CN100581556C - Chinese traditional extraction and the function containing dammarane type four-ring triterpene sapogenin - Google Patents
Chinese traditional extraction and the function containing dammarane type four-ring triterpene sapogenin Download PDFInfo
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- CN100581556C CN100581556C CN200710068245A CN200710068245A CN100581556C CN 100581556 C CN100581556 C CN 100581556C CN 200710068245 A CN200710068245 A CN 200710068245A CN 200710068245 A CN200710068245 A CN 200710068245A CN 100581556 C CN100581556 C CN 100581556C
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- amycin
- drug
- arasaponin
- cancer
- notoginseng
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Abstract
The invention relates to a Chinese drug extractive which contains dammarane tetracyclic triterpene saponin. And the extractive is from notoginseng, which at least contains notoginseng saponin R1, panaxoside Rg1, Rb1, Re, and Rd at 45-95wt%. The inventive extractive on the anthracene nucleus resistant anti-cancer heart toxicity, via body test, has proved that the notoginseng saponin can significantly protect heart hurt induced by adriablastina, without reducing the anti-cancer effect of anthracene nucleus resistant anti-cancer drug. Therefore, the extractive can be used to prevent and reduce the heart toxicity of anthracene nucleus resistant anti-cancer drug, or added into other drug to form novel radiation auxiliary drug. The invention discloses the activity for resisting anthracene heart toxicity to widen the application of notoginseng.
Description
Technical field
The invention belongs to Chinese medicine extract, relate to the dammarane type four-ring triterpenoid saponins extract that extracts from the Chinese medicine Radix Notoginseng, this extract and anthracene ring antitumor medicinal are united when using, and can alleviate its cardiac toxicity, and can not reduce the latter's antitumor curative effect.
Technical background
Since nineteen fifty-seven was isolated first anthracene nucleus kind anti-cancer drugs daunorubicin (Daunorubicin), the anthracene nucleus kind anti-cancer drugs had become a widely used clinically based chemotherapy medicine.(ADM) after entering clinical trial the seventies, distinguishing feature, especially effective to hypoxic tumor cells such as antitumor spectra is wide because of having, clinical efficacy is good has become the representative medicine of anthracene nucleus kind anti-cancer drugs to amycin for Doxorubicin.DXR, Adriamycin.ADM is effective to kinds of tumors, comprising: hematological system tumor, malignant lymphoma, breast carcinoma, bladder cancer, pulmonary carcinoma, ovarian cancer, cervical cancer, carcinoma of testis, tumor of head and neck and bone and soft tissue tumor etc.ADM is cheap, and curative effect-expense is one of current antitumor drug commonly used clinically than higher.But because restriction, especially the dose accumulation cardiac toxicity of its main toxicity cardiac toxicity have seriously limited its extensive and life-time service clinically.
In order to solve the cardiac toxicity problem of anthracene nucleus kind anti-cancer drugs, the various countries scholar has proposed different countermeasures, comprises the analog of seeking high-efficiency low-toxicity and uses the myocardial preservation medicine.
At present, found multiple amycin analog.Two analogs that have been used widely clinically be pirarubicin [Perarubicin, Pirarubicin, (2R)-4-O-Tetrahydropyranyladriamycin, THP] and epirubicin (Epirubicin, EPI).THP in 1979 by discoveries such as Japanese scholar Umezawa, be the Pentamethylene oxide. derivatives of ADM, added THP trtrahydropyranyl in the 4 three-dimensional positions of ADM.EPI is the isomer of ADM.The cardiac toxicity of these 2 kinds of medicines will be lower than amycin.But the bone marrow toxicity of Perarubicin is more much higher than amycin, and epirubicin still has cardiac toxicity, has certain bone marrow toxicity simultaneously, and price is higher, therefore can not replace amycin fully.
