CN100417377C - Application of garcinolic acid in preparing medicine for treating tumor metastasis - Google Patents
Application of garcinolic acid in preparing medicine for treating tumor metastasis Download PDFInfo
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- CN100417377C CN100417377C CNB2005100391241A CN200510039124A CN100417377C CN 100417377 C CN100417377 C CN 100417377C CN B2005100391241 A CNB2005100391241 A CN B2005100391241A CN 200510039124 A CN200510039124 A CN 200510039124A CN 100417377 C CN100417377 C CN 100417377C
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Abstract
The present invention belongs to the field of medical preparation and discloses the application of gambogic acid to the preparation of medicine for treating tumor metastases. The present invention provides the new application of gambogic acid to the preparation of medicine for treating tumor metastases, particularly the application of medicine for treating the metastases of liver cancer or gastric cancer or mammary cancer or intestinal cancer or lung cancer. The gambogic acid has a good inhibiting effect on tumor metastases, has the good selectivity of inhibiting effects on tumor cells, has an obvious influence on genes relevant to metastases and has an obvious influence on protein relevant to metastases.
Description
Technical field
The present invention relates to the application of gamlogic acid in the preparation antineoplastic agent, particularly relate to the application of gamlogic acid in the preparation medicine for treating tumor metastasis.
Background technology
Ascendant trend in the incidence rate of malignant tumor continues in the world, the cancer new cases in the World Health Organization (WHO) statistics whole world in 2000 reach 1,000 ten thousand examples, 6,000,000 routine cancer mortalities are arranged, wherein the cause of death mostly is greatly due to the malignant tumor transfer in late period. and cancer has become one of principal disease that threatens human life's health, how to overcome the recurrence of tumor cell and translates into the obstacle of capturing maximum on the cancer road for the mankind.
Tumor invasion is meant that malignant tumor leaves the long position of former generation, break through the barrier that basement membrane and extracellular matrix constitute, the normal structure that infringement is adjoined, stymied tissue generation degeneration and necrosis. neoplasm metastasis refers to that malignant cell breaks away from its former position, the discontinuous tissue that is transported to through various channels continues proliferate, forming the process of same property tumor. invasion and attack and transfer are interdependent each other, promptly follow another appearance for one. tumor invasion and attack takes place and shifts is a process that complicated multistep is rapid, generally can be divided into following a few step: tumor cell breaks away from from the primary tumo(u)r focus, tumor cell passes extracellular matrix (ECM) and soaks into, move in vascular endothelial cell, tumor cell enters blood circulation, arrive and stay in the blood vessel wall in site, distant place along with blood flow, tumor cell passes blood vessel, by ECM, form metastasis at specific tissue or organ at last.
Chemotherapy of tumors has been obtained very big progress in recent years, the tumor patient life span obviously prolongs, but because the toxic and side effects of chemotherapeutics, make clinical practice be subjected to certain limitation. cytotoxic drug still is antineoplastic basis and main path at present, but the medicine that really can reach the high-efficiency low-toxicity target is few, though the medicine that wherein can suppress neoplasm metastasis is still less. use the cytotoxic drug can the kill tumor cell, but also often normal cell is produced injury simultaneously, therefore using dosage is unsuitable excessive, the raising medicine that also constantly uses of the new technology in chemotherapy process distributes in the tumor by local high concentration and (injects as orientation, make targeting prodrug etc.), to alleviate the whole body toxicity, but because these medicines can not effectively suppress the transfer of tumor cell, usually be that primary tumors alleviates to some extent, but the many places metastasis appears again in other parts of health, causes finally that sb.'s illness took a turn for the worse.
Gamlogic acid (6ambogicAcid, GA, C
38H
44O8) being one of effective ingredient in the Chinese medicine Resina garciniae. Resina garciniae is the secreted dry resin of Guttiferae plant Resina garciniae. experimental studies results shows, the antitumaous effect of gamlogic acid and general chemotherapy anticarcinogen are distinguished to some extent, kill cancer cell optionally, and normal hemopoietic system and leukocyte are not had influence. this provides novel prospect for seeking new antitumor drug, might enlighten new anticancer mechanism simultaneously.
Summary of the invention
The purpose of this invention is to provide the new purposes of gamlogic acid in pharmaceutical field, i.e. the application of gamlogic acid in the preparation medicine for treating tumor metastasis.
The objective of the invention is to realize by following measures:
The application of gamlogic acid in the preparation medicine for treating tumor metastasis.
