CN102688493B - Pharmaceutical composition containing resveratrol, resveratrol derivative and Bc1-2 inhibitor, and application thereof - Google Patents
Pharmaceutical composition containing resveratrol, resveratrol derivative and Bc1-2 inhibitor, and application thereof Download PDFInfo
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- CN102688493B CN102688493B CN201110080495.XA CN201110080495A CN102688493B CN 102688493 B CN102688493 B CN 102688493B CN 201110080495 A CN201110080495 A CN 201110080495A CN 102688493 B CN102688493 B CN 102688493B
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Abstract
The present invention relates to a pharmaceutical composition containing resveratrol, a resveratrol derivative and a Bc1-2 inhibitor, and applications of the pharmaceutical composition for preparing pharmaceuticals to cure colorectal carcinoma, liver cancer, lung cancer, kidney cancer, stomach cancer, brain tumor, sarcoma, neuroglioma, pancreas cancer, ovary cancer, breast cancer or prostate cancer. The pharmaceutical composition has an obvious synergistic effect, increases the pharmic curative effect, reduces the administration dosage and reduces the adverse reactions.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and the application in the medicine of preparation treatment cancer thereof, be specifically related to the pharmaceutical composition and the application in the medicine of preparation treatment colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, glioma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof that contain resveratrol and resveratrol analog derivative and Bcl-2 inhibitor.
Background technology
World Health Organization's investigation report shows, global cancer condition is day by day serious, and 20 years new patients' number will be increased to 1,500 ten thousand by current annual 1000 ten thousand from now on, because the dead number of cancer also will be increased to 1,000 ten thousand by annual 6000000.Primary hepatocarcinoma is the canceration that occurs in hepatocyte and intrahepatic biliary epithelium cell, is one of modal malignant tumor of the mankind; The morbidity of colon cancer and environment, living habit, especially diet style is relevant, it is generally acknowledged that high fat diet and cellulose deficiency are main pathogenic factors, along with growth in the living standard, the change of dietary structure, the sickness rate of colon cancer is ascendant trend year by year; Glioma is to originate from neurogliocyte, betides neuroectodermal tumor, and its principal character is tumor cell diffuse infiltrating growth, without clear and definite border, infinite multiplication and have Highly invasive.Although in recent years neurosurgery skill constantly perfect, radiotherapy accurately locate and the continuous research and development of chemotherapeutics, patients with gliomas more after still barely satisfactory, the medicine of therefore studying glioma is extremely urgent.
The antitumor drug having gone on the market is at present more, and as alkylating agent medicine, antimetabolite, antitumor antibiotics, immunomodulator etc., but medicine is because toxicity is larger mostly, and patient does not tolerate.A large amount of clinical practices prove, malignant tumor can be effectively treated in Chinese medicine or the combination of Chinese and Western medicine, can alleviate the toxic and side effects of chemicotherapy simultaneously.Use modern medicine means, find the effectively growth of inhibition tumor cell of some bioactive natural products, have the effect of cell death inducing.Numerous antibiotic and the antitumor drug using at present or be directed to natural product, or obtain through its structure of modification.Therefore, safe bioactive natural product apply to clinical with treatment cancer will have broad prospects.Along with the Study on Molecular Mechanism of the generation development to tumor is more and more clearer, molecular targeted therapy Several Kinds of Malignancy has been subject to paying close attention to widely and paying much attention to.Molecular targeted agents selectivity is high, wide spectrum is effective, and its safety is better than cytotoxicity chemotherapeutics, is the new direction of current therapeutic field of tumor development.
Resveratrol (Resveratrol) is a kind of polyphenolic substance being extensively present in the various plants such as Fructus Vitis viniferae, Rhizoma Polygoni Cuspidati, Semen arachidis hypogaeae, is a kind of natural phytoalexin, is the green cancer therapy drug of anti-curing oncoma.Experiment in vivo and vitro shows, resveratrol to most of tumors initial, breed, develop these three Main Stage and all have and suppress and even reverse effect.Its antitumor mechanism can play a role by antioxidation, the activity that blocks cell cycle, promotion apoptosis of tumor cells, inducing tumor cell differentiation, inhibition epoxide hydrolase and cytochrome P450, interference Signal Transduction path, inhibition tumor-blood-vessel growth etc.
