CN102008495B - Application of berberine and doxorubicine mixed preparation in preparation of medicament against doxorubicine cardiac dysfunction or tumor - Google Patents
Application of berberine and doxorubicine mixed preparation in preparation of medicament against doxorubicine cardiac dysfunction or tumor Download PDFInfo
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- CN102008495B CN102008495B CN201010558160XA CN201010558160A CN102008495B CN 102008495 B CN102008495 B CN 102008495B CN 201010558160X A CN201010558160X A CN 201010558160XA CN 201010558160 A CN201010558160 A CN 201010558160A CN 102008495 B CN102008495 B CN 102008495B
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Abstract
The invention discloses application of a berberine and doxorubicine mixed preparation in preparation of a medicament against doxorubicine cardiac dysfunction or tumor. The molar concentration ratio of the berberine to the doxorubicine in the medicament is (0.625-4): 1, and the optimal ratio is 1:1. The medicament is an oral preparation or an injection preparation. The combined use of the berberine and the doxorubicine can lighten myocardial damage caused by the doxorubicine, also can play a role in inhibiting myocardial apoptosis caused by the doxorubicine, and does not weaken, even enhance the anti-tumor effect of the doxorubicine at the same time.
Description
Technical field
The present invention relates to berberine and amycin, be specifically related to the application in anti-amycin property cardiac dysfunction of preparation or antitumor drug of berberine and amycin mix preparation.
Background technology
Amycin is to use antitumor drug very widely clinically, and it all has the curative effect of highly significant for leukemia, lymphoma, breast carcinoma, pulmonary carcinoma etc., is one of at present the most frequently used clinically antitumor drug.The main toxic and side effects of amycin is a myocardial toxicity, and it not only can cause arrhythmia, and along with the accumulation of dosage, can also bring out carrying out property cardiomyopathy, congestive heart failure.Since the eighties; Amycin myocardial toxicity Molecular Study has obtained many new progresses; Most studies is thought and possibly can be passed through the oxidative stress approach with amycin at present; Or the non-oxidative stress approach that depends on, start the apoptotic signal path of inside and outside source property, induce cardiomyocyte cell death relevant.Therefore inhibitor of a series of antioxidants, iron chelator and free radical scavenger, calcium ion inhibitor, ceramide inhibitor, some related genes of apoptosis or the like appears.As: dexrazoxane, Carvedilol, flavonoid, Statins, vitamin E etc.Clinical research finds also do not have a kind of preparation can under the prerequisite that does not influence the amycin antitumor action, can significantly reduce the reaction of amycin myocardial toxicity simultaneously again but up to now.Therefore, Cardioprotective medicine how to develop new anti-amycin myocardial toxicity is the important topic that medical science faces always.
Domestic in recent years constantly have the bibliographical information berberine that the patient of risk factors such as control heart failure, arrhythmia, hypertension is had significant curative effect and do not have obvious toxic-side effects.Research finds that also berberine can obviously improve the cardiac function of heart failure patient, increases exercise tolerance, and it possibly be the effect through its treatment heart failure of many aspects such as release performance of positive inotropic, reduction Peripheral resistance and inhibition inflammatory mediator.Also find that in former experiments berberine can effectively prevent and treat lipopolysaccharide property cardiac dysfunction, its mechanism of action maybe be unusual with calcium ion stable state in its correction myocardial cell, and it is relevant to suppress myocardial cell release tumor necrosis factor α.The experiment in early stage simultaneously shows that berberine can alleviate the myocardial cell injury that norepinephrine causes, possibly be to suppress the inductive apoptosis of cardiac muscle of norepinephrine through blocking-up ROS-TNF α-Caspase signal path.In sum, berberine and amycin mix preparation can be used as the novel formulation of oncotherapy, control amycin myocardial toxicity.
The present invention finds that (berberine, Ber) (Doxorubicine DOX) during Combined application, can prevent and treat amycin property myocardial toxicity to berberine effectively, can not influence even increase simultaneously the antitumor curative effect of amycin again with amycin.For the myocardial toxicity of treating amycin clinically provides new measure, thereby improve patient's after the amycin chemotherapy life quality, amycin can better be widely used in the antineoplastic clinical treatment.
