CN102526046B - Antitumor medicinal composition containing epigallocatechin gallate (EGCG) and sorafenib and application thereof - Google Patents
Antitumor medicinal composition containing epigallocatechin gallate (EGCG) and sorafenib and application thereof Download PDFInfo
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Abstract
The invention belongs to the fields of medicine and gene engineering, and provides a composition for suppressing tumor cell proliferation. The composition contains epigallocatechin gallate (EGCG) and sorafenib, wherein the molar ratio of the EGCG to the sorafenib is 200:1-4:1. By using the EGCG in the composition together with the sorafenib, a tumor cell proliferation suppressing effect is more remarkable than that of overlaying of separate use effects; and by using the EGCG together with the sorafenib, the toxicity on the liver and kidney of a nude mouse is avoided basically, and the antitumor effect of sorafenib is enhanced. The EGCG in the composition is derived from a natural tea extract, so that the resource is rich, and the price is low; and as proved by long-term drinking, the composition is free from toxic and side effects, so that the antitumor effect is enhanced and the medicament toxicity and the medicament cost are lowered by using the EGCG together with the sorafenib.
Description
Technical field
The invention belongs to medicine and genetic engineering field, relate to epigallocatechin gallate (EGCG) (EGCG) and Sorafenib (SORA) combination and the application in the preparation anti-tumor agents thereof.
Background technology
Sorafenib (sorafenib) is the biological targeting new drug of a kind of many target spots of the common development of Bayer and ONYX company, and preclinical study and clinical trial prompting Sorafenib have antitumor action widely.U.S. FDA was ratified Sorafenib on the 20th in December in 2005 and has been used for the treatment of the renal cell carcinoma in late period, and this is nearly first new drug of approved treatment renal carcinoma in late period in the world during the last ten years, is the major progress of renal carcinoma treatment in late period.On November 30th, 2006, Sorafenib also went on the market in China.The CAS of Suo Lafeini is numbered 284461-73-0, and molecular formula is C
21H
16C
lF
3N
4O
3, molecular weight is 464.83, chemistry 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl by name)-uride]-phenoxy group }-pyridine-2-carboxylic acids methylamine-4-toluene fulfonate.
Sorafenib is first pair of oral many inhibitors of kinases of aryl carbamide class, i.e. tyrosine kinase inhibitor, angiogenesis inhibitor and vascular endothelial growth factor receptor inhibitors.It has dual antitumor action, directly suppress tumor growth by suppressing the Raf/MEK/ERK signal transduction pathway on the one hand, on the other hand by suppressing the activity of several tyrosine kinase receptors relevant with tumor development with the new vessels generation, comprise vascular endothelial growth factor receptor-2(VEGFR-2), VEGFR-3, platelet-derived growth factor receptors-β (PDGFR-β) and c-KIT proto-oncogene, the blocking-up tumor neogenetic blood vessels generates, suppress the growth of tumor cell indirectly, thereby play antitumor action.Sorafenib be in this compounds the 1st enter the medicine of clinical trial, can under the dosage that suppresses the Raf activity, significantly suppress tumor cell proliferation.
Sorafenib also has splendid therapeutic effect to advanced liver cancer.Sorafenib is used for the treatment of the phase iii clinical trial of advanced liver cancer to be finished, and has entered quick examination and approval procedures at U.S. FDA and Bureau of Drugs Supervision of European Union at present.Simultaneously, Sorafenib also can be used for treatment for cancer such as metastasis melanin tumor, nonsmall-cell lung cancer.The modal untoward reaction of Sorafenib comprises hand-foot syndrome, tired, diarrhoea, erythra, hypertension, alopecia, skin pruritus and feels sick or appetite descends.