Apoptosis (program cell death) is the natural way that body is removed abnormal or unwanted cells, if it is affected, may cause various diseases as the generation of cancer.Bcl-2 family protein is the important regulator of apoptosis, Bcl-2 and Bcl-xL overexpression in polytype tumor wherein, being considered to may be relevant with generation, development and the drug resistance generation of tumor, therefore become the study hotspot of antineoplaston in recent years for the drug development of Bcl-2 and Bcl-xL anti-apoptotic proteins.The micromolecule Bcl-2 inhibitor of ABT-263 and ABT-737 Shi You U.S. Abbott Laboratories (Abbott) pharmacy exploitation, remarkable to kinds of tumors effect, and can orally use, have a good application prospect.
Along with the progress of oncomolecularbiology, tumor molecular targeted therapy has become the focus of tumor research, has brought into play important effect in the treatment of kinds of tumors.Yet the biological behaviour of most of tumor is not arranged by single signal pathway, but a plurality of signal transduction pathway concurs, and Chinese medicine receives publicity just day by day with the Action advantage of the many target spots of its polygenes.Therefore rational drug combination, there is the incomparable superiority of alone medicine, drug combination carries out targeted therapy for many target spots and will not only be intended to reduce or delay appearance, the reduction toxicity of drug resistance, and synergism cancerous cell being killed and wounded by multi-medicament is obtained better curative effect.
Summary of the invention
For above technological deficiency, the invention provides a kind of pharmaceutical composition and the application in the medicine of preparation treatment cancer thereof, be specially the pharmaceutical composition and the application in the medicine of preparation treatment colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, glioma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof that contain resveratrol and resveratrol analog derivative and Bcl-2 inhibitor.
In the pharmaceutical composition that the present invention contains resveratrol and resveratrol analog derivative and Bcl-2 inhibitor, described resveratrol and resveratrol analog derivative are resveratrol; Bcl-2 inhibitor can be ABT-263 or ABT-737, or both corresponding analogs, derivant.
Resveratrol in pharmaceutical composition of the present invention and resveratrol analog derivative are preferably resveratrol, and its corresponding structural formula is suc as formula shown in I.
In pharmaceutical composition of the present invention, described component is not limited to resveratrol medicine itself, can also be its pharmaceutically useful salt, hydrate or derivant etc.
In the present invention, described Bcl-2 inhibitor can, for the medicine of the Bcl-2 inhibitor of any structure type, be preferably ABT-263 or ABT-737.Wherein ABT-263 is the compound shown in the formula II recording in US2007027135:
Wherein ABT-737 is the compound shown in the formula III of recording in WO2005049594 and WO2005049593:
In pharmaceutical composition of the present invention, described component is not limited to above-mentioned ABT-263 and ABT-737 itself, can also be the salt of their hydrate, analog, derivant and other organic or inorganic.
In the pharmaceutical composition that the present invention contains resveratrol and resveratrol analog derivative and Bcl-2 inhibitor, the mol ratio of resveratrol and resveratrol analog derivative and Bcl-2 inhibitor is 15.0-200.0: 0.5-4.0; Further preferably the mol ratio of resveratrol and resveratrol analog derivative and Bcl-2 inhibitor is 30.0-100.0: 1.0-2.0.
The pharmaceutical composition that the present invention contains resveratrol and resveratrol analog derivative and Bc l-2 inhibitor can be used for the treatment of various tumors, and described tumor includes but not limited to colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, glioma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate.
The pharmaceutical composition of the preferred resveratrol of the present invention and resveratrol analog derivative and Bcl-2 inhibitor is for the preparation of the application in treatment colon cancer, hepatocarcinoma and gliomatous medicine.
In the application of pharmaceutical composition of the present invention in preparation treatment colon cancer, hepatocarcinoma and gliomatous medicine, the mol ratio of resveratrol and resveratrol analog derivative and Bcl-2 inhibitor is 30.0-100.0: 1.0-2.0; Preferably the mol ratio of resveratrol and resveratrol analog derivative and Bcl-2 inhibitor is 50.0-100.0: 1.5-2.0; Further preferably the mol ratio of resveratrol and resveratrol analog derivative and Bcl-2 inhibitor is 100.0: 2.0.