Summary of the invention
In order to overcome the deficiency of prior art, the present invention provides a kind of berberine and the application of amycin mix preparation in anti-amycin property cardiac dysfunction of preparation or antitumor drug.
The technical scheme that the present invention adopts is: the application in anti-amycin property cardiac dysfunction of preparation or antitumor drug of berberine and amycin mix preparation; The molar concentration rate of berberine and amycin is (0.625～4) in the said medicine: 1, and optimal proportion is 1: 1.
Said medicine is oral formulations or ejection preparation.
Support neonatal rat myocardial cell after 48 hours through external former being commissioned to train, set up matched group respectively; DOX (1 μ mol/L) group; Ber (0.625 μ mol/L)+DOX group; Ber (0.25 μ mol/L)+DOX group; Ber (1.00 μ mol/L)+DOX group; Ber (4.00 μ mol/L)+DOX group; Ber (4.00 μ mol/L) is single with group.Drug treating detected the vigor of respectively organizing cell with CCK-8 after 24 hours.The cell survival rate that result's proof gives berberine and amycin mix preparation group all is higher than the amycin list with group, and shows certain dose dependent.(Lactate dehydrogenase, LDH) content finds that berberine can significantly alleviate the myocardial damage that amycin causes through detecting lactic acid dehydrogenase in the cell conditioned medium simultaneously.The ELISA method detects the histone content of each group, finds that further the apoptosis rate of berberine and amycin mix preparation group all obviously reduces with group than the amycin list.Select tumor cell MCF-7 cell on the other hand for use, CCK-8 detection cell viability behind dosing processing 24 and the 48h behind the cultivation 24h, and calculate the cell inhibiting rate, the observation berberine is to the influence of amycin antitumor action.The result shows that berberine and amycin mix preparation group are higher than the amycin list with group to MCF-7 cell inhibiting rate.Based on above-mentioned result of study, berberine not only can alleviate the myocardial damage that amycin causes, can also play inhibitory action to the cardiomyocyte apoptosis that amycin causes, can not weaken even strengthen simultaneously the antitumor effectiveness of amycin again.
Description of drawings
Fig. 1 is LDH assay figure as a result in each processed group cell conditioned medium.N=4.
#Compare with matched group P＜0.05,
*Compare with DOX (1 μ M) group P＜0.05.
Fig. 2 is each processed group myocardial cell lysate OD pH-value determination pH figure as a result.N=4.
#Compare with matched group P＜0.05,
*Compare with DOX (1 μ M) group P＜0.05.
Fig. 3-1 is that the berberine/amycin of various dose is handled behind the 24h MCF-7 cell inhibiting rate figure as a result, n=3.
Fig. 3-2 is that the berberine/amycin of various dose is handled behind the 48h MCF-7 cell inhibiting rate figure as a result, n=4.
The specific embodiment
Below in conjunction with embodiment and accompanying drawing the present invention is done further detailed description, but embodiment of the present invention is not limited thereto.
Get 1 day newborn SD neonatal rat (Nanfang Medical Univ's Experimental Animal Center provides), get its apex of the heart part, take the conventional digestion of pancreatin (U.S. Sigma company), obtain myocardial cell by existing method.
DMEM (purchasing the company in Gibico) suspension cell with containing 10% hyclone (purchasing the company in Hyclone) places 37 ℃, 5%CO
2In the incubator, hatched the myocardial cell of purification gained 2 hours.According to 1 * 10
5Individual/mL cell density is inoculated in and continues in 96 orifice plates to cultivate 48 hours.With 5mL physiological saline solution 10mg amycin (DOX) (U.S. Sigma company), the dilution of reuse DMEM (purchasing the company in Gibico) culture medium is the amycin working solution of 10 μ mol/L.Berberine (Ber) (U.S. Sigma company) is dissolved to 4.00 μ mol/L working solutions with distilled water, and DMEM is diluted to 1.00 μ mol/L, 0.25 μ mol/L, 0.625 μ mol/L working solution respectively again.Do following dosing respectively and handle cultivating myocardial cell after 48 hours:
1. matched group (control) is organized: 200 μ L DMEM
2. amycin (1 μ mol/L) is organized: 180 μ L DMEM+20 μ L DOX
3. berberine (0.625 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
4. berberine (0.25 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
5. berberine (1.00 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
6. berberine (4.00 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ L DOX+20 μ L Ber
7. berberine (4.00 μ mol/L) is organized: 180 μ L DMEM+20 μ L Ber
After dosing is handled 24 hours, extract each processed group cell conditioned medium liquid respectively, detect lactic acid dehydrogenase (LDH) content of each group with automatic clinical chemistry analyzer.