The generation evolution of malignant tumor is participated in by multifactor inducing with polygenes.Sorafenib has the antitumor action of unique many target spots, is based on the new drug of succeeding in developing on the basis to tumorigenic molecular biology mechanism understanding.The clinical test results of Sorafenib shows that Sorafenib is different with chemotherapeutics, and its effect is mainly the growth of inhibition tumor cell and the formation of blood vessel, but not cellulotoxic effect, so toxicity is lighter, toleration is better.Many target spots inhibitor is better than single target spot inhibitor aspect treatment, Sorafenib has the antitumor action of potential wide spectrum.How further to improve Sorafenib curative effect (as with the other drug coupling) also be the problem of the anxious solution to be studied of present clinical trial undoubtedly.Rapamycin is a kind of mTOR pathway inhibitor, and certain antineoplastic action is arranged.Existing preclinical study shows, in liver cancer treatment rapamycin and Sorafenib is united the curative effect that use can greatly improve Sorafenib, but the toxic and side effects that these two kinds of chemical compounds are united when using is stronger.So how when strengthening the Sorafenib anti-tumor activity, keeping lower toxic and side effects also is the problem that needs consideration.
Folium Camelliae sinensis (tea, camellia sinensis) is one of beverage that is loved by the people.The whole world is annual to produce about 2,500,000 tons, and wherein 20% is that green tea, 78% is that black tea, 2% is oolong tea.Though the kind of Folium Camelliae sinensis is a lot, attract attention with the green tea behaviour.A large amount of in vitro studies and zoopery proof green tea extract have multiple biological activity and pharmacodynamics effect, as cancer-resisting, angiogenesis inhibitor, mutation, antioxidation, defying age, antibiotic, antiinflammatory, blood fat reducing, antiplatelet aggregation etc., wherein with the relation of cancer be study the most extensively, also be the most complicated significant important topic.
Main component in the green tea is tea polyphenols, account for about 30% of dry weight of tea leaves, major part is catechin in the tea polyphenols, epigallocatechin gallate (EGCG) ((-)-epigallocatechin gallate, (EGCG)) content is the highest, accounts for about 80% of catechin.The EGCG molecular formula is C
22H
18O
11, molecular weight is 458.4.It is the biological anti-oxidant that a kind of high-efficiency broad spectrum has no side effect, and is commonly called as nutgall catechin gallic acid ester.Epicatechol gallate can effectively be removed and cause multiple disease and old and feeble interior free yl and peroxide, improve body immunity, slow down aging has usefulness such as excellent antiviral, blood fat reducing, fresh-keeping, beauty treatment, has been widely used in industries such as medicine, health care, food, daily use chemicals.But green tea extract is not cytotoxic drug after all, is not very strong in external direct killing effect to tumor cell.Green tea extract and main component thereof can not replace existing antitumor drug, and its unique value is as the biochemical regulator in the chemotherapy of tumors, can strengthen the anti-tumor activity of existing antitumor drug, reduces the toxicity of antitumor drug.
Up to the present, also there are not EGCG and Sorafenib to unite the report of use.
Summary of the invention
The purpose of this invention is to provide a kind of new antitumor drug.
The invention provides a kind of compositions that suppresses tumor cell proliferation, said composition contains epigallocatechin gallate (EGCG) and Sorafenib, and both mol ratios are 200:1-4:1.Preferably, the mol ratio of epigallocatechin gallate (EGCG) and Sorafenib is 160:1～8:1.Better, mol ratio is 120:1～8:1, perhaps 80:1～13:1,40:1,60:1,100:1,32:1,20:1,26:1,39:1,52:1 etc.
The CAS of Suo Lafeini is numbered 284461-73-0, and molecular formula is C
21H
16C
lF
3N
4O
3, molecular weight is 464.83, chemistry 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl by name)-uride]-phenoxy group }-pyridine-2-carboxylic acids methylamine-4-toluene fulfonate.Be derived from Bayer A.G.
((-)-epigallocatechin gallate, (EGCG)) molecular formula is C to epigallocatechin gallate (EGCG)
22H
18O
11, molecular weight is 458.4.EGCG is available from Sigma company, article No. 50299, English full name: ()-cis-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1 (2H)-benzopyran-3,5,7-triol 3-gallate, ()-cis-3,3 ', 4 ', 5,5 ', 7-Hexahydroxy-flavane-3-gallate, EGCG; CAS number: 989-51-5.MDL number: MFCD00075940.
Among the present invention, EGCG and clinical medicines resistant to liver cancer sorafenib commonly used all have certain cooperative effect in tumor cell line.