Contain resveratrol and resveratrol analog derivative and Bcl-2 inhibitor combination in preparation treatment colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, glioma, cancer of pancreas, ovarian cancer, in the application of the medicine of breast carcinoma or carcinoma of prostate, in the scheme of medicament of the present composition being made to administration simultaneously, resveratrol and resveratrol analog derivative and Bcl-2 inhibitor can be contained in same pharmaceutical preparation as in tablet or capsule, also resveratrol and resveratrol analog derivative and Bcl-2 inhibitor can be made respectively to preparation, as made respectively tablet or capsule, and adopt the mode of this area routine that their are packed or are combined, then patient takes according to the indication of package insert simultaneously, in the scheme of medicament of the present composition being made to successively administration, resveratrol and resveratrol analog derivative and Bcl-2 inhibitor can be made respectively to different preparations, and adopt the mode of this area routine that their are packed or are combined, then patient takes according to the sequencing of package insert indication, or two kinds of compositions in above-mentioned composition are made to a kind of preparation of controlled release, a kind of composition in first release composition and then the another kind of composition in release composition, patient only need to take this controlled release composition preparation, in the scheme of medicament that the present composition is prepared into intersection administration, resveratrol and resveratrol analog derivative and Bcl-2 inhibitor can be made respectively to different preparations, and adopt the mode of this area routine that their are packed or are combined, then patient takes according to the chi sequence of package insert indication, or this pharmaceutical composition is prepared into the controlled release preparation that resveratrol and resveratrol analog derivative and Bcl-2 inhibitor intersection discharge.
In the application in the medicine of preparation treatment colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, glioma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate of resveratrol and resveratrol analog derivative and Bcl-2 inhibitor combination, resveratrol in described compositions and resveratrol analog derivative and Bcl-2 inhibitor can be used or with the using in order of any priority simultaneously, as resveratrol and resveratrol analog derivative and Bcl-2 inhibitor can taken to patient simultaneously; Also can first Bcl-2 inhibitor be taken, then be taken to resveratrol and resveratrol analog derivative medicine to patient, or first take Bcl-2 inhibitor, then take resveratrol and resveratrol analog derivative medicine, the interval of taking for both does not have special requirement, but the interval of preferably taking two kinds of medicines is no more than one day; Or two kinds of medicines replace administration.
In the present invention, the method of resveratrol of the present invention and resveratrol analog derivative and Bcl-2 inhibitor employing this area routine can be prepared into the pharmaceutical preparation that is suitable for gastrointestinal administration or parenteral administration, the pharmaceutical preparation that the present invention preferably makes gastrointestinal administration by resveratrol and resveratrol analog derivative and Bcl-2 inhibitor, its dosage form can be conventional tablet or capsule or controlled release, slow releasing preparation.In the pharmaceutical preparation of resveratrol of the present invention and resveratrol analog derivative and Bcl-2 inhibitor combination, according to different dosage forms and preparation specification, the content of described compositions in preparation can be counted 1-99% for quality, is preferably 10%-90%; The adjuvant that preparation is used can adopt the adjuvant of this area routine, and the curative effect of getting along well that the present composition reacts or not affecting medicine of the present invention of take is prerequisite; The preparation method of described preparation can adopt the preparation method of this area routine to be prepared.
In the present invention, the preparation method of compositions is not particularly limited, resveratrol and resveratrol analog derivative and Bcl-2 inhibitor can carry out direct mixing and then make preparation, or respectively and/or corresponding adjuvant mix and make respectively preparation, and then be packaging together according to the mode of this area routine, or mix and then mix and make preparation with corresponding adjuvant respectively.
The dosage of the pharmaceutical composition in the present invention can carry out suitable variation according to the dosage form difference of administration object, route of administration or medicine, but take, guarantees that this pharmaceutical composition can reach effective blood drug level as prerequisite in mammalian body.
The present invention has carried out respectively the test that resveratrol and resveratrol analog derivative and the combination of Bcl-2 inhibitor kill DLD1 (colon cancer cell line), HUH-7 (hepatoma cell strain) and U251 (neuroglial cytoma strain), result shows, resveratrol of the present invention and resveratrol analog derivative and Bcl-2 inhibitor combined therapy colon cancer, hepatocarcinoma and glioma have significant cooperative effect, improved the curative effect of medicine, reduce dosage, reduced the generation of side effect.
The specific embodiment
The invention will be further elaborated with the following Examples, but the present invention is not limited to this.
