CN104666289A - Application of danshinolic acid A in preparation of anti-tumor cell epithelial-mesenchymal transition drug - Google Patents
Application of danshinolic acid A in preparation of anti-tumor cell epithelial-mesenchymal transition drug Download PDFInfo
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- CN104666289A CN104666289A CN201410467822.0A CN201410467822A CN104666289A CN 104666289 A CN104666289 A CN 104666289A CN 201410467822 A CN201410467822 A CN 201410467822A CN 104666289 A CN104666289 A CN 104666289A
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Abstract
The invention discloses an application of danshinolic acid A in preparation of an anti-tumor cell epithelial-mesenchymal transition drug. The application has the characteristics that danshinolic acid A is found to have a significant inhibition action on tumor cell epithelial-mesenchymal transition and a significant influence on epithelial-mesenchymal transition key protein genes, and has application prospects for preparation of the anti-tumor cell epithelial-mesenchymal transition drug.
Description
Technical field
The present invention relates to the new opplication of salvianolic acid A, particularly relate to salvianolic acid A and preparing the application in antitumor cell Epithelial and stromal conversion medicine.
Background technology
Research shows, Epithelial and stromal transforms (epithelial mesenchymal transition, EMT) in benign tumor vicious transformation process, play tremendous influence, in the generation of malignant tumor, development, metastasis process, play pivotal role.EMT refers to the phenomenon of epithelial cell to transition of mesenchymal cells, in this course, epithelial cell loses the epithelial phenotype feature such as polarity and intercellular adhesion connection, is converted into the Interstitial cell with features such as high migration, invasion and attack, anti-apoptotic and degradation of cell epimatrixs.Evidence suggests, in the process of the original position of most tumors, malignant cell tissue invasion and distant metastasis of human towards periphery, all there is EMT phenomenon, carry out in process at EMT, the transfer ability of cell and invasive ability increase, opposing apoptosis and cell ageing, thus form the tumor of far-end.
In EMT process, not only cell phenotype is converted into Interstitial cell by epithelial cell, and cell sign thing also there occurs change: epithelium mark as mucoprotein in E-calcium (E-cadherin, E-cad), Cytokeratin etc. are expressed and reduced; Interstitial mark is expressed as Vimentin (Vimentin), Fn Fiberonectin (Fibronectin), N-calcium mucoprotein (N-cadherin), smooth muscle actin etc. to be increased.Large quantity research shows, E-cad is normal in low expression in multiple human body malignant cell, differentiation, the Infiltration and metastasis of the low expression of E-cad and tumor have significance relevant, E-cad is the important adhesion molecule maintaining epithelial phenotype, intercellular adhesion effect and cell polarity are played a decisive role, tumor cell E-cad expresses to decline or lack in EMT, is not only considered to the goldstandard that cancerous cell loses epithelial character, is also the important behaviour promoting neoplasm metastasis simultaneously.Transfer is the Basic biological characteristics of malignant tumor, is also the main cause for the treatment of malignant tumor failure and death.
Since 20 century 70s, the M & M of China's malignant tumor is always in rising trend, adds up according to Chinese Anti-Cancer Association, China's cancer new cases 2,200,000 in 2005, dead 1,600,000, suffer from carninomatosis people 3,100,000, estimate that the year two thousand twenty new cases will reach 3,000,000.The statistics display of American Cancer Society, within 2002, the whole world has 670 to die ten thousand deaths in cancer, estimates that this numeral will rise to 1,310 ten thousand in the year two thousand thirty, and the whole world at present tumor number of patients is estimated to exceed 4,000 ten thousand.Due to non-specific toxicities, the multidrug resistance etc. lacking tumor-selective and tumor, most of antitumor drug is also effective unlike expection, and the toxic and side effects of its normal tissue perplexs the subject matter of Drug therapy especially.Therefore, the significant to the antitumor drug of tumor cell specific selectivity of clear and definite targeting is sought.
The Chinese medicine resource of China is a treasure-house, for new type antineoplastic medicine provides abundant material base, finds that antitumor active drug has unique advantage and extensively wide prospect from Chinese medicine.Salvianolic acid A (Salvianolic acid A; SalA) be one of the effective ingredient of salviamiltiorrhizabung; our early-stage Study finds the characteristic of salvianolic acid A tool specificity antineoplastic; to human normal cell's safety, low toxicity; 2010105847730 and 2010105847764 disclose the obvious inhibition tumor cell propagation of salvianolic acid A and have defencive function to normal cell, the application of energy inducing apoptosis of tumour cell, the effect of inhibition tumor cell Invasion and Metastasis.But the effect that salvianolic acid A inhibition tumor cell Epithelial and stromal transforms has no report.
Salviol acid A is water soluble ingredient main in Radix Salviae Miltiorrhizae, molecular weight 494.45, molecular formula: C
26h
22o
10, its chemical structural formula is as follows:
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of novelty teabag of salvianolic acid A, is specifically related to salvianolic acid A and is preparing the application in antitumor cell Epithelial and stromal conversion medicine.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
Salvianolic acid A is preparing the application in antitumor cell Epithelial and stromal conversion medicine.