Myocardial preservation medicine commonly used does not have significant curative effect to the cardiac toxicity that amycin causes.Recently, FDA has ratified dexrazoxane (dexrazoxane) can effectively prevent the cardiac toxicity that anthracene ring antitumor medicinal such as amycin etc. bring out as chemical protective agent, and does not influence the anti-tumor activity of chemotherapeutics.It combines with iron ion by be hydrolyzed into chelating agen in cell, disturbs Fe
3+The formation of-anthracycline drug chelate, and then reduced the oxygen-derived free radicals generation.In addition, dexrazoxane has also suppressed the peroxidating of this class chelate to cardiolipin, thereby heart is had unique protective effect.This medicine now in North America and European countries' listing, is mainly used in the advanced breast cancer patient.These product have the protective agent of preventive effect as unique listing to anthracene nucleus antineoplastic chemical drugs cardiac toxicity, have obtained significant curative effect clinically.But the dosage of dexrazoxane is very big, normally 10 of amycin times, and certain nephrotoxicity is arranged.Show that from clinical information if adopt dexrazoxane and amycin to merge the scheme of administration, patient's financial burden will improve 5-10 doubly.Therefore, the new anti-amycin cardiac toxicity medicine of exploitation has realistic meaning.
The mechanism that amycin causes cardiac toxicity is not clear and definite fully yet.But existing several hypothesis obtain the support of experimental evidence: 1) amycin is induced and is produced a large amount of oxygen-derived free radicals, and excessive oxygen-derived free radicals causes the damage and the death (or apoptosis) of cell function; 2) amycin is accumulated in the mitochondrion, causes electron transport chain to take off coupling, and the cellular energy dysbolismus is also therefore downright bad; 3) amycin causes the intracellular calcium overload, causes apoptosis; 4) amycin causes a large amount of releases of NO excessive secretion and ultra-oxygen anion free radical, causes proteinic nitration to modify, and causes protein function to destroy.
Arasaponin derives from panax araliaceae plant (Panax notoginseng (Burk.) F.H.Chen), has pharmacologically active widely.A large amount of experimentation and clinical practices show; arasaponin itself does not have or only has faint antioxidant activity; but the heart and injury that oxidative stress causes is had protective effect, especially reperfusion injury of ischemic heart desease, heart etc. is had definite curative effect.
Summary of the invention
The objective of the invention is to overcome the deficiency that prior art exists, it is the Chinese medicine extract that contains dammarane type four-ring triterpenoid saponins compounds that a kind of main active is provided, derive from panax araliaceae plant (Panaxnotoginseng (Burk.) F.H.Chen), contain Panax Notoginseng saponin R at least
1, the ginsenoside Rg
1, Rb
1, Re and Rd, its content (HPLC method mensuration) is 45～95% (w/w).These compositions also can extract from other plant and obtain, and perhaps the approach by chemosynthesis or biotransformation obtains.
Chinese medicine extract provided by the invention can add in the other medicines, is combined into new chemicotherapy ancillary drug.
Another object of the present invention provides the Chinese medicine extract that contains dammarane type four-ring triterpenoid saponins compounds and alleviates application in the medicine of anthracene ring antitumor medicinal cardiac toxicity in preparation.The antagonism anthracene ring antitumor medicinal cardiac toxicity that the present invention uses Chinese medicine extract has carried out in the body, experiment in vitro studies have shown that; arasaponin also has significant protection effect to the inductive heart and injury of amycin, but does not weaken the antitumous effect of anthracene ring antitumor medicinal (as amycin).Can be used as prevention, alleviate anthracene nucleus medicament cardiac toxicity new type natural preparation.
Innovation part of the present invention is: 1. arasaponin compounds, belong to the dammarane type four-ring triterpenoid saponins, the activity that does not have tangible antioxidation or removing free radical, there is not tangible calcium ion complexing yet, but can bring into play the effect of anti-amycin cardiac toxicity, mean that its mechanism of action is novel; Reported first of the present invention a kind of Chinese medicinal plant extract can alleviate the cardiac toxicity of amycin, and do not influence the anti-tumor activity of amycin, still do not have any Chinese medicine extract before this and be in the news and have related activity; 3. although the physiologically active of arasaponin has obtained extensive studies, the someone reports the activity of arasaponin aspect anti-amycin cardiac toxicity as yet, and the present invention will further enlarge the clinical practice of Radix Notoginseng.In view of Radix Notoginseng and the secular human history of extract thereof, its safety is extensively admitted, and this means that the present invention has bright potential applicability in clinical practice.
Description of drawings
Fig. 1 causes the influence of myocardial cell injury to amycin for arasaponin.
Fig. 2 is arasaponin suppresses the human breast cancer cell effect to amycin influence
The specific embodiment
In order to understand the present invention better, be further described below in conjunction with embodiment.
