CN103690519A - Application of salvianolic acid A in preparation of medicine for treating tumour multi-drug resistance - Google Patents
Application of salvianolic acid A in preparation of medicine for treating tumour multi-drug resistance Download PDFInfo
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- CN103690519A CN103690519A CN201310705521.2A CN201310705521A CN103690519A CN 103690519 A CN103690519 A CN 103690519A CN 201310705521 A CN201310705521 A CN 201310705521A CN 103690519 A CN103690519 A CN 103690519A
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Abstract
The invention relates to the field of natural medicines, and discloses application of salvianolic acid A in preparation of a medicine for treating tumour multi-drug resistance. Compared with salvia extracts of tanshinones, the salvianolic acid A disclosed by the invention has good water solubility, and therefore, the salvianolic acid A has better bioavailability. According to the invention, the salvianolic acid A has obvious inhibiting effect to drug-resistant tumour cells; the mechanism is as follows: apoptosis of drug-resistant tumour cells is induced through up regulation of expression of proapoprotic protein is up-regulated and down regulation of expression of inhibitor of apoptosis protein; tumour drug-resistant protein P-gp expression is inhibited by increasing active oxygen expression level of drug-resistant tumour cells, so that tumour multi-drug drug-resistant cells are overcome, and therefore, the salvianolic acid A disclosed by the invention has the application prospect for preparing the medicine for overcoming tumour multi-drug resistance.
Description
Technical field
The present invention relates to salvianolic acid A in the application of anti-tumor aspect, relate in particular to the application of salvianolic acid A in preparation treatment multi-drug resistance of the tumor medicine.
Background technology
The People's Republic of China's Ministry of Public Health to the whole nation for the third time cause of the death Retrospect spot-check result show, malignant tumor is China resident's the 2nd large cause of death.Tumor be a complexity, long-term process, be subject to the inside and outside multifactorial impact of body, cell forms malignant cell by processes such as increment, differentiation, atypical hyperplasia, conversion and changes.In the chemotherapy of various tumors, tumor multi-medicine drug-resistant is a key factor that affects chemotherapy effect, and can cause recurrence and shift, and becomes the biggest obstacle of oncotherapy, has become a main cause of tumor chemical therapy failure.
Multi-drug resistance of the tumor refers to when drug resistance is appearred in a kind of antitumor drug, other many configurations, the different antitumor drug of mechanism of action is also produced to the phenomenon of crossing drug resistant.The mechanism of action of tumor multi-medicine drug-resistant is very complicated, mainly comprises the following aspects: (1) thus by reducing medicine, take in and increase medicine outflow and cause drug concentration to reduce.(2), by the metabolism of medicine in cell, activate or deactivation medicine.(3) by changing the level of drug resistance target enzyme or the affinity of desmoenzyme and medicine in cell, make drug failure.(4) strengthen DNA damage repair function.(5) strengthen the anti-apoptosis regulating power of cell etc.Wherein that most study is multidrug resistance gene 1 (multidrug resistance1, mdr1) and coding drug-resistant protein P-glycoprotein (P-gp), the main task of P-gp is that intracellular medicine is pumped to extracellular, thereby reduce the damage of medicine to cell, so P-gp albumen is the major reason that causes tumor cell multidrug resistance.For multidrug resistance mechanism, there are many reversal agent of drug resistance to be constantly found, but its toxic and side effects is large etc., that reason causes it to be widely used in is clinical.Therefore must seek effectively to overcome the medicine of multidrug resistance.
Active oxygen (reactive oxygen species, ROS) belongs to oxygen-derived free radicals, is intermediate product and derivant thereof that oxygen produces in body reduction process, participates in the conduction of signal of interest approach in cell proliferation, differentiation, conversion and apoptosis and cell.ROS level has complicated impact to generation and the process of the oxidative stress relevant diseases such as tumor, diabetes, nerve retrograde affection.Studies have reported that in cell, ROS level increases, can reduce the level of Mdr-p P-gp in cell.By intervening ROS, reduce Multidrug Resistance Protein Expression, promote the apoptotic effective ways of drug-resistant tumor.
Salvianolic acid A is a kind of water solublity effective monomer component extracting from salviamiltiorrhizabung, English name: Salvianolicacid A, molecular weight 494.45, molecular formula: C
26h
22o
10, the following salvianolic acid A general formula of its chemical structural formula.
Salvianolic acid A is a kind of water soluble ingredient with extensive pharmacological action, and most study is the effect of salvianolic acid A aspect cardiovascular protection, anti-hepatic fibrosis at present.Recent research finds that again salvianolic acid A has anti-tumor activity, can suppress nucleoside transporting and strengthen the antitumor action of chemotherapeutics.
Summary of the invention
Technical problem to be solved by this invention is to provide the new purposes of salvianolic acid A.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
The application of salvianolic acid A in preparation treatment multi-drug resistance of the tumor medicine.
