CN103110660A - Mangiferin-cis-platinum composition and use thereof for treating cancer - Google Patents
Mangiferin-cis-platinum composition and use thereof for treating cancer Download PDFInfo
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- CN103110660A CN103110660A CN2013100826619A CN201310082661A CN103110660A CN 103110660 A CN103110660 A CN 103110660A CN 2013100826619 A CN2013100826619 A CN 2013100826619A CN 201310082661 A CN201310082661 A CN 201310082661A CN 103110660 A CN103110660 A CN 103110660A
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Abstract
The invention relates to a mangiferin-cis-platinum composition, a preparation method of the composition and use thereof as a medicine. The cis-platinum aqueous solution is unstable, and the stability of cis-platinum in physiological saline solution is remarkably increased by preparing the mangiferin-cis-platinum composition. In-vitro pharmacological test result shows that the mangiferin-cis-platinum composition is remarkably superior to singly used cis-platinum in effect of inhibiting tumor cell proliferation of liver cancer and the like, so that the use level of cis-platinum is correspondingly reduced, therefore, the side effect is reduced, the patient pain is reduced, and the patient prognosis is improved. The mangiferin-cis-platinum composition can be used for preparing medicines for treating tumors such as liver caner.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind ofly obviously increase at water stability, the preparation method of chimonin that anticancer cel l proliferation obviously strengthens-cisplatin compositions, compositions and as the application of medicine.
Background technology
At present, clinical practice complexation platinum-based chemotherapy medicine the most widely is cisplatin, cisplatin Main Function position is at purine and the pyrimidine bases of DNA, have that anticancer spectrum is wide, effect is strong, synergism arranged and without characteristics such as crossing drug resistants, be one of medicine the most frequently used in current combined chemotherapy with multiple antineoplastic agent.Yet cisplatin is met light degradation, and under light, light hydration reaction and photoredox reaction can occur cisplatin solution, and final precipitating metal platinum reduces medicine effective concentration, affects chemotherapeutic efficacy, even causes chemotherapy resistance.
Chimonin (mangiferin) has another name called Chinonin, is a kind of natural flavone c-glycosides, derives from the plants such as mango, the Rhizoma Anemarrhenae, has certain antioxidation, antiinflammatory and anti-cancer and kill cancer action.Research in recent years is found the generation that it can prophylaxis of cancer, but and the anticancer growing multiplication, induce its apoptosis.But Peng Zhi has just waited research discovery chimonin inducing leukemia K562 and HL-60 cell G2/M phase to block, thereby anticancer propagation.The researchs such as Huang Huayi find that Mengiferin has obvious toxic action to hepatoma cell strain BEL-7404, and energy liver cancer apoptosis reducing and retardance cell cycle are in the G2/M phase.Agriculture is partly cloudy waits research to find that hepatoma carcinoma cell is after EGF stimulates, tyrosine phosphorylation occurs in P120ctn, the cell adhesion ability reduces and the transfer ability enhancing, and after Mengiferin is processed, these pernicious performances are reversed, show as P120ctn tyrosine phosphorylation degree lighter, the prompting Mengiferin has inhibitory action to the P120ctn tyrosine phosphorylation.The researchs such as Plessis-Stoman find that coupling chimonin (10.0 μ g/ml) has reduced the IC50 value of oxaliplatin to HeLa and two kinds of tumor cells of HT29, be respectively 1.7 times with 3.4 times, find that simultaneously chimonin can delay tumor cell to the drug resistance of oxaliplatin.
The present invention can make cisplatin aqueous solution stability obviously increase by preparation chimonin one cisplatin compositions, and antitumor action obviously strengthens, therefore can corresponding minimizing cisplatin consumption, thus reduce side effect, reduce the patient suffering, improve patient's prognosis.Can be used for preparing the various anti-tumor medicines such as anti-hepatocarcinoma.