Among the present invention, the compositions of EGCG and Sorafenib is used for tumor cell (for example, hepatoma cell strain SK-Hep1), the result shows, compares with only using Sorafenib, and the effect that suppresses tumor cell proliferation obviously strengthens.EGCG and Sorafenib coupling have obviously reduced the use amount of Sorafenib, and it is more obvious along with the increase of EGCG consumption that it reduces effect.
Among the present invention, the compositions of EGCG and Sorafenib is used for the transplanted tumor in nude mice model, the result shows, with only use Sorafenib and compare, EGCG of the present invention and Sorafenib compositions significantly strengthen the inhibition of transplanted tumor in nude mice growth, and effect is better than rapamycin and Sorafenib compositions.Simultaneously, detecting with the body weight change is that the poisonous effect of medicine shows after the administration of index, and EGCG and Sorafenib are united when using the not obviously influence of nude mice body weight, and rapamycin and Sorafenib are united the reduction of the nude mice body weight that use then causes.And liver and kidney to nude mice when EGCG and Sorafenib are united use do not have toxicity substantially, and rapamycin and Sorafenib are united use then to be had than high toxicity liver and the kidney of nude mice.
EGCG and Sorafenib coupling are compared with independent use EGCG or Sorafenib, suppressing to have obvious synergistic effect aspect the growth of tumour cell, and potentiation have EGCG and Sorafenib Concentraton gradient effect.Embodiments of the invention have enumerated EGCG and Sorafenib content ratio is 20:1,100:1,200:1 etc.Experiment shows, is that the scope of 200:1-13:1 all is resultful at both content.
A kind of method of killing tumor cell also is provided among the present invention, namely adds EGCG and Sorafenib compositions in tumor cell, the mol ratio of EGCG and Sorafenib is 200:1-13:1.
Among the present invention, described tumor cell can be HepG2, SK-hep-1, YY1, L02 or PLC cell.
Compositions of the present invention when when (administration) used in treatment, can provide different effects.Usually, but these materials are formulated in nontoxic, inertia with pharmaceutically acceptable aqueous carrier medium in, wherein pH is about 7-8 usually, although pH value can change to some extent with being formulated Substance Properties and disease to be treated.The pharmaceutical composition for preparing can carry out administration by conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, Intradermal or topical.
Compositions with EGCG of the present invention and Sorafenib is example, can be with itself and suitable pharmaceutically acceptable carrier coupling.This class pharmaceutical composition contains protein and pharmaceutically acceptable carrier or the excipient for the treatment of effective dose.This class carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should be complementary with administering mode.EGCG of the present invention and Sorafenib can be made into the injection form, for example are prepared by conventional method with normal saline or the aqueous solution that contains glucose and other adjuvant.Pharmaceutical composition such as tablet and capsule can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule should be made under aseptic condition.In addition, EGCG of the present invention also can use with the other treatment agent with the compositions of Sorafenib.
Among the present invention, the compositions of EGCG and Sorafenib can be injection or tablet.
When the compositions of EGCG of the present invention and Sorafenib is used as medicine, can with the treatment effective dose this medicament administration in mammal, wherein should the treatment effective dose usually at least about 60 milligrams of Sorafenib+50 milligram EGCG/ kg body weight.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
The invention provides a kind of new compositions, said composition contains EGCG and Sorafenib.Said composition can be used for preparing antitumor drug.EGCG and Sorafenib coupling for the preparation of antitumor drug, can strengthen the antitumous effect of Sorafenib greatly, have reduced consumption and the medicine cost of Sorafenib simultaneously relatively.Because EGCG is natural Folium Camelliae sinensis extract, and Folium Camelliae sinensis is the frequent drinking beverage of population in the whole world 2/3rds.Not only aboundresources is cheap, has passed through drinking more than thousand, does not almost have toxic and side effects.EGCG uses as the ancillary drug of Sorafenib, is a kind of compatibility program of new efficient and cheap antitumor drug, has improved the suppression ratio of tumor, has reduced the treatment cost of tumor patient.
Description of drawings
Fig. 1 is that EGCG and CBP, MITOC, SORA, DAU have synergism in the SK-Hep1 cell.Wherein, abscissa fa is the drug effect effect.