Experimental result
As shown in Figure 1: behind the myocardial cell packet transaction 24h, the LDH content in the 1 μ mol/L DOX group cell conditioned medium is 34.94 ± 2.17U/mL, is higher than matched group (7.12 ± 0.43U/mL, P＜0.05); And the LDH activity all is lower than the single group (P＜0.05) of using of DOX in berberine+amycin group of 0.25 μ mol/L, 1.00 μ mol/L and 4.00 μ mol/L, and demonstrates certain dose-dependence between the berberine of variant concentration+amycin group; 0.625 0.25,1.00 and 4.00 μ mol/L berberine lists are used LDH of group active (be respectively 6.37 ± 0.69,7.94 ± 0.26,7.93 ± 0.26,8.37 ± 0.43U/mL shows among the figure) and matched group LDH activity, and (7.12 ± 0.43U/mL) are close.Through the statistical disposition of SPSS statistics software, there was no significant difference (P＞0.05).
Embodiment 2 berberine are to the influence of amycin injury of myocardium cell viability
Get 1 day newborn SD neonatal rat, get its apex of the heart part, take trypsin digestion, obtain myocardial cell.DMEM suspension cell with containing 10% hyclone places 37 ℃, 5%CO
2In the incubator, hatched the myocardial cell of purification gained 2 hours.According to 1 * 10
5Individual/mL cell density is inoculated in and continues in 96 orifice plates to cultivate 48 hours.With 5mL physiological saline solution doxorubicin injection (DOX), the dilution of reuse DMEM culture medium is the amycin working solution of 10 μ mol/L.Berberine (Ber) is dissolved to 4.00 μ mol/L working solutions with distilled water, is diluted to 1.00 μ mol/L, 0.25 μ mol/L, 0.625 μ mol/L working solution more respectively.The myocardial cell of purification gained is done following dosing respectively to be handled:
1. matched group (control) is organized: 200 μ L DMEM
2. amycin (1 μ mol/L) is organized: 180 μ L DMEM+20 μ L DOX
3. berberine (0.625 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
4. berberine (0.25 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
5. berberine (1.00 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
6. berberine (4.00 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ L DOX+20 μ L Ber
7. berberine (4.00 μ mol/L) is organized: 180 μ L DMEM+20 μ L Ber
Place 37 ℃ then, 5%CO
2In the incubator, hatch 24h after, the situation of change of group switching centre myocyte vigor is respectively handled in our further observation.
Experimental result
As shown in table 1: behind the myocardial cell packet transaction 24h, in the detected OD value of CCK-8, the OD value of 1 μ mol/LDOX group is lower than matched group (P＜0.05); And except 0.625; 0.25 the OD value of μ mol/L berberine+amycin group and amycin list do not have outside the difference with group; 1.00 the OD value all is higher than the DOX list with group (P＜0.05) in the berberine of μ mol/L and 4 μ mol/L+amycin group, and demonstrates certain dose-dependence between the berberine intervention group of variant concentration; 0.625,0.25,1.0 and 4.0 μ mol/L berberine lists are with the OD value and the matched group OD value of group be close (0.625,0.25 and 1.0 μ mol/L berberine lists with organize to tabulate in).Through the statistical disposition of SPSS statistics software, there was no significant difference (P＞0.05).
After table 1. berberine/amycin was handled myocardial cell 24h, each was handled group switching centre myocyte vigor and changes
N=4.
#Compare with matched group P＜0.05,
*P＜0.05 and Dox (1 μ mol/L) organize relatively.