Embodiment 1
Get pseudo-ginseng granule (3mm-8mm) 500g, 50 ℃ of dryings 6 hours add 10 times of amount 70% ethanol slight boiling condition heating and refluxing extraction 2 times, and each 2 hours, extracting liquid filtering merged, and is evaporated to 0.5g/mL (crude drug amount), last D
101Macroporous resin.With 4 times of amount column volume deionized water rinsings, discard, the flushing of reuse 4BV 0.05% ammonia discards, then with deionized water rinsing to effluent pH=7, continue to discard, use 5BV 70% alcoholic solution eluting at last with the flushing of 4BV 30% alcoholic solution, collect eluent, being evaporated to does not have alcohol, and lyophilization promptly gets Radix Notoginseng total arasaponins.Through the HPLC external standard method, Panax Notoginseng saponin R in the refining thing
18%, ginsenoside Rg
144%, ginsenoside Rb
128%, ginsenoside Rd 10%, ginsenoside Re 5%, total saponin content reaches more than 95%.
Embodiment 2
Pseudo-ginseng is pulverized the Semen Glycines size to coarse powder, extracts 4 times with 40% aqueous alcohol hot reflux, reclaims solvent, with equal-volume n-butanol extraction 3 times, combining extraction liquid, is concentrated into driedly, after the pulverizing, adds petroleum ether 2 times, and desolventizing is drying to obtain.Adopt high-efficient liquid phase technique (HPLC) that it is detected, analysis condition is Agilent Extend-C18, mobile phase H
2O-CH3CN detects wavelength 203nm, adopts its content of external standard method, and the content of five kinds of compositions is respectively Panax Notoginseng saponin R
13%, ginsenoside Rg
125%, ginsenoside Rb
114%, ginsenoside Rd 4%, ginsenoside Re 1.5%.Total content 47.5%.
Embodiment 3
Separate obtaining neonatal rat (Wistar rat) myocardial cell, plant 96 orifice plates.Cell density 5 * 10
5Individual/hole.After 48 hours, cell is normally adherent with the cultivation of DMEM+20%FBS culture fluid, and the part cell is beaten regularly.Establish matched group respectively, model group (containing 0.1,1 μ M doxorubicin hydrochloride), and the arasaponin group of variable concentrations (12.5-100 μ g/ml) (adding amycin adding in preceding 1 hour).Cultivate after 24 hours, measure, with 490nm colourimetric number reflecting myocardium cell viability with mtt assay.The result is referring to Fig. 1 (* * P＜0.01; * P＜0.05).
Experiment shows that 0.1 and 1 μ M doxorubicin hydrochloride can cause significant myocardial cell injury, and the MTT value significantly descends; And arasaponin shows the certain protection effect with the concentration administration in advance of 12.5～100 μ g/ml.Illustrate that arasaponin can prevent and alleviate the myocardial cell injury that amycin causes in experiment in vitro.
Embodiment 4
40 ICR male mices, body weight 20 ± 2g, being divided into is four groups, 10 every group.The normal control group is irritated stomach and is given normal saline, continuous five days; The arasaponin matched group, gastric infusion arasaponin 100mg/Kg, continuous five days; Amycin modeling group is irritated stomach and is given normal saline, continuous five days, irritate stomach 1h for the last time after, lumbar injection amycin 20mg/Kg; Radix Notoginseng treatment group, gastric infusion arasaponin 100mg/Kg, continuous five days, irritate stomach 1h for the last time after, lumbar injection amycin 20mg/Kg.Continue then to feed 72 hours.After animal is anaesthetized with pentobarbital, fixing, open the thoracic cavity, insert left ventriclies with No. 26 syringe needles, connect pressure transducer, monitor with physiograph.Data such as recorded heart rate, maximum intraventricular pressure, minimum intraventricular pressure, intraventricular pressure rising maximum rate.
Abdominal vein is got blood, after the blood coagulation, measures biochemical indicator lactic acid dehydrogenase (LDH), swashs acid kinase (CK) and sharp acid kinase isozyme (CKMB); And it is dirty to core, and divides centrifugal chamber to weigh.The low temperature tissue homogenate is got 5% tissue homogenate and is measured superoxide dismutase (SOD), glutathione oxidase (GSH-Px) and catalase (CAT) then.