The salvianolic acid A that inventor studies has better water solublity than many antineoplastic Radix Salviae Miltiorrhizae effective monomers (as TANSHINONES and derivant thereof), therefore has better bioavailability.The invention discloses salvianolic acid A drug-resistant tumor cell is had to stronger fragmentation effect, mechanism for salvianolic acid A can be by the reactive oxygen species of increase drug-resistant tumor cell, inducible resistance apoptosis of tumor cells, and reduce the expression of Mdr-p P-gp, thereby overcome the tumor cell of multidrug resistance.
Beneficial effect: the invention discloses the application of salvianolic acid A in preparation treatment multi-drug resistance of the tumor medicine.Salvianolic acid A has advantages of the Radix Salviae Miltiorrhizae extract good water solubility compared with tanshinone, has better bioavailability.Salvianolic acid A has the more significant inhibitory action of comparison parent tumor cell to drug-resistant tumor cell, its mechanism is for passing through to increase active oxygen expression, rise pro apoptotic protein is expressed, lower apoptosis inhibit protein expression, inducible resistance apoptosis of tumor cells, suppress tumor drug resistance albumen P-gp and express, thereby overcome tumor multi-medicine drug-resistant cell.Therefore, salvianolic acid A has the application prospect that preparation overcomes the medicine of tumor multi-medicine drug-resistant.
Accompanying drawing explanation
Fig. 1 cytotoxicity MTT experiment shows that salvianolic acid A has the inhibitory action of dose dependent to the survival rate of breast cancer cell MCF-7 and multidrug resistance cell MCF-7/MDR thereof, more obvious to the inhibitory action of multidrug resistance cell MCF-7/MDR.
Fig. 2 flow cytometer detects the two apoptotic cells that dye of Annexin V/PI and tests demonstration salvianolic acid A energy inducible resistance tumor cell MCF-7/MDR apoptosis, and has dose dependent (in figure, A-F salvianolic acid A concentration is 0,20,40,60,80,100 μ M).
Fig. 3 DCFH-DA method detects cytoactive oxygen ROS level, and A figure shows that drug-resistant tumor cell strain has the ROS level higher than parent tumor cell line, and B figure shows that salvianolic acid A can raise the level of drug-resistant tumor cell strain active oxygen ROS, and has dose dependent.
Fig. 4 Western Blot detects protein expression, the IAP Bcl-2 that demonstration salvianolic acid A can be lowered drug-resistant tumor expresses, raising pro apoptotic protein Bax expresses, and use after scavenger N-acetylcystein (NAC) intervention of active oxygen ROS, the ability of its inducible resistance tumor death reduces.
Fig. 5 Western Blot detects protein expression, A figure is that drug-resistant tumor cell strain has the drug-resistant protein P-gp expression higher than parent tumor cell line, B figure demonstration salvianolic acid A can be lowered tumor drug resistance albumen P-gp and express, and use after scavenger N-acetylcystein (NAC) intervention of active oxygen ROS, its downward ability reduces, and illustrates that its mechanism that suppresses drug-resistant protein P-gp is the level that raises active oxygen ROS.
The specific embodiment
According to following embodiment, the present invention may be better understood.The described content of embodiment, only for the present invention is described, those skilled in the art will readily understand, and should also can not limit claim described in detail in the present invention.
Following examples salvianolic acid A (sterling) used is purchased from Shanghai You Si Bioisystech Co., Ltd, content 99.4% ,-20 ℃ of preservations.Before use, fresh configuration is containing the solution of medicine.
Embodiment 1:
Mtt assay detects salvianolic acid A to human breast cancer cell MCF-7 and mdr cell MCF-7/MDR propagation influence thereof.Take the logarithm trophophase human breast cancer cell MCF-7 and mdr cell MCF-7/MDR thereof, be inoculated in 96 well plates, and cell number is 5 * 10
3/ hole, at 37 ℃, 5%CO
2in incubator, cultivate after 12 hours, grouping dosing, each concentration is set up parallel hole, negative control adds normal saline, after 24 hours, every hole adds MTT10 μ l (5mg/ml), cultivates 4 hours again in incubator, abandon supernatant, every hole adds DMSO100 μ l, and vibration to precipitation is dissolved completely, surveys every hole optical density (OD) value under 490nm.Cytotoxicity MTT experiment shows that salvianolic acid A has the inhibitory action of dose dependent to the survival rate of breast cancer cell MCF-7 and multidrug resistance cell MCF-7/MDR thereof, more obvious to the inhibitory action of multidrug resistance cell MCF-7/MDR.The results are shown in Figure 1.