Further, the application of gamlogic acid in the medicine of the anti-hepatocarcinoma of preparation, gastric cancer, breast carcinoma, intestinal cancer or lung cancer metastasis.
Beneficial effect:
1, gamlogic acid has significant inhibitory effect to the growth in vitro of people's hepatocarcinoma SMMC-7721 and QGY-7701 cell strain, human lung adenocarcinoma SPC-A1 cell strain, human breast carcinoma MDA-MB-231, people's Gastric Cancer MGC-803 and SGC-7901 cell strain.
2, gamlogic acid has good inhibition effect to neoplasm metastasis.
3, gamlogic acid has selectivity preferably to the inhibitory action of tumor cell.
4, gamlogic acid shows the inhibitory action of tumor cell:
(1) to the significant again metastasis effect of nude mouse metastasis model of human breast carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer and other tumor strain of inoculation; (2) metastasis related gene is had a significant effect; (3) metastasis related protein is had a significant effect.
Description of drawings
Fig. 1 acts on human breast cancer cell MDA-MB-231 48h amount effect curve for gamlogic acid.
Fig. 2 is that blank group nude mouse lung shifts tuberosity entity photo.
Fig. 3 is that ADM (2mg/kg) matched group nude mouse lung shifts tuberosity entity photo.
Fig. 4 is that gamlogic acid high dose (8mg/kg) group nude mouse lung shifts tuberosity entity photo.
Fig. 5 is that gamlogic acid low dosage (4mg/kg) group nude mouse lung shifts tuberosity entity photo.
Fig. 6 acts on behind the MDA-MB-231 cell figure as a result to the RT-PCR of the influence of MMP-2 gene expression for gamlogic acid, and wherein Actin is confidential reference items; 1 is NS; 2 is Taxol (0.30 μ M); 3 is GA (3.00 μ M); 4 is GA (1.50 μ M); 5 is GA (0.75 μ M); 6 is GA (0.30 μ M).
Fig. 7 is Fig. 6 each group behind gray scale scanning to be expressed be converted into numerical value for gamlogic acid acts on behind the MDA-MB-231 cell bar diagram to the influence of MMP-2 gene expression, obtains relative value after removing the confidential reference items value of actin.
Fig. 8 acts on behind the MDA-MB-231 cell figure as a result to the RT-PCR of the influence of TIMP-1 gene expression for gamlogic acid, and wherein Actin is confidential reference items; 1 is NS; 2 is Taxol (0.30 μ M); 3 is GA (3.00 μ M); 4 is GA (1.50 μ M); 5 is GA (0.75 μ M); 6 is GA (0.30 μ M).
Fig. 9 is Fig. 8 each group behind gray scale scanning to be expressed be converted into numerical value for gamlogic acid acts on behind the MDA-MB-231 cell bar diagram to the influence of TIMP-1 gene expression, obtains relative value after removing the confidential reference items value of actin.
Figure 10 acts on behind the MDA-MB-231 cell figure as a result to the RT-PCR of the influence of TIMP-2 gene expression for gamlogic acid, and wherein Actin is confidential reference items; 1 is NS; 2 is Taxol (0.30 μ M); 3 is GA (3.00 μ M); 4 is GA (1.50 μ M); 5 is GA (0.75 μ M).
Figure 11 is Figure 10 each group behind gray scale scanning to be expressed be converted into numerical value for gamlogic acid acts on behind the MDA-MB-231 cell bar diagram to the influence of TIMP-2 gene expression, obtains relative value after removing the confidential reference items value of actin.
Figure 12 is the RT-PCR figure of gamlogic acid to MDA-MB-435 nude mouse lung metastasis model tumor tissue TIMP-1 influence, and wherein GAPDH is confidential reference items; NS is administration blank group not; ADM is amycin (2mg/kg) positive controls; GA8 is gamlogic acid (8mg/kg) group; GA4 is gamlogic acid (4mg/kg) group.
Figure 13 is a gamlogic acid to the bar diagram of MDA-MB-435 nude mouse lung metastasis model tumor tissue TIMP-1 influence, is Figure 12 each group behind gray scale scanning to be expressed be converted into numerical value, obtains relative value after removing the confidential reference items value of GAPDH.
Figure 14 is the RT-PCR figure of gamlogic acid to MDA-MB-435 nude mouse lung metastasis model tumor tissue TIMP-2 influence, and wherein GAPDH is confidential reference items; NS: be administration blank group not; ADM is amycin (2mg/kg) positive controls; GA8 is gamlogic acid (8mg/kg) group; GA4 is gamlogic acid (4mg/kg) group.