Fig. 2 is that EGCG and SORA have synergism in Hep3B cell and the SMMC7721 cell.Wherein, abscissa fa is the drug effect effect.
Fig. 3 is EGCG potentiation SORA.
Fig. 4 is that EGCG reduces the SORA consumption.
Fig. 5 is that EGCG and SORA unite use the nude mice body weight is not had influence.
Fig. 6 is that EGCG and SORA unite gross tumor volume is reduced.
Fig. 7 is that EGCG and SORA unite the tumor body weight is reduced.
Fig. 8 is the corresponding block diagram of Fig. 7.
The specific embodiment
Our fixing concentration of EGCG in ten kinds of hepatoma cell line is respectively with four kinds of medicines resistant to liver cancer drug combinations.Use Jin Shi formula Q-value to estimate the coupling effect.(Ea+Eb-Ea * Eb), Ea+b is the drug combination suppression ratio to Q=Ea+b/, and Ea and Eb are respectively the suppression ratio of A medicine and B medicine.Two medicines that molecule represents actual measurement merge suppression ratio, and denominator is that expectation merges suppression ratio.The Q=0.85-1.15 scope is represented simple addition, and the Q=1.15-2 scope represents enhancing is arranged, Q〉obviously enhancing of 2 expressions, Q＜0.55-0.85 represents that antagonistic effect is arranged, the Q＜obvious antagonism of 0.55 expression.As shown in Table 1, EGCG and four kinds of medicines resistant to liver cancer all have certain synergy in specific cell strain, illustrate that EGCG can strengthen the anti-tumor activity of existing medicines resistant to liver cancer in specific cell strain.
Following cell all derives from ATCC, is human liver cancer cell.
Carboplatin, Mitomycin C, sorafenib, Daunorubicin are respectively carboplatin, ametycin, Sorafenib daunorubicin.Anticancer mechanism and the interaction property of these four kinds of medicines are different: Carboplatin is the DNA synthetic inhibitor, and Daunorubicin is DNA, rna synthesis inhibitor, and Mitomycin C is antifol, and sorafenib is many inhibitors of kinases.
The drug combination effect of table 1 EGCG and medicines resistant to liver cancer
In order to verify above experimental result, further use the method for geometric ratio coupling, use CI(combination index) value estimates the coupling effect.Calculate suppression ratio fa by the MTS method, i.e. drug effect effect, the average OD value of the fa=1-experimental group/average OD value of tumor cell matched group.Calculate then that two kinds of cancer therapy drugs use separately and the drug level when uniting when using separately middle effect concentration Dm(0.5 effect), the coupling index CI value in the time of further can calculating two medicine couplings when various effect.CI=D
1/ D
X1+ D
2/ D
X2+ α D
1D
2/ D
X1D
X2, D wherein
1, D
2Be two medicines, two medicines desired concns separately when producing the X effect when share, D
X1, D
X2Be two prescriptions, two medicines concentration separately when producing the X effect when solely using.α=0 is two kinds of mutual repellency medicines, and α=1 is two kinds of mutual nonexclusion medicines.CI＜1 is synergism; CI=1 is summation action; CI〉1 be antagonism.
In the SK-Hep1 cell, we have selected Q-value greater than four kinds of medicines resistant to liver cancer carboplatin (CBP of 1.5, Carboplatin), ametycin (MITOC, Mitomycin C), Sorafenib (SORA, sorafenib, Nexavar, Bay 43-9006) and daunorubicin (DAU, Daunorubicin) respectively with the coupling of EGCG geometric ratio, when the result showed EGCG and this four kinds of medicines resistant to liver cancer drug combinations, the CI value was all less than 1(Fig. 1 in certain effect scope).What the coupling effect was the strongest is the sorafenib group, in fa＜0.85 o'clock CI＜1, is cooperative effect; And fa〉0.9 o'clock CI〉1, be antagonistic effect.Next is Mitomycin C group, and fa is between 0.85 and 0.25 the time, and CI＜1 is cooperative effect; Fa＜0.2 or fa〉0.9 o'clock, CI〉1, be antagonistic effect.Carboplatin group fa is between 0.9 and 0.5 the time, and CI＜1 is cooperative effect; Fa＜0.45 or fa〉0.95 o'clock, CI〉1, be antagonistic effect.Daunorubicin group is at fa〉0.6 o'clock CI＜1, be cooperative effect; And fa＜0.55 o'clock CI 1, be antagonistic effect.Illustrate that Q-value is consistent with CI value evaluation effect, in the SK-Hep1 cell, all have cooperative effect when EGCG and this four kinds of medicines resistant to liver cancer couplings.