Summary of the invention
The inventor's result of study shows, it is acid that chimonin is, and has antioxidation, and cisplatin is alkalescence, both can react generation chimonin-cisplatin compositions under certain condition, has obviously increased the stability of cisplatin in aqueous solution.Orientating compositions as, is because both combinations are very infirm, is the result of intermolecular van der Waals interaction.This compositions is larger in concentration, or when entering in body, separated from each other and independent existence the, and then performance pharmacological action separately again.
Technical scheme of the present invention has been addressed the preparation method of chimonin-cisplatin compositions and as the application of medicine.
The inventor finds under study for action, chimonin and cisplatin mixed proportion (quality) 〉=and 4: 1 o'clock, cisplatin is just stable in normal saline.In practical operation, the mass ratio of chimonin and cisplatin can have floating of certain amplitude, be generally ± 10%.That is to say, in practical operation, the percentage by weight of chimonin and cisplatin is:
Chimonin 70～90%
Cisplatin 10～30%
The preparation method of chimonin-cisplatin compositions is as follows: under the lucifuge condition, chimonin and cisplatin are dissolved in the pharmacy acceptable solvent in proportion, remove impurity, according to dosage fill are sterilized in withstand voltage medicinal glass bottle, lyophilization, and capping, and get final product.Facing the used time gets final product with physiological saline solution.
Result of the test shows, chimonin and cisplatin mixed proportion (quality) 〉=and 4: 1 o'clock, under room temperature and common illumination condition, chimonin-cisplatin compositions normal saline solution is very stable, and in 4 hours, Determination of cisplatin is without reduction.And the solution of chimonin-cisplatin compositions 0.5-1% is preserved in 4 ℃ of environment, can crystallization in 8 hours; The solution of 1-2%, namely join i.e. use in this way, can crystallization in 3 hours.
The specific embodiment
The following example is used for illustrating the present invention, is not any restriction to protection domain of the present invention.
Embodiment one
The preparation of chimonin-cisplatin compositions: under the lucifuge condition, chimonin and cisplatin are dissolved in distilled water in mass ratio at 4: 1, remove impurity, according to dosage fill are sterilized in withstand voltage medicinal 10ml vial, lyophilization, and capping, and get final product.Facing the used time gets final product with appropriate physiological saline solution.
Embodiment two
The preparation of chimonin-cisplatin compositions: under the lucifuge condition, chimonin and cisplatin are dissolved in distilled water in mass ratio at 5: 1, remove impurity, according to dosage fill are sterilized in withstand voltage medicinal 10ml vial, lyophilization, and capping, and get final product.Facing the used time gets final product with appropriate physiological saline solution.
Attached pharmacological experiment study data
1 materials and methods
1.1 tumor cell line human liver cancer cell HepG2 is by Guangxi traditional Chinese medicine university's molecular biology experiment center being so kind as to give.
1.2 medicine and reagent chimonin, Guangxi Bang Er vegetable products company limited (purity is 98.6%), lot number 20100801; Cisplatin for inj, Shandong Qilu Pharmaceutical Factory, lot number 1050141DB; DMEM, U.S. Gibco company, lot number 1397535; Hyclone, Hangzhou Ilex purpurea Hassk.[I.chinensis Sims company product, lot number 101102; MTT (Thiazolyl blue), U.S. Amresco company, lot number 0793; Trypsin, U.S. Amresco company, lot number 3518B039.
1.3 instrument Thermo Forma381 type C2 incubator, THERMO Electron Corporation; The Leica-DMR inverted microscope, German Leica company; ELX-800 type microplate reader, U.S. BIO-Tek; Simplicity UV ultra-pure water instrument, U.S. MILLIPORE; EL204 ten thousand/gram electronic balance, prunus mume (sieb.) sieb.et zucc. Teller-Tuo benefit instrument Shanghai company limited; Allegra X-22R Centrifuge centrifuge, U.S. BECKMAN COULTER company.
1.4 cell culture HepG2 cell routine is incubated in DMEM, tests with the cell that inoculation was gone down to posterity the 3rd day.The experiment grouping: be divided into the A group: add merely chimonin, final concentration is 5.0,10.0,20.0 a μ g/ml3 concentration; The B group: add merely cisplatin, final concentration is 0.25,0.5,1.0,2.0 a μ g/ml4 concentration; C group: A organizes each concentration chimonin and adds B and organize each concentration cisplatin; The D group: matched group, only have hepatoma Hep G 2 cells, do not add medicine.