Figure 15 is a gamlogic acid to the bar diagram of MDA-MB-435 nude mouse lung metastasis model tumor tissue TIMP-2 influence, is Figure 14 each group behind gray scale scanning to be expressed be converted into numerical value, obtains relative value after removing the confidential reference items value of GAPDH.
Figure 16 acts on behind the MDA-MB-231 cell electrophoretogram to MMP-2 and MMP-9 albumen and activity influence thereof for gamlogic acid, and NS is administration matched group not among the figure; 1 is gamlogic acid administration (8 μ M) group; 2 is gamlogic acid administration (0.4 μ M) group; 3 is gamlogic acid administration (0.08 μ M) group.
Figure 17 is Figure 16 each group behind gray scale scanning to be expressed be converted into the relative value that numerical value obtains for gamlogic acid acts on behind the MDA-MB-231 cell the bar diagram of MMP-2 and MMP-9 albumen and activity influence thereof.
The specific embodiment
The invention will be further elaborated by the following examples, but the present invention is not imposed any restrictions.
The preparation of the gamlogic acid that the embodiment of the invention is used can also can be adopted commercially available gamlogic acid standard substance referring to the disclosed content of patent CN1557816A.
In vitro culture breast carcinoma cell strain MDA-MB-231 adds gamlogic acid, the situation of breast cancer cell behind the mensuration gamlogic acid effect 48h, and the result shows, IC
50Be 3.16 μ M, and present good amount effect curve (see figure 1).
The take the logarithm breast cancer cell MDA-MB-435 of In vitro culture of growth, cell concentration is adjusted into 1 * 10
7Under/ml. the aseptic condition, inoculate the fat pad of sub-nude mouse left side second nipple, inoculum concentration is that only (cell number is 1.0 * 10 to 0.1ml/
6/ only) .2 after week with the animal random packet. gamlogic acid high dose (8mg/kg) group, gamlogic acid low dosage (4mg/kg) group, ADM (amycin) matched group weekly intravenous administration once, totally 10 times; The blank group is given the equivalent normal saline. 11 days execution animals after the drug withdrawal, weigh, lung is heavy and tumor is heavy, the nude mouse ABW is deducted tumor by weighing heavy. with lung tissue in BouinShi liquid (saturated picric acid: formaldehyde: fix 24 hours glacial acetic acid=75: 25: 5), the reuse anhydrous alcohol is dipped to the lung tissue color restoration, metastasis is white tuberosity. numeration lung metastatic nodules amount under anatomic microscope. and lung tissue segment and tumor tissue is fixing in formalin, conventional dehydration embedding, H.E dyeing carrying out pathologic finding. the result adopts heterogeneity of variance Aspin-Welch check.
The result shows, with respect to the blank group, the heavy coefficient of the lung of gamlogic acid administration group has utmost point significant difference, pulmonary's state significantly improved after administration was described, metastatic nodules reduces (seeing Table 1). perusal, blank group tuberosity number is many and protruding, and progressively shifts to lung central authorities, and lung is essence shape (see figure 2); ADM matched group lung metastatic nodules is many, concentrates on the edge mostly, and projection is few than matched group, and metastasis is implied in (see figure 3) in the lung mostly; Gamlogic acid high dose (8mg/kg) group lung metastasis only several, concentrate on the edge, the intact (see figure 4) of lung tissue; Most of gamlogic acid low dosage (4mg/kg) group lung metastasis higher dosage groups concentrate on the edge, the intact (see figure 5) of lung tissue.
Every index after the administration of table 1. nude mouse (body weight, tumor weight, lung weight, the rate of transform and metastatic nodules) statistics.
Compare with matched group: * P＜0.05, * * P＜0.01
1.RT-PCR
Adopt the RT-PCR method to detect the change that gamlogic acid acts on MMP-2, TIMP-1 and TIMP-2 gene expression behind the breast carcinoma MDA-MB-231 cell. primer is synthetic by Shanghai Sangon Biological Engineering Technology And Service Co., Ltd.