Above-mentioned tumor includes but not limited to pulmonary carcinoma.
The content of above-mentioned salvianolic acid A in medicine is more than or equal to 50% and is less than 100%, and pharmaceutically acceptable carrier is preparing the application in antitumor drug.
The dosage form that above-mentioned antitumor cell Epithelial and stromal transforms medicine is liquid preparation, granule, tablet, electuary, soft gelatin capsule, capsule, slow releasing agent, drop pill, oral cavity disintegration preparation or injection.
Beneficial effect of the present invention:
(1) salviol acid A can effectively transform by inhibition tumor cell Epithelial and stromal.
(2) salvianolic acid A can regulate Epithelial and stromal to transform key protein gene expression.
(3) salvianolic acid A targets neoplastic cells Epithelial and stromal conversion process, target spot is clear and definite, is the antitumor drug that a kind of potential targets neoplastic cells Epithelial and stromal transforms.
Accompanying drawing explanation
Fig. 1 morphological observation display salvianolic acid A reversible TGF-β 1 induces lung cancer A549 cell Epithelial and stromal to transform.
The lung cancer A549 cell migration that Fig. 2 cell scratch experiment detection display salvianolic acid A can suppress TGF-β 1 to induce.
The lung carcinoma cell invasion that Fig. 3 cell invasion measuring display salvianolic acid A can suppress TGF-β 1 to induce.
Fig. 4 Q-PCR detects salvianolic acid A to the impact of the mucoprotein mrna expression of E-calcium.
Fig. 5 Q-PCR detects salvianolic acid A to the impact of fibronectin mrna expression.
Fig. 6 Q-PCR detects salvianolic acid A to the impact of Vimentin mrna expression.
Detailed description of the invention
The present invention is further elaborated by the following examples, but do not impose any restrictions the present invention.
Following examples salvianolic acid A (sterling) used is purchased from Shanghai You Si Bioisystech Co., Ltd, and lot number Lot120826, content 99.4%, human lung carcinoma cell line A549 is purchased from Shanghai Inst. of Life Science, CAS cellular resources center.
Embodiment 1: the impact that the pulmonary carcinoma Epithelial and stromal that morphological observation salvianolic acid A is induced TGF-β 1 transforms
Lung cancer A549 cell is made single cell suspension, by 1 × 10
5individual/mL is inoculated on 6 orifice plates, every hole 1mL, if negative control group, TGF-β 1 induction group and salvianolic acid A administration group, often group establishes 3 multiple holes, puts 37 DEG C of CO
2and after cultivating 24h in cell culture incubator under saturated humidity 5% condition, negative control group adds isopyknic cell culture fluid, TGF-β 1 induction group and salvianolic acid A administration group all add after TGF-β 1 (10ng/mL) induces 24h, salvianolic acid A administration group adds salvianolic acid A (40 μ g/mL), every hole 1mL, continue to cultivate 24h, observe the cellular morphology of lung cell A549 and growing state under being directly put in inverted microscope and take pictures.
Result: matched group presents the epithelial cell Morphological Features of paving stone sample, has adhesiveness between cell; TGF-β 1 induction group cell is the morphological characteristic of spindle shape Interstitial cell; Salvianolic acid A administration group cell is based on epithelial cell form, and a few cell is fusiformis.Display salvianolic acid A can reverse the pulmonary carcinoma epithelial cell mesenchymal transformation that TGF-β 1 induces, and sees Fig. 1.
Embodiment 2: cell scratch experiment detects salvianolic acid A to the impact of the lung carcinoma cell transfer ability that TGF-β 1 induces
Get the A549 cell being cultured to logarithmic (log) phase, use 0.25% trypsinization, with dropper piping and druming to single cell suspension, adjustment cell density is 1 × 10
5individual/mL, is inoculated on 6 orifice plates, every hole 1mL, if negative control group, TGF-β 1 induction group and salvianolic acid A administration group, often group establishes 3 multiple holes, is placed in 37 DEG C, cultivates 24h under 5%CO2 and saturated humidity condition in cell culture incubator.Negative control group adds isopyknic cell culture fluid, TGF-β 1 induction group and salvianolic acid A administration group all add after TGF-β 1 (10ng/mL) induces 24h, with 100 μ L micropipette heads vertical cut in 6 orifice plates, after PBS liquid rinses twice, salvianolic acid A administration group adds salvianolic acid A (40 μ g/mL), every hole 1mL, continue to cultivate 24h, culture plate is inserted 37 DEG C, cultivate 48 rearmounted phase contrast microscopes in 5%CO2 incubator to observe, Stochastic choice 5 also calculates in 100 × visual field the total cellular score moved in cut space.