Embodiment 3 observes the influence of berberine to amycin cardiac muscle cell death inducing
Get 1 day newborn SD neonatal rat, get its apex of the heart part, take trypsin digestion, obtain myocardial cell.DMEM (purchasing the company in Gibico) suspension cell with containing 10% hyclone (purchasing the company in Hyclone) places 37 ℃, 5%CO
2In the incubator, hatched the myocardial cell of purification gained 2 hours.According to 1 * 10
5Individual/mL cell density is inoculated in and continues in 96 orifice plates to cultivate 48 hours.With 5mL physiological saline solution doxorubicin injection (DOX), the dilution of reuse DMEM culture medium is the amycin working solution of 10 μ mol/L.Berberine (Ber) is dissolved to 4.00 μ mol/L working solutions with distilled water, is diluted to 1.00 μ mol/L, 0.25 μ mol/L, 0.625 μ mol/L working solution more respectively.Do following dosing respectively and handle cultivating myocardial cell after 48 hours:
1. matched group (control) is organized: 200 μ L DMEM
2. amycin (1 μ mol/L) is organized: 180 μ L DMEM+20 μ L DOX
3. berberine (0.625 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
4. berberine (0.25 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
5. berberine (1.00 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
6. berberine (4.00 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ L DOX+20 μ L Ber
7. berberine (4.00 μ mol/L) is organized: 180 μ L DMEM+20 μ L Ber
Then in 37 ℃, 5%CO
2In the incubator, hatch cracking myocardial cell behind the 24h, on ELIASA, measure the OD value of reflection nucleosome content in the lysate with the ELISA method.(lysis and ELISA measure the method for apoptosis and see nucleosome content reflection apoptosis of cardiac muscle: Singla DK; Singla RD, McDonaldDE.Factors released from embryonic stem cells inhibit apoptosis in H9c2 cellsthrough PI3K/Akt but not ERK pathway.Am J Physiol Heart Circ Physiol.2008; 295 (2): H907-13)
Experimental result
In order further to observe berberine amycin is induced the influence of apoptosis of cardiac muscle, this experiment adopts the content of nucleosome in the ELISA standard measure detection product of cell lysis to estimate the apoptosis situation.As shown in Figure 2, behind the myocardial cell packet transaction 24h, OD detected value 0.923 in the 1 μ mol/L DOX group is higher than matched group; And the OD value all is lower than the single group of using of DOX in berberine+amycin group of 0.625 μ mol/L, 0.25 μ mol/L, 1.00 μ mol/L and 4.00 μ mol/L.Through the statistical disposition of SPSS statistics software, as shown in Figure 2, the OD value of berberine+amycin group of 0.25 μ mol/L, 1.00 μ mol/L and the 4.00 μ mol/L significant difference (P＜0.05) of having compared with the OD value that 1 μ mol/L DOX organizes wherein.
Embodiment 4 observation in vitro berberine suppress the influence of activity of tumor cells to amycin.
Select for use MCF-7 tumor cell (purchasing Fu Erbo biotechnology) according to 2 * 10 in Guangzhou
3Individual/ml density inoculation, the DMEM that contains 10% hyclone is in 37 ℃, 5%CO
2Dosing is handled after cultivating 24h in the incubator, and with 5mL physiological saline solution doxorubicin injection (DOX), the dilution of reuse DMEM culture medium is the amycin working solution of 10 μ mol/L.Berberine (Ber) is dissolved to 4.00 μ mol/L working solutions with distilled water, is diluted to 1.00 μ mol/L, 0.25 μ mol/L, 0.625 μ mol/L working solution more respectively.
