against on 48 orifice plates, in 37 ℃, 5%CO
2After incubator was placed 30min and treated that it solidifies, every hole added 60000 cells, adds the culture medium that 500 μ l contain the variable concentrations embellin again, mixing.Cultivate in 37 ℃ of 5% incubator and examine under a microscope microtubule formation situation after 16-18 hour, middle totally five different parts are selected to reach up and down in every hole, calculate microtubule and form quantity and carry out statistical analysis.
Result and evaluation: endotheliocyte is grown in Matrigel behind the 16-18h, and cell becomes spindle shape by original polygon, and elongation growth in Matrigel, individual cells are rolled into tubulose and interconnect, and forms tridimensional network.The result is: A wherein: matched group, B:10 μ M embellin; Compare with matched group, give after the embellin, endothelium becomes the pipe process to be affected, and three-dimensional net structure is damaged, and illustrates that embellin can suppress the endotheliocyte microtubule and form.
Embodiment 5: embellin suppresses the chick chorioallantoic membrane angiogenesis
Purpose and principle: early stage in the Embryo Gallus domesticus growth, its body immune system is not set up as yet fully, is in the various exotic antigen immunologic tolerance stages, can not produce rejection to added testing drug.The carrier that will contain medicine places its surface, can be observed the influence of medicine to the chick chorioallantoic membrane new vessels.Be a kind of life of comparatively ideal research angiogenesis at present.
Method: the hatching egg shell is carried out disinfection, place the constant temperature and humidity incubator to hatch 5 days after, in superclean bench, with its surface of alcohol swab wiping, open an osculum that diameter is about 1 centimetre at eggshell air chamber end, observe the position at embryo place by aperture, divest the part shell, expose chorioallantoic membrane.Be ready to add the variable concentrations embellin, diameter is 5 millimeters sterilization circular filter papers, and filter paper is added in avascular area on the chorioallantoic membrane, uses the sterile transparent tape seal before.(A: matched group does not add embellin, B:1 μ g/disc embellin)
Result and evaluation: the Embryo Gallus domesticus of putting into filter paper is put into after incubator continued to hatch two days, throws off adhesive tape, and peel off exposes chorioallantoic membrane as far as possible, takes pictures under stereomicroscope, the results are shown in Figure 5.Compare with matched group, give after the embellin, new blood capillary generates and is suppressed, and illustrates that embellin can suppress the generation of chick chorioallantoic membrane neovascularity.
Claims (18)
1. the application of embellin in the preparation anti-angiogenic drugs.
2. application according to claim 1 is characterized in that anti-angiogenic drugs is the medicine that suppresses neonate tumour blood vessel.
3. application according to claim 1 is characterized in that anti-angiogenic drugs is the medicine that suppresses the angiogenesis of arthritis pathological changes tissue.
4. application according to claim 3 is characterized in that arthritis is rheumatoid arthritis or inflammatory arthritis.
5. application according to claim 1 is characterized in that anti-angiogenic drugs is the medicine that suppresses neovascular oculopathy.
6. application according to claim 5 is characterized in that oculopathy is the neovascular keratopathy; Perhaps neovascular retinal diseases; Perhaps angiogenesis inhibiting iris disease; Perhaps make neovascular glaucoma; Perhaps neovascular choroidal diseases; Perhaps neovascular conjunctiva oculopathy; Perhaps generate the vascular type cataract; Perhaps neovascular vitreous body oculopathy; Perhaps neovascular optic nerve disease.
7. application according to claim 6 is characterized in that the neovascular retinal diseases is diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity or retinal arterial obstruction.
8. application according to claim 6 is characterized in that the neovascular choroidal diseases is moist old maculopathy.
9. application according to claim 1 is characterized in that anti-angiogenic drugs is the medicine that suppresses hemangioma pathological changes tissue blood vessel new life.
10. application according to claim 1 is characterized in that anti-angiogenic drugs is the medicine that suppresses psoriatic lesions tissue blood vessel new life.
11. application according to claim 1 is characterized in that anti-angiogenic drugs is the medicine that suppresses solid tumor pathological tissues angiogenesis.
12. application according to claim 11 is characterized in that solid tumor is constitutional or insecondary solid tumor.
13. application according to claim 1, the medicine that it is characterized in that angiogenesis inhibiting is for suppressing angiomatous medicine.
14. application according to claim 13 is characterized in that hemangioma comprises angiomatosis or hemangioblastoma.
15. application according to claim 1 is characterized in that anti-angiogenic drugs is the medicine that suppresses Kaposi ' s sarcoma pathological changes tissue blood vessel new life.
16. application according to claim 1 is characterized in that anti-angiogenic drugs is the medicine that suppresses leukemia, lymphoma or myeloma hematologic cancers.
17. application according to claim 1 is characterized in that anti-angiogenic drugs is the medicine that suppresses Paget ' s disease.
18., it is characterized in that embellin is in the application on preparation angiogenesis inhibitors compositions according to the described application of claim 1-17.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008100381012A CN101278925A (en) | 2008-05-27 | 2008-05-27 | Application of embellin in preparation of medicament for inhibiting angiogenesis |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102488678A (en) * | 2011-12-22 | 2012-06-13 | 天津医科大学 | Application of embelin to preparation of medicament for treating autoimmune disease |
| CN102633615A (en) * | 2012-03-27 | 2012-08-15 | 广西壮族自治区中医药研究院 | Method of using embelia laeta to prepare bisexual antifertility material embelin |
| CN105087471A (en) * | 2015-09-08 | 2015-11-25 | 中国人民解放军成都军区总医院 | Preparation method of tissue engineering vascularization model from chicken embryo chorioallantoic membrane |
-
2008
- 2008-05-27 CN CNA2008100381012A patent/CN101278925A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102488678A (en) * | 2011-12-22 | 2012-06-13 | 天津医科大学 | Application of embelin to preparation of medicament for treating autoimmune disease |
| CN102488678B (en) * | 2011-12-22 | 2013-05-01 | 天津医科大学 | Application of embelin to preparation of medicament for treating autoimmune disease |
| CN102633615A (en) * | 2012-03-27 | 2012-08-15 | 广西壮族自治区中医药研究院 | Method of using embelia laeta to prepare bisexual antifertility material embelin |
| CN105087471A (en) * | 2015-09-08 | 2015-11-25 | 中国人民解放军成都军区总医院 | Preparation method of tissue engineering vascularization model from chicken embryo chorioallantoic membrane |
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Open date: 20081008 |