Embodiment
Reagent and method:
Cell: DLD1 (colon cancer cell line), HUH-7 (hepatoma cell strain) and U251 (neuroglial cytoma strain) are all purchased from American Type Culture Collection (ATCC), Maryland, USA Rockwell.
Medicine: in following examples, institute's pharmaceutical composition is all prepared described in following method 1 or method 2; Resveratrol replaces this Ai Me institute of Chinese materia medica purchased from Nanjing; Bcl-2 inhibitor is all synthesized into by document, and ABT-263 and ABT-737 synthesized reference document are: Synthesis, 15,2398-2404, WO2005049594, WO2005049593 and US2007027135.
Method 1: accurately weigh each component of corresponding pharmaceutical composition, dissolve respectively with dimethyl sulfoxide, be made into separately the stock solution of 10mM, at-20 ℃, preserve, during use, by fresh culture medium, be diluted to suitable concentration, the solution of each component of 1 microlitre of then respectively asking for, mixes standby.In all tests, answer≤5g/L of the ultimate density of dimethyl sulfoxide, to do not affect the activity of cell.
By all cells in RPMI 1640 culture medium containing 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2damp condition under cultivate, in the previous day of dosing, on six orifice plates, carry out cell inoculation 2 * 10
5/ hole, then, to adding the medicinal composition solution of preparation as stated above in cell, makes each component reach its working concentration, specifically in Table 1-6 in 1.
After drug treating, by trypan blue (Trypan Blue), measure cell death, cell turns into 10 minutes by carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Because dead cell comes off and enters in culture medium from incubator, by all cells of centrifugal collection under 1200 revs/min, and then with culture medium Eddy diffusion precipitate, mix with trypan blue dyestuff.After dyeing, with optical microscope and hematimeter, count.By the dead cell of counting of dyes au bleu.Choose at random 500 cells and count, dead cell is recently expressed to account for the percentage of grand total cell.
Method 2: accurately weigh each component of corresponding pharmaceutical composition, dissolve respectively with dimethyl sulfoxide, be made into separately the stock solution of 10mM, preserve at-20 ℃.During use, by fresh culture medium, be diluted to suitable concentration, the solution for standby of each component of 1 microlitre of then respectively asking for.In all tests, answer≤5g/L of the ultimate density of dimethyl sulfoxide, to do not affect the activity of cell.
By all cells in RPMI 1640 culture medium containing 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2damp condition under cultivate, in the previous day of dosing, on six orifice plates, carry out cell inoculation 2 * 10
5/ hole, then with any order to adding each component solution of the pharmaceutical composition of preparation as stated above in cell, make each component reach its working concentration, specifically in Table 7-12 in 1.
After drug treating, by trypan blue (Trypan Blue), measure cell death, cell turns into 10 minutes by carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Because dead cell comes off and enters in culture medium from incubator, by all cells of centrifugal collection under 1200 revs/min, and then with culture medium Eddy diffusion precipitate, mix with trypan blue dyestuff.After dyeing, with optical microscope and hematimeter, count.By the dead cell of counting of dyes au bleu.Choose at random 500 cells and count, dead cell is recently expressed to account for the percentage of grand total cell.
In drug regimen shown in lower list 1, the combination of 1-6 is by method 1 preparation, and the combination of 7-12 is by method 2 preparations.
Table 1
The resveratrol of embodiment 1 different proportion and the combination Synergistic of ABT-263 promote the test of DLD1 cell death, in Table 2.
Table 2
At investigation related compound, cause in the test of colon cancer cell line DLD1 cell death, find almost acellular death when use 2.0 μ M ABT-263 separately or lower concentration, even if only have an appointment 20% cell death while using separately 100.0 μ M resveratrol; When both share under low concentration, (50.0 μ M resveratrol+1.5 μ M ABT-263) produces obvious synergism, causes 48% cancer cell death; When both share with the ratio of 100.0 μ M resveratrol+2.0 μ M ABT-263, produce more significant synergism, cause 68% cancer cell death.
The resveratrol of embodiment 2 different proportions and the combination Synergistic of ABT-737 promote the test of DLD1 cell death, in Table 3.
Table 3
Cause in the test of colon cancer cell line DLD1 cell death the cell death of the 15-20% that finds only to have an appointment investigating related compound when use 2.0 μ M ABT-737 separately or 100.0 μ M resveratrol; When both share under low concentration, (50.0 μ M resveratrol+1.5 μ M ABT-737) produces obvious synergism, causes 31% cancer cell death; When both share with the ratio of 100.0 μ M resveratrol+2.0 μ M ABT-737, produce more significant synergism, cause 55% cancer cell death.
