CN102441168B - Medicine composition containing apigenin, apigenin derivant and Bc1-2 inhibitor and application thereof in preparation of medicines capable of treating cancer - Google Patents
Medicine composition containing apigenin, apigenin derivant and Bc1-2 inhibitor and application thereof in preparation of medicines capable of treating cancer Download PDFInfo
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Abstract
The invention relates to a medicine composition containing apigenin, apigenin derivant and Bc1-2 inhibitor and application thereof in the preparation of medicines capable of treating lung cancer, pancreatic cancer, colon cancer, liver cancer, prostatic cancer, renal carcinoma, gastric cancer, brain tumor, sarcoma, ovarian cancer, breast cancer or glioma. The medicine composition disclosed by the invention has the advantages that the synergy is obvious, the curative effect of the medicine is improved, the medicine dosage is lowered, and the side effects are reduced.
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 preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer, breast carcinoma or gliomatous medicine thereof that contain apigenin and apigenin 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; Sarcoma and cancer belong to malignant tumor together, and sarcoma derives from mesenchymal tissue, can betide any histoorgan, the multiple youngster of being born in, and grade malignancy is high, poor prognosis.At present operation is primary treatment method, and only the only a few sarcoma such as rhabdomyosarcoma, Ewing' s tumor, part osteosarcoma has outside good therapeutic effect, and all the other sarcoma curative effects are all undesirable; Pulmonary carcinoma is one of common malignant tumor, comes from bronchiolar epitheliums at different levels, is divided into small cell lung cancer and nonsmall-cell lung cancer; Breast carcinoma is relevant with the estrogen in human body.The morbidity of breast carcinoma, is closely related with patient's gene, living habit, Foods, bearing status etc., and the breast cancer incidence of different ethnic groups, region has obvious difference.Breast carcinoma has become the highest malignant tumor of global women's sickness rate, and along with the national economic development and living standards of the people improve, the M & M of Chinese Breast Cancer is all swift and violent rising situation; 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; Carcinoma of prostate is most important a kind of in male genitourinary system tumor, is the distinctive diseases of the mankind.Carcinoma of prostate is senile disease, mostly at 50 years old with sequela.Along with the prolongation of mankind's average life, the raising of diagnostic techniques, the change of life style, the sickness rate of carcinoma of prostate is in continuous rising, and the medicine of therefore studying carcinoma of prostate 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.
Apigenin is a kind of flavone compound, is extensively present in various fruits and vegetable, has the various biological effects such as antitumor, antioxidation and antiinflammatory.By pharmacological research, find in recent years, apigenin antitumor action is obvious, can grow by inhibition tumor cell, and inducing apoptosis of tumour cell, and can suppress tumor vessel formation, invasion and attack and shift, in addition, can also disturb the signal transduction path of tumor cell.Apigenin receives much concern in the application of anti-tumor aspect.
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 preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer, breast carcinoma or gliomatous medicine thereof, be specially the pharmaceutical composition that contains apigenin and apigenin analog derivative and Bcl-2 inhibitor and treat the application in pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer, breast carcinoma or gliomatous medicine in preparation.
In the pharmaceutical composition that the present invention contains apigenin and apigenin analog derivative and Bcl-2 inhibitor, described apigenin and apigenin analog derivative are apigenin; Described Bcl-2 inhibitor is ABT-263 or ABT-737, or both corresponding analogs, derivant.
Apigenin in pharmaceutical composition of the present invention and apigenin analog derivative are preferably apigenin, and its structural formula is suc as formula shown in I.
In pharmaceutical composition of the present invention, described component is not limited to apigenin 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 of the formula II that records in US2007027135:
Wherein ABT-737 is the compound of the formula III recorded 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 apigenin and apigenin analog derivative and Bcl-2 inhibitor, the mol ratio of apigenin and apigenin analog derivative and Bcl-2 inhibitor is 8.5-60.0: 0.15-6.0; Further the mol ratio of preferred described apigenin and apigenin analog derivative and Bcl-2 inhibitor is 17.5-30.0: 0.25-5.0.
The pharmaceutical composition that the present invention contains apigenin and apigenin analog derivative and Bcl-2 inhibitor can be used for the treatment of various tumors, and described tumor includes but not limited to pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer, breast carcinoma or glioma.
The pharmaceutical composition of preferably celery element of the present invention and apigenin analog derivative and Bcl-2 inhibitor is for the preparation of the application in the medicine of Hepatoma therapy, pulmonary carcinoma, carcinoma of prostate, colon cancer, sarcoma, glioma and breast carcinoma.