Experimental result sees Table 1, table 2, and after animal gave amycin, Serum LDH, CK and CKMB had risen 3～10 times, illustrated that myocardial damage is serious.GSH-Px in the tissue and CAT also have remarkable decline, illustrate that heavy damage is received by the system of body antagonism oxidative stress.Cardiac function is representative with intraventricular pressure rising maximum rate, has almost reduced by 50%, illustrates that heart acting ability has also seriously undermined.Arasaponin is when giving the intact animal, to the not obviously influence of every biochemistry, physical signs.But after five days, every damage that amycin is caused all shows certain recovery, sluggishness and alleviates effect at preventive administration.Vigor to various sero-enzymes has reduced by 20～50%, and animal intraventricular pressure rising maximum rate is high by about 30% than model group, has significantly improved cardiac function.In cardiac muscular tissue, significantly improve the vigor of CAT, may be the main cause of its performance protective effect.
Table 1 arasaponin is to the toxic protective effect of amycin acute cardiac (biochemical indicator)
Aa, compare with the normal control group, have highly significant difference P＜0.01;
a, compare with the normal control group, have significant difference P＜0.05;
Bb, compare with model group, have highly significant difference P＜0.01;
b, compare according to group with model, have significant difference P＜0.05.
Table 2 arasaponin is to the toxic protective effect of amycin acute cardiac (cardiac function)
Aa, compare with the normal control group, have highly significant difference P＜0.01;
a, compare with the normal control group, have significant difference P＜0.05;
Bb, compare with model group, have highly significant difference P＜0.01;
b, compare according to group with model, have significant difference P＜0.05.
In sum, arasaponin is under the dosage of 100mg/Kg, and the continuous irrigation stomach gives 5 days in advance, can significantly alleviate the myocardial damage that heavy dose of amycin causes, and can suppress weakening of cardiac function to a certain extent.
Embodiment 5
Human breast carcinoma tumor cell MCF-7 is seeded to 96 orifice plates, every hole 5000 cells.After cultivating 24h, establish matched group respectively, model group (containing 0,0.1,1 μ M doxorubicin hydrochloride), and the arasaponin group of variable concentrations (12.5～200 μ g/ml) (adding amycin adding in preceding 1 hour).After cultivating 24h, measure, with 490nm colourimetric number reflection cell quantity and vigor with mtt assay.The result is referring to Fig. 2.
Experiment shows that amycin has the obvious suppression effect to breast cancer tumour cell MCF-7 vigor, and the arasaponin that gives 100～12.5 μ g/ml in advance has no significant effect suppression ratio.Arasaponin itself just has the effect that suppresses tumor cell activity down in high concentration (200 μ g/ml).Illustrate that arasaponin does not weaken the inhibitory action of amycin to growth of tumour cell.
Embodiment 6
40 ICR male mices, body weight 20 ± 2g, oxter inoculation murine sarcoma S180.After raising 48h, be divided into four groups, 10 every group.Lotus tumor matched group, irritate stomach and give normal saline every day; The Radix Notoginseng matched group, gastric infusion arasaponin 100mg/Kg; Amycin treatment group, irritate stomach and give normal saline every day, every day lumbar injection 1mg/Kg doxorubicin hydrochloride; Amycin and Radix Notoginseng combined treatment group, every day gastric infusion arasaponin 100mg/Kg, every day lumbar injection 1mg/Kg doxorubicin hydrochloride.Successive administration 11 days takes off neck and puts to death animal, dissects animal, separates and gets the oxter sarcoma, weighs.
Table 3 arasaponin suppresses the influence of transplanted tumor effect to amycin
* compare P＜0.01 with lotus tumor matched group
Experiment shows that doxorubicin hydrochloride is under the situation of 1mg/Kg administration in continuous 11 days, and S180 has significant inhibitory effect to transplanted tumor, and suppression ratio reaches 51.9%.Arasaponin does not suppress the effect of tumor growth, but does not reduce suppression ratio with the amycin drug combination.Illustrate that arasaponin does not reduce the antitumor drug effect of amycin.
Claims (1)
1. a Chinese medicine extract that contains the dammarane type four-ring triterpenoid saponins alleviates application in the medicine of amycin cardiac toxicity as unique active component in preparation, described Chinese medicine extract is from panax araliaceae plant, effective ingredient is the dammarane type four-ring triterpenoid saponins, wherein contains arasaponin R1, ginsenoside Rg at least
1, Rb
1, Re and Rd, the weight percentage of described 5 kinds of saponin is 45～95%.
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