The resveratrol of embodiment 3 different proportions and the combination Synergistic of ABT-263 promote the test of HUH-7 cell death, in Table 4.
Table 4
At investigation related compound, cause in the test of hepatoma cell strain HUH-7 cell death, 10% the cell death of finding only to have an appointment when use 2.0 μ M ABT-263 separately or lower concentration, while separately using 50.0 μ M resveratrol, almost there is no cell death, even if only have an appointment 25% cell death while using separately 100.0 μ M resveratrol; When both share under low concentration, (50.0 μ M resveratrol+1.5 μ M ABT-263) produces obvious synergism, causes 31% cancer cell death; When both share with the ratio of 100.0 μ M resveratrol+2.0 μ M ABT-263, produce more significant synergism, cause 86% cancer cell death.
The resveratrol of embodiment 4 different proportions and the combination Synergistic of ABT-263 promote the test of U251 cell death, in Table 5.
Table 5
Cause in the test of neuroglial cytoma strain U251 cell death 10% the cell death of finding only to have an appointment investigating related compound when use 1.5 μ M ABT-263 separately or 50.0 μ M resveratrol; The cell death of about 20-35% while using 2.0 μ M ABT-263 or 100.0 μ M resveratrol separately; When both share under low concentration, (50.0 μ M resveratrol+1.5 μ M ABT-263) produces obvious synergism, causes 44% cancer cell death; When both share with the ratio of 100.0 μ M resveratrol+2.0 μ M ABT-263, produce more significant synergism, cause 90% cancer cell death.
Although above-described embodiment describes in detail technical scheme of the present invention, but technical scheme of the present invention is not limited to above embodiment, in the situation that not departing from thought of the present invention and aim, any change that technical scheme of the present invention is done all will fall into claims limited range of the present invention.
Claims (3)
1. a pharmaceutical composition that is used for the treatment of cancer, is characterized in that, described pharmaceutical composition contains resveratrol and Bcl-2 inhibitor; Wherein, the mol ratio of described resveratrol and Bcl-2 inhibitor is 30.0-100.0:1.0-2.0; Described Bcl-2 inhibitor is ABT-263 or ABT-737; Described cancer is colon cancer, hepatocarcinoma or glioma.
2. pharmaceutical composition according to claim 1, is characterized in that, in being used for the treatment of colon cancer, hepatocarcinoma and gliomatous pharmaceutical composition, the mol ratio of described resveratrol and Bcl-2 inhibitor is 30.0-100.0:1.0-2.0.
3. pharmaceutical composition according to claim 2, is characterized in that, the mol ratio of described resveratrol and Bcl-2 inhibitor is 50.0-100.0:1.5-2.0.
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| CN104288156B (en) * | 2014-09-22 | 2017-01-18 | 新乡医学院 | Pharmaceutical composition for treating stomach cancer and application thereof |
| ES2954860T3 (en) * | 2014-10-24 | 2023-11-27 | Launx Biomedical Co Ltd | Use of azelnidipine in the preparation of a medicinal composition for the treatment of cancers |
| CN106967049B (en) | 2017-03-22 | 2018-06-26 | 杭州师范大学 | A kind of resveratrol line fluorescent mark molecule and its synthetic method |
| WO2019108773A1 (en) * | 2017-11-29 | 2019-06-06 | Stc.Unm | Substituted stilbenes as inhibitors of nf-kb and activators of nrf2 |
| IT201800007787A1 (en) * | 2018-08-02 | 2020-02-02 | Giampietro Ravagnan | Compositions comprising resveratrolosides and curcumins |
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| WO2010019914A2 (en) * | 2008-08-14 | 2010-02-18 | The Uab Research Foundation | Anti-arrhythmia agents, methods of their use, methods for their identification, and kits thereofre |
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| WO2010019914A2 (en) * | 2008-08-14 | 2010-02-18 | The Uab Research Foundation | Anti-arrhythmia agents, methods of their use, methods for their identification, and kits thereofre |
Non-Patent Citations (4)
| Title |
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| 白藜芦醇抗肿瘤作用机制的研究进展;陈卫琼等;《国际病理科学与临床杂志》;20081028(第05期);403-407 * |
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