1.5MTT method is measured medicine the suppression ratio of hepatoma Hep G 2 cells growing multiplication is collected the human hepatoma HepG2 cell who is in exponential phase, is mixed with 1x10
4Individual/ml cell suspension is inoculated in 96 well culture plates, every hole 180 μ l.Hatch add respectively A group, B group and each 100 μ l of C group medicine after cell attachment, establish 4 multiple holes and blank hole for every group, the blank hole only adds the equal-volume culture fluid, repeats identical 3 96 orifice plates.Be placed in 37 ℃, 5%CO2 incubator and cultivate respectively 24,48, after 72h, every hole adds the 10 μ l with the freshly prepared MTT of normal saline (5mg/ml), continues to cultivate 4h, abandons supernatant, add DMSO150 μ l, vibration 10min at each hole absorbance (OD) of 490nm place's survey, calculates inhibitory rate of cell growth according to following formula: suppression ratio (%)=(the average OD value of the average OD value/control wells of 1-experimental port) * 100% with microplate reader.
Adopt two medicine interaction coefficients (coefficient ofdrug in interaction, CDI) to estimate two medicine interactive properties.CDI calculates by following formula: CDI=AB/A * B, calculate according to viable count (absorbance), and AB is the ratio of uniting group and matched group, A or B are the ratio of solely use group of each prescription and matched group.CDI＜1, two interactional character of medicine is for collaborative; CDI＜0.7, two medicine synergism highly significant each other; CDI=1, the interactive property of two medicines is addition; The interactive property of CDI＞1, two medicine is antagonism.
1.6ELISA the method detection of drugs is inoculated in Tissue Culture Plate the take the logarithm HepG2 cell of trophophase of the suppression ratio of PTK, the chimonin and the cisplatin that add respectively variable concentrations by 1.5 methods, be placed in 37 ℃, the 5%CO2 incubator is cultivated certain hour (24h, 48h, 72h), after cleaning cell culture fluid, add again fully resuspended and ice bath cracking of cell lysis buffer solution, the centrifugal 10min of 12000g, obtain the cell pyrolysis liquid that contains protein tyrosine kinase after drug effect, get supernatant and detect its PTK active (detecting in the 450nm wavelength with microplate reader) by the ELISA method.Suppression ratio (%)=(control wells OD value-sample well OD value)/control wells OD value * 100%.
1.7 statistical method adopts spss19.0 software, data with
The t check is relatively adopted in expression between group, P＜0.05 is for there being statistical significance.
2 results
2.1 each Drug level of chimonin and cisplatin on the chimonin that affects variable concentrations of Growth of Human Hepatoma Cell Line HepG 2 suppression ratio and the independent medication of cisplatin or drug combination respectively to HepG2 cytosis 24,48,72h, all can suppress the growth of human hepatoma HepG2 cell's strain, and have obvious dosage-time-effect relationship, inhibitory action is along with the improve of drug level, the prolongation of action time and strengthen; Can observe simultaneously each concentration chimonin and cisplatin combined medication from experimental result the growth inhibition ratio of hepatoma carcinoma cell is all significantly strengthened (P＜0.05) than each corresponding independent medication group; After medication 72h, cisplatin (2.0 μ g/ml), chimonin (20.0 μ g/ml), cisplatin+chimonin (2.0+20.0 μ g/ml) are respectively 72.49%, 36.49% and 88.67% to the maximal percentage inhibition of HepG2 Growth of Cells; And when chimonin and the independent medication of cisplatin, along with the raising of drug level separately, cisplatin on the impact of HepG2 growth inhibition ratio obviously greater than chimonin.See Table 1.
Table 1 chimonin and Cisplatin to the growth inhibition ratio (%) of human liver cancer cell HepG2 (
N=4)
Annotate: drug combination group and each independent medication group be P＜0.05 relatively.