EGCG and four kinds of medicines resistant to liver cancer are united use and all had cooperative effect, and are wherein very remarkable with the synergy of Sorafenib in the SK-Hep1 cell.So we have further verified the coupling effect of EGCG and Sorafenib in Hep3B cell and SMMC7721 cell, result's proof CI value in certain concentration range all has synergism (Fig. 2) less than 1, two kind of medicine.In the Hep3B cell, fa is between 0.75 and 0.1 the time, and CI＜1 is cooperative effect; Fa＜0.05 and fa〉0.8 o'clock, CI〉1, be antagonistic effect.In the SMMC7721 cell, fa〉0.5 o'clock CI＜1, be cooperative effect; And fa＜0.45 o'clock CI 1, be antagonistic effect.Above result shows that EGCG and Sorafenib unite the antitumous effect that use can improve Sorafenib, reduces the toxicity of Sorafenib.
Table 2 adding consistency and suppression ratio fa
In the SK-Hep1 cell with the Sorafenib of 0.25,0.5,0.75 μ M respectively with the EGCG coupling of 10,20,30,40,50 μ M, as shown in Figure 3, can meet or exceed the effect that 1 μ M Sorafenib uses separately after the EGCG coupling of the Sorafenib of 0.25,0.5,0.75 μ M and variable concentrations.Analyze according to the LOGIT software statistics, unite with EGCG and use that needed Sorafenib amount reduces (Fig. 4) along with the increase of EGCG amount when reaching the half inhibition, and have dosage effect.Above experimental result explanation EGCG and Sorafenib are united use, can effectively strengthen the antitumous effect of Sorafenib and reduce its consumption.
The administering mode to the nude mice chemotherapy of embodiment 4 EGCG associating Sorafenib
The medicine preparation: the compound method of EGCG is that the EGCG powder is dissolved in the normal saline, and is now with the current.
The compound method of Sorafenib is the Sorafenib powder to be dissolved in the normal saline that contains 0.5% sodium carboxymethyl cellulose prepare, and is now with the current.
The compound method of rapamycin is the rapamycin powder to be dissolved in the normal saline that contains 0.5% sodium carboxymethyl cellulose prepare, and is now with the current.
Administering mode: (1) matched group: every day intraperitoneal injection of saline.
(2) sodium carboxymethyl cellulose group: every day the oral normal saline that contains 0.5% sodium carboxymethyl cellulose.
(3) EGCG group: dosage is 50 mg/kg body weight/day, and administration is 13 days altogether, lumbar injection.
(4) Sorafenib group: dosage is the 60mg/kg body weight/day, and administration is 13 days altogether, and is oral.
(5) rapamycin group: dosage is 2 mg/kg body weight/day, and administration is 13 days altogether, and is oral.
(6) EGCG+ Sorafenib group: dosage is the addition of (3) and (4) group.Administering mode is lumbar injection EGCG of same time of every day, and is consistent with the EGCG group, oral Sorafenib after 2 hours.
(7) rapamycin+Sorafenib group: dosage is the addition of (4) and (5) group.Administering mode is oral rapamycin of same time of every day, and is consistent with the rapamycin group, oral Sorafenib after 2 hours.
Above administration volume is the 0.2ml/20g body weight.
The variation of nude mice body weight is an index of chemotherapeutics toxicity.The situation of change of nude mice body weight can be done an evaluation intuitively to the toxicity of medicine in the xenotransplantation tumor model of detection SMMC7721 cell.As shown in Figure 5, in the process of dosing, EGCG group, Sorafenib group, rapamycin group and EGCG and Sorafenib coupling group do not have influence substantially to the nude mice body weight, illustrate that toxic and side effects is lower; And rapamycin and Sorafenib coupling group are bigger to nude mouse ghost image sound, and significant difference illustrates that two kinds of drug combination toxic and side effects are stronger.