Result: compare with negative control group, TGF-β 1 induction group can significantly promote that lung carcinoma cell moves, and after salvianolic acid A administration, compares with TGF-β 1 induction group, and the lung carcinoma cell migration that can significantly suppress TGF-β 1 to induce, is shown in Fig. 2.
Embodiment 3: cell sensing resistor instrument cell invasion measuring salvianolic acid A is on the impact of the lung carcinoma cell invasion ability that TGF-β 1 induces
Infiltrate on check-out console at CIM-plate cell migration and add one deck Matrigel gel in room, lower room adds chemotactic factor 600 μ L.Then in upper room, add cell suspension, adjustment cell density is 1 × 10
5individual/mL, every hole 200 μ L, if negative control group, TGF-β 1 induction group and salvianolic acid A administration group, often group establishes 3 multiple holes, is placed in 37 DEG C, cultivates 24h under 5%CO2 and saturated humidity condition in cell culture incubator.Negative control group adds isopyknic cell culture fluid, TGF-β 1 induction group and salvianolic acid A administration group all add after TGF-β 1 (10ng/mL) induces 24h, salvianolic acid A administration group adds salvianolic acid A (40 μ g/mL), continues detection of dynamic 48h at cell sensing resistor instrument.
Result: compare with negative control group, TGF-β 1 induction group significantly can promote lung carcinoma cell invasion, the lung carcinoma cell invasion that salvianolic acid A administration can significantly suppress TGF-β 1 to induce, Fig. 3.
Embodiment 4:Q-PCR detects salvianolic acid A transforms mark mrna expression impact on Epithelial and stromal.
Be suspended in by cell dissociation in culture fluid, piping and druming evenly adjustment cell density is 1 × 10
5individual/mL, in inoculation plate, every hole 10mL cell suspension, is placed in 37 DEG C, cultivates administration induction EMT after 24h, if negative control group, TGF-β 1 induction group and salvianolic acid A administration group under 5%CO2 and saturated humidity condition in cell culture incubator.Negative control group adds isopyknic cell culture fluid, TGF-β 1 induction group and salvianolic acid A administration group all add after TGF-β 1 (10ng/mL) induces 48h, salvianolic acid A administration group adds salvianolic acid A (40 μ g/mL), and often group establishes 3 multiple holes.Trizol method extracts total serum IgE, and Q-PCR detects Epithelial and stromal and transforms marker protein E-calcium mucoprotein (E-cadherin), fibronectin (Fibronectin), Vimentin (Vimentin) mrna expression
Result: compare with negative control group, TGF-β 1 induction group significantly can reduce the expression (P < 0.01) of the mucoprotein mRNA of E-calcium and significantly increase the expression (P < 0.01) of fibronectin and Vimentin mRNA; Salvianolic acid A administration group compares with TGF-β 1 induction group, significantly can increase the expression (P < 0.01) of the mucoprotein mRNA of E-calcium and significantly reduce the expression (P < 0.01) of fibronectin and Vimentin mRNA, seeing Fig. 4 ~ 6.
Claims (5)
1. salvianolic acid A transforms the application of medicine for the preparation of antitumor cell Epithelial and stromal.
2. application according to claim 1, is characterized in that salvianolic acid A can effectively transform by inhibition tumor cell Epithelial and stromal, and significantly increase E-calcium Mucin gene express and significantly reduce fibronectin, vimentin dna is expressed.
3. application according to claim 1, is characterized in that described tumor is pulmonary carcinoma.
4. application according to claim 1, is characterized in that the content of salvianolic acid A in medicine is more than or equal to 50% and is less than 100%.
5. application according to claim 1, is characterized in that the dosage form of described antitumor cell Epithelial and stromal conversion medicine is liquid preparation, granule, tablet, electuary, soft gelatin capsule, capsule, slow releasing agent, drop pill, oral cavity disintegration preparation or injection.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101991565A (en) * | 2010-12-13 | 2011-03-30 | 南京中医药大学 | Application of salvianolic acid A in preparing medicament for inducing apoptosis of tumor cells and/or inhibiting propagation of tumor cells |
| CN102028678A (en) * | 2010-12-13 | 2011-04-27 | 南京中医药大学 | Application of salvianolic acid A in preparing anti-tumor metastasis medicine |
| CN102218140A (en) * | 2010-04-15 | 2011-10-19 | 上海天甲生物医药有限公司 | Tumor resistance effect of medicine combination of salvianolic acid B and coxib medicaments |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102218140A (en) * | 2010-04-15 | 2011-10-19 | 上海天甲生物医药有限公司 | Tumor resistance effect of medicine combination of salvianolic acid B and coxib medicaments |
| CN101991565A (en) * | 2010-12-13 | 2011-03-30 | 南京中医药大学 | Application of salvianolic acid A in preparing medicament for inducing apoptosis of tumor cells and/or inhibiting propagation of tumor cells |
| CN102028678A (en) * | 2010-12-13 | 2011-04-27 | 南京中医药大学 | Application of salvianolic acid A in preparing anti-tumor metastasis medicine |
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