1. matched group (control) is organized: 200 μ L DMEM
2. amycin (1 μ mol/L) is organized: 180 μ L DMEM+20 μ L DOX
3. berberine (0.625 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
4. berberine (0.25 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
5. berberine (1.00 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ LDOX+20 μ L Ber
6. berberine (4.00 μ mol/L)+amycin (1 μ mol/L) is organized: 160 μ L DMEM+20 μ L DOX+20 μ L Ber
7. berberine (4.00 μ mol/L) is organized: 180 μ L DMEM+20 μ L Ber
In 37 ℃, 5%CO
2Detect cell viability with CCK-8 behind cultivation 24 and the 48h in the incubator, and calculate cell inhibiting rate (cell inhibitory rate=1-drug group light absorption value average/matched group light absorption value average * 100%)
Experimental result
Whether can influence the antitumor curative effect of amycin in order to understand berberine; After In vitro culture MCF-7 tumor cell 24h is carried out in this experiment; Berberine/DOX with variable concentrations handles cell; Detect each processed group cell activity respectively at 24h and 48h with CCK-8, and calculate suppression ratio according to light absorption value.Shown in Fig. 3-1; After 24h is handled in dosing; 0.625 μ mol/L, 0.25 μ mol/L, 1.00 μ mol/L berberine+amycin groups are higher than the amycin list with group to MCF-7 cell inhibiting rate; 4.00 μ mol/L berberine+amycin group is lower than the amycin list with group to MCF-7 cell inhibiting rate, but does not have significant difference (P＞0.05) between each group; Shown in Fig. 3-2, after 48h was handled in dosing, 0.25 μ mol/L, 1.00 μ mol/L berberine+amycin groups were higher than the amycin list with group to MCF-7 cell inhibiting rate.4.00 μ mol/L berberine list was respectively 2.5% ± 1% (not shown) with 24 hours to MCF-7 cell inhibiting rate; Above presentation of results all can not weaken the amycin antitumor curative effect at external 0.625 μ mol/L, 0.25 μ mol/L, 1.00 μ mol/L and 4.00 μ mol/L berberine, and 0.25 μ mol/L, 1.00 μ mol/L berberine possibly strengthen the amycin antitumor curative effect.
1 * 10
7Individual MCF-7 cell inoculation is subcutaneous in the nude mice back, occurs macroscopic transplanted tumor about 1 week, and nude mice is divided into 4 groups after becoming tumor at random: berberine group, amycin group, berberine and amycin mixture group and matched group.Irritate stomach or lumbar injection with 5mg/kg DOX and/or 5mg/kg Ber respectively, 1 time/3 days, in totally 4 weeks, measure cardiac function with the toy ultrasonic system the 4th weekend, and measure the weight of various tumors.
Experimental result
During intraperitoneal injection; The matched group tumor weight is 0.9 ± 0.2g; 5mg/kg DOX group tumor weight is 0.50 ± 0.21g; 5mg/kg DOX+5mg/kg Ber group tumor weight is 0.38 ± 0.19g, and 5mg/kg DOX group is starkly lower than matched group with 5mg/kg DOX+5mg/kg Ber group tumor weight, and 5mg/kg DOX+5mg/kg Ber group tumor weight is lower than 5mg/kg DOX group; Tangible myocardial damage and dysfunction appear in 5mg/kg DOX group mice, and left ventricular ejection mark (EF) obviously reduces.Compare with 5mg/kg DOX group, myocardial damage and the cardiac dysfunction of 5mg/kg DOX+5mg/kg Ber group mice obviously alleviate.During gastric infusion: 5mg/kg DOX group tumor weight is 0.58 ± 0.21g, and 5mg/kg DOX+5mg/kg Ber group tumor weight is 0.45 ± 0.19g, is lower than matched group, but does not see significant difference between two groups; Tangible myocardial damage appears in 5mg/kg DOX group mice, compares with 5mg/kg DOX group, and the myocardial damage of 5mg/kg DOX+5mg/kg Ber group mice obviously alleviates.In vivo test is the result tentatively explain, berberine not only can alleviate the myocardial damage that amycin causes, can not weaken even strengthen simultaneously the antitumor effectiveness of amycin again.
The foregoing description is a preferred implementation of the present invention; But embodiment of the present invention is not restricted to the described embodiments; Other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; All should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (3)
1. berberine and the amycin mix preparation application in anti-amycin property cardiac dysfunction of preparation or antitumor drug is characterized in that: the molar concentration rate of berberine and amycin is (0.625～4) in the said medicine: 1.
2. according to said berberine of claim 1 and the application of amycin mix preparation in anti-amycin property cardiac dysfunction of preparation or antitumor drug, it is characterized in that: the molar concentration rate of berberine and amycin is 1: 1 in the said medicine.
3. according to said berberine of claim 1 and the application of amycin mix preparation in anti-amycin property cardiac dysfunction of preparation or antitumor drug, it is characterized in that: said medicine is oral formulations or ejection preparation.
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