Embodiment 6 EGCG associating Sorafenib is to the toxicity of nude mice liver and kidney
The rising of glutamate pyruvate transaminase (ALT) and blood urea nitrogen (BUN) content is the important indicator of liver and kidney injury.In SMMC7721 transplanted tumor model, the content of rapamycin group and rapamycin and Sorafenib coupling group glutamate pyruvate transaminase (ALT) and blood urea nitrogen (BUN) all is higher than matched group, significant difference illustrates that the rapamycin list is used and two kinds of drug combinations are bigger to the damage of nude mice liver and kidney; EGCG group, Sorafenib group and EGCG and Sorafenib coupling group then do not have toxicity substantially to nude mice liver and kidney.
Table 3 EGCG associating Sorafenib is to the influence of glutamate pyruvate transaminase and blood urea nitrogen
| ? | Glutamate pyruvate transaminase (ALT) | Blood urea nitrogen (BUN) |
| control | 108±48 | 13.3±4.4 |
| EGCG | 114±58 | 15.5±6.1 |
| |
122±35 | 11.9±1.8 |
| EGCG+SORA | 116±44 | 11.3±3.2 |
| Rapa | 210±63 | 19.3±2.4 |
| Rapa+SORA | 246±55 | 13.5±0.8 |
| cMcNa | 148±45 | 16.4±5.4 |
In whole experiment, we measured in per 2 days to gross tumor volume, continuous monitoring growth of tumor situation, thus observe EGCG associating Sorafenib to suppressing the influence of transplanted tumor in nude mice growth effect.As can see from Figure 6, in the transplanted tumor model of SMMC7721 cell, the dosing initial stage, 7 groups tumor mean size difference is little, the drug effect middle and late stage, EGCG associating Sorafenib group and rapamycin associating Sorafenib group tumor growth are slower, significant difference, and the effect of EGCG coupling group is better than rapamycin coupling group.
The zoopery successive administration was put to death nude mice after 13 days, took out tumor body weigh (Fig. 7 and Fig. 8).The result shows that the suppression ratio of the tumor of independent use EGCG is 31.09%, using Sorafenib separately is 31.37% to the suppression ratio of tumor, using rapamycin separately is 6.16% to the suppression ratio of tumor, it is 56.16% to the suppression ratio of tumor that EGCG and Sorafenib are united use, and it is 43.84% to the suppression ratio of tumor that rapamycin and Sorafenib are united use.Above result shows that EGCG and Sorafenib unite the antitumous effect that use can strengthen Sorafenib, and effect is better than the effect that rapamycin and Sorafenib are united use.This points out us EGCG and Sorafenib can be united use as a kind of new liver cancer treatment scheme, in order to strengthen the antitumous effect of Sorafenib, reduces toxicity and the consumption of Sorafenib.
Claims (8)
1. a compositions that suppresses tumor cell proliferation is characterized in that, said composition contains epigallocatechin gallate (EGCG) and Sorafenib, and both mol ratios are 200:1～4:1.
2. compositions as claimed in claim 1 is characterized in that, the mol ratio of epigallocatechin gallate (EGCG) and Sorafenib is 160:1～8:1.
3. compositions as claimed in claim 1 is characterized in that, the mol ratio of epigallocatechin gallate (EGCG) and Sorafenib is 120:1～8:1.
4. compositions as claimed in claim 1 is characterized in that, the mol ratio of epigallocatechin gallate (EGCG) and Sorafenib is 80:1～13:1.
5. the application of the described compositions of claim 1 in the preparation antitumor drug.
6. application as claimed in claim 5 is characterized in that, described tumor is hepatocarcinoma.
7. application as claimed in claim 5 is characterized in that, adds the described compositions of claim 1 in the tumor cell culture liquid of In vitro culture.
8. application as claimed in claim 7 is characterized in that, described tumor cell is HepG2, SK-hep-1, YY1, L02 or PLC cell.
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