(1) gamlogic acid is to the influence of breast cancer cell MDA-MB-231 MMP-2, TIMP-1 and TIMP-2:
The result shows, it is obvious that gamlogic acid acts on behind the breast carcinoma MDA-MB-231 cell 3.00 μ M and 1.5 μ M dosage group results, significantly reduced the MMP-2 expression, and the inhibitory action of MMP-2 is had dose-effect relationship (experiment triplicate, mean value SD), the results are shown in Figure 6,7; Also can promote TIMP-1 and TIMP-2 gene expression, but do not have a dose-effect relationship, the results are shown in Figure 8,9 to what TIMP-1 influenced, to TIMP-2 influence the results are shown in Figure 10,11. Fig. 8,9 show, gamlogic acid promotes TIMP-1 gene expression after acting on the MDA-MB-231 cell. experiment triplicate, mean value SD; Figure 10,11 shows, gamlogic acid acts on behind the MDA-MB-231 cell except that 1.50 μ M dosage groups, and holding concurrently promotes TIMP-2 gene expression. experiment triplicate, mean value SD.
(2) gamlogic acid has the influence of breast cancer cell MDA-MB-435 nude mouse tumor tissue TIMP-1 and TIMP-2 to inoculation:
After gamlogic acid acts on MDA-MB-435 nude mouse lung metastasis model, extracting the total RNA of tumor tissue, the RT-PCR experiment. the result shows, gives to promote TIMP-1 (seeing Figure 12,13) and TIMP-2 to express (seeing Figure 14,15) behind the gamlogic acid.
2. gelatinase analysis of spectrum.
Gamlogic acid (8 μ M, 0.4 μ M, 0.08 μ M) act on MDA-MB-231 cell 48h after, being changed to serum-free medium cultivated 4 hours, collect supernatant, each organize living cells with the MTT method quantitatively to determine respectively to organize supernatant applied sample amount unanimity. 10% polyacrylamide that preparation contains 0.1% gelatin coagulates, last sample, the 100V electrophoresis. glue in 2.5%Trixon-100 solution in room temperature shaking table jog to remove SDS, put reactant liquor (50mM Tris-HCl (pH 7.5), 150 mM NaCl, 10mMCaCl2, and 0.5mMZnCl2) in, 37 ℃ of overnight incubation, the back is with 0.1% Coomassie brilliant blue (preparing with 30% methanol and the 10% acetic acid) 1h that dyes, and (sees Figure 16 in decolouring in the destaining solution (30% methanol, 10% acetic acid) to band till clear, 17).
The result shows, administration matched group (NS) not relatively, and pro-MMP-2 and pro-MMP-9 are suppressed after the administration.
Getting gamlogic acid 10g adds suitable adjuvant by the injection common process and makes injection.
Getting gamlogic acid 10g adds suitable adjuvant by the tablet common process and makes tablet.
Claims (1)
1. the application of gamlogic acid in preparation anti-breast cancer transfer medicine.
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| CNB2005100391241A CN100417377C (en) | 2005-04-27 | 2005-04-27 | Application of garcinolic acid in preparing medicine for treating tumor metastasis |
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| CN100417377C true CN100417377C (en) | 2008-09-10 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101361732B (en) * | 2007-08-09 | 2011-06-01 | 江苏康缘药业股份有限公司 | Medicinal preparation containing garcinia acid and use thereof |
| CN113952329A (en) * | 2021-08-27 | 2022-01-21 | 广州医科大学附属第二医院 | Application of gambogic acid in preparation of Src inhibitor and preparation of liver cancer treatment drug |
| CN114306414B (en) * | 2022-02-08 | 2023-01-24 | 东北林业大学 | Application of gamboge and disulfiram composition in preparation of medicine for treating colon cancer |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1452960A (en) * | 2003-05-21 | 2003-11-05 | 戴建国 | Garcinolic acid injection and its prepn |
| CN1513448A (en) * | 2003-08-16 | 2004-07-21 | 江苏康缘药业股份有限公司 | Prepn. of medicine composition contg. garcinolic acid and garcinolic acid compound |
| CN1557816A (en) * | 2004-02-12 | 2004-12-29 | 江苏康缘药业股份有限公司 | Process for preparation of garcinia acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1452960A (en) * | 2003-05-21 | 2003-11-05 | 戴建国 | Garcinolic acid injection and its prepn |
| CN1513448A (en) * | 2003-08-16 | 2004-07-21 | 江苏康缘药业股份有限公司 | Prepn. of medicine composition contg. garcinolic acid and garcinolic acid compound |
| CN1557816A (en) * | 2004-02-12 | 2004-12-29 | 江苏康缘药业股份有限公司 | Process for preparation of garcinia acid |
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