Embodiment 2:
MCF-7/MDR is apoptotic for the induction of Flow cytometry salvianolic acid A.MCF-7/MDR cell is inoculated in 6 orifice plates, after 12h, with salvianolic acid A, process cell 24h, the culture medium that contains medicine in each hole is abandoned in suction, with PBS, wash 2 times, press Annexin V-FITC test kit description operation, utilize machine testing on flow cytometer, result shows salvianolic acid A energy inducible resistance tumor cell MCF-7/MDR apoptosis, and has dose dependent.The results are shown in Figure 2.
Embodiment 3:
Fluorescence spectrophotometry detects the variation of intracellular reactive oxygen-derived free radicals (reactive oxygenspecies, ROS) under salvianolic acid A effect.MCF-7/MDR cell is inoculated in 24 orifice plates, after cell attachment, with salvianolic acid A, process cell 24h suction and abandon the culture medium that contains medicine in each hole, with PBS, wash 2 times, according to active oxygen detection kit, require step to add reactive oxygen free radical fluorescent probe DCFH-DA, use fluorescence spectrophotometry fluorescence intensity.The results are shown in Figure 3B.
Embodiment 4:
Western Blot detects the impact of salvianolic acid A on Bcl-2 and Bax protein expression.After MCF-7/MDR cell is processed with the salvianolic acid A of variable concentrations, PBS washed cell, places on slab, and cell sleaker scrapes collection by cell, adds cell pyrolysis liquid and protease inhibitor, and at cracking 10min on ice, 13200rpm, centrifugal 15min, gets supernatant.Sds polyacrylamide gel electrophoresis isolated protein, by protein delivery on acetate membrane, conventional primary antibodie and two resists hatches rear persistency chemical luminous substrate (Thermo scientific company) the detection protein expression of using, result shows that salvianolic acid A can lower the IAP Bcl-2 of drug-resistant tumor and express, raising pro apoptotic protein Bax expresses, and use after scavenger N-acetylcystein (NAC) intervention of active oxygen ROS, the effect of salvianolic acid A inducible resistance tumor death declines.Protein expression the results are shown in Figure 4.
Embodiment 5:
Western Blot detects the impact that salvianolic acid A is expressed drug-resistant protein P-gp.Western Blot detecting step is the same, and result demonstration salvianolic acid A can be lowered tumor drug resistance albumen P-gp and express, and uses after scavenger N-acetylcystein (NAC) intervention of active oxygen ROS, and it suppresses ability reduction of drug-resistant protein P-gp.The results are shown in Figure 5B.
Claims (6)
1. the application of salvianolic acid A in preparation treatment multi-drug resistance of the tumor medicine.
2. application according to claim 1, is characterized in that, described salvianolic acid A can be replaced with its sodium salt, magnesium salt, ammonium salt or calcium salt.
3. application according to claim 1, is characterized in that, described tumor comprises the tumor of P-gp overexpression.
4. application according to claim 1, is characterized in that, described tumor comprises entity tumor, hematological system tumor.
5. application according to claim 2, is characterized in that, the content of the salt of salvianolic acid A in medicine is more than 50%.
6. application according to claim 1, is characterized in that, described pharmaceutical dosage form is liquid preparation, granule, tablet, electuary, soft gelatin capsule, capsule, drop pill, oral cavity disintegration preparation, injection, slow releasing preparation, controlled release preparation or various particulate delivery system.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105523926A (en) * | 2015-12-29 | 2016-04-27 | 山东大学 | An extracting, separating and purifying method of salvianolic acid A and a preparing method of salvianolic acid salts |
| CN105769845A (en) * | 2016-05-12 | 2016-07-20 | 南京中医药大学 | Application of salvianolic acid A in preparation of medicine for resisting tumor multi-drug resistance |
| WO2024048998A1 (en) * | 2022-09-02 | 2024-03-07 | 한국 한의학 연구원 | Composition for prevention, alleviation, or treatment of bone disease, containing salvianolic acid as active ingredient |
-
2013
- 2013-12-19 CN CN201310705521.2A patent/CN103690519B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| 高冬冬等: "肿瘤多药耐药治疗的研究进展", 《第三届国际中医、中西医结合肿瘤学术交流大会暨第十二届全国中西医结合肿瘤学术大会论文汇编》, 31 December 2010 (2010-12-31), pages 1010 - 1011 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105523926A (en) * | 2015-12-29 | 2016-04-27 | 山东大学 | An extracting, separating and purifying method of salvianolic acid A and a preparing method of salvianolic acid salts |
| CN105769845A (en) * | 2016-05-12 | 2016-07-20 | 南京中医药大学 | Application of salvianolic acid A in preparation of medicine for resisting tumor multi-drug resistance |
| WO2024048998A1 (en) * | 2022-09-02 | 2024-03-07 | 한국 한의학 연구원 | Composition for prevention, alleviation, or treatment of bone disease, containing salvianolic acid as active ingredient |
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