2.2 chimonin and the cisplatin chimonin (5.0 to inhibiting each concentration of interactive property of Growth of Human Hepatoma Cell Line HepG 2,10.0,0.0 μ g/ml) with the cisplatin (0.25 of each concentration, 0.5,1.0,2.0 μ g/ml) and drug combination is to hepatoma carcinoma cell HepG2 effect 24,48, during 72h, the CDI of each drug combination group shows that all less than 0.7 two medicines synergism each other is remarkable.
2.3 in chimonin and cisplatin on human hepatoma Hep G 2 cells, the chimonin that affects variable concentrations of PTK activity and the independent medication of cisplatin or drug combination are respectively to HepG2 cytosis 24,48,72h, each group is obvious dosage-time-effect relationship along with the increase of drug level and the prolongation of action time to the inhibitory action of PTK activity.And each concentration chimonin all significantly strengthens (P＜0.05) than each corresponding independent medication group with cisplatin combined medication to the PTK maximum inhibition in hepatoma Hep G 2 cells; After medication 72h, cisplatin (2.0 μ g/ml), chimonin (20.0 μ g/ml), cisplatin+chimonin (2.0+20.0 μ g/ml) are maximum to the suppression ratio of PTK activity in the HepG2 cell, are respectively 36.47%, 63.84% and 76.27%; And when chimonin and the independent medication of cisplatin, along with the raising of drug level separately, chimonin on the impact of PTK maximum inhibition in hepatoma carcinoma cell HepG2 obviously greater than cisplatin.See Table 3.
Table 3 chimonin and Cisplatin to the suppression ratio (%) of PTK activity influence in human liver cancer cell HepG2 (
N=4)
2.4 chimonin and cisplatin are worth the chimonin (5.0 of each concentration to the interaction coefficient (CDI) of PTK activity inhibition in hepatoma carcinoma cell HepG2,10.0,20.0 μ g/ml) with the cisplatin (0.25 of each concentration, 0.5,1.0,2.0 μ g/ml) and drug combination is to hepatoma carcinoma cell HepG2 effect 24,48, during 72h, the CDI of each drug combination group shows that all less than 0.7 two medicines synergism each other is remarkable.
Claims (4)
1. chimonin-cisplatin compositions is characterized in that: calculate in mass ratio, the chimonin by 70～90% and 10～30% cisplatin form.
2. chimonin according to claim 1-cisplatin compositions, it is characterized in that: preparation method is as follows: under the lucifuge condition, chimonin and cisplatin are dissolved in the pharmacy acceptable solvent in proportion, remove impurity, according to dosage fill are sterilized in withstand voltage medicinal glass bottle, lyophilization, capping, and get final product.Facing the used time gets final product with physiological saline solution.
3. chimonin according to claim 1-cisplatin compositions is characterized in that: chimonin-cisplatin compositions is in normal saline solution, and the stability of cisplatin obviously increases.
4. chimonin according to claim 1-cisplatin compositions, it is characterized in that: chimonin-cisplatin compositions antitumor action obviously is better than alone cisplatin, can be used for preparing the various anti-tumor medicines such as anti-hepatocarcinoma.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103860573A (en) * | 2014-03-07 | 2014-06-18 | 张真 | Composition for synergistic inhibition of tumour effect and application thereof |
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| CN1977855A (en) * | 2005-12-09 | 2007-06-13 | 海南盛科天然药物研究院有限公司 | Medicinal composition containing mangiferin and its preparing method |
| CN101229181A (en) * | 2006-09-12 | 2008-07-30 | 徐广爱 | Medicine compounds for curing diabetes and complications thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103860573A (en) * | 2014-03-07 | 2014-06-18 | 张真 | Composition for synergistic inhibition of tumour effect and application thereof |
| CN103860573B (en) * | 2014-03-07 | 2015-10-21 | 张真 | A kind of pharmaceutical composition and application thereof with collaborative function of tumor inhibition |
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Application publication date: 20130522 |