In the application of pharmaceutical composition of the present invention in preparing the medicine of Hepatoma therapy, the mol ratio of described apigenin and apigenin analog derivative and Bcl-2 inhibitor is 17.5-30.0: 0.35-1.5; The mol ratio of preferred described apigenin and apigenin analog derivative and Bcl-2 inhibitor is 20.0-30.0: 0.35-1.5.Wherein, in the application of medicine of preparing treatment HepG2 and HUH7 type hepatocarcinoma, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and apigenin analog derivative and ABT-263 is 20.0-30.0: 0.35-1.0; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-263 is 25.0-30.0: 0.75-1.0; The best mol ratio for described apigenin and apigenin analog derivative and ABT-263 is 30.0: 1.0; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and apigenin analog derivative and ABT-737 is 20.0-30.0: 0.75-1.5; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-737 is 25.0-30.0: 1.0-1.5; The best mol ratio for described apigenin and apigenin analog derivative and ABT-737 is 30.0: 1.5.In the application of medicine of preparing treatment PLC/PRF5 type hepatocarcinoma, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and apigenin analog derivative and ABT-263 is 17.5-25.0: 0.5-1.0; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-263 is 20.0-25.0: 0.75-1.0; The best mol ratio for described apigenin and apigenin analog derivative and ABT-263 is 25.0: 1.0; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and apigenin analog derivative and ABT-737 is 17.5-25.0: 0.75-1.5; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-737 is 20.0-25.0: 1.0-1.5; The best mol ratio for described apigenin and apigenin analog derivative and ABT-737 is 25.0: 1.5.
In the application of pharmaceutical composition of the present invention in the medicine of preparation treatment pulmonary carcinoma or carcinoma of prostate, the mol ratio of described apigenin and apigenin analog derivative and Bcl-2 inhibitor is 20.0-30.0: 0.35-1.5.Wherein, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and apigenin analog derivative and ABT-263 is 20.0-30.0: 0.35-1.0; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-263 is 25.0-30.0: 0.75-1.0; The best mol ratio for described apigenin and apigenin analog derivative and ABT-263 is 30.0: 1.0; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and apigenin analog derivative and ABT-737 is 20.0-30.0: 0.75-1.5; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-737 is 25.0-30.0: 1.0-1.5; The best mol ratio for described apigenin and apigenin analog derivative and ABT-737 is 30.0: 1.5.
In the application of pharmaceutical composition of the present invention in the medicine of preparation treatment colon cancer or sarcoma, the mol ratio of described apigenin and apigenin analog derivative and Bcl-2 inhibitor is 20.0-30.0: 1.0-3.0.Wherein, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and apigenin analog derivative and ABT-263 is 20.0-30.0: 1.0-2.0; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-263 is 25.0-30.0: 1.5-2.0; The best mol ratio for described apigenin and apigenin analog derivative and ABT-263 is 30.0: 2.0; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and apigenin analog derivative and ABT-737 is 20.0-30.0: 1.0-3.0; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-737 is 25.0-30.0: 2.0-3.0; The best mol ratio for described apigenin and apigenin analog derivative and ABT-737 is 30.0: 3.0.
In the application of pharmaceutical composition of the present invention in the gliomatous medicine of preparation treatment, the mol ratio of described apigenin and apigenin analog derivative and Bcl-2 inhibitor is 20.0-30.0: 0.25-1.0.Wherein, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and apigenin analog derivative and ABT-263 is 20.0-30.0: 0.25-0.75; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-263 is 25.0-30.0: 0.5-0.75; The best mol ratio for described apigenin and apigenin analog derivative and ABT-263 is 30.0: 0.75; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and apigenin analog derivative and ABT-737 is 20.0-30.0: 0.5-1.0; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-737 is 25.0-30.0: 0.75-1.0; The best mol ratio for described apigenin and apigenin analog derivative and ABT-737 is 30.0: 1.0.
In the application of pharmaceutical composition of the present invention in the medicine of preparation treatment breast carcinoma, the mol ratio of described apigenin and apigenin analog derivative and Bcl-2 inhibitor is 20.0-30.0: 1.0-5.0.Wherein, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and apigenin analog derivative and ABT-263 is 20.0-30.0: 1.0-3.0; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-263 is 25.0-30.0: 2.0-3.0; The best mol ratio for described apigenin and apigenin analog derivative and ABT-263 is 30.0: 3.0; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and apigenin analog derivative and ABT-737 is 20.0-30.0: 1.0-5.0; Further the mol ratio of preferred described apigenin and apigenin analog derivative and ABT-737 is 25.0-30.0: 3.0-5.0; The best mol ratio for described apigenin and apigenin analog derivative and ABT-737 is 30.0: 5.0.
The pharmaceutical composition that contains apigenin and apigenin analog derivative and Bcl-2 inhibitor is in preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer, in the application of breast carcinoma or gliomatous medicine, in the scheme of medicament of the present composition being made to administration simultaneously, Bcl-2 inhibitor and apigenin and apigenin analog derivative can be contained in same pharmaceutical preparation as in tablet or capsule, also Bcl-2 inhibitor and apigenin and apigenin analog derivative 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, Bcl-2 inhibitor and apigenin and apigenin analog derivative 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, Bcl-2 inhibitor and apigenin and apigenin analog derivative 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 Bcl-2 inhibitor and apigenin and apigenin analog derivative intersection discharge.
In the application of the pharmaceutical composition of apigenin and apigenin analog derivative and Bcl-2 inhibitor in preparation treatment pulmonary carcinoma, cancer of pancreas, colon cancer, hepatocarcinoma, carcinoma of prostate, renal carcinoma, gastric cancer, cerebroma, sarcoma, ovarian cancer, breast carcinoma or gliomatous medicine, Bcl-2 inhibitor in described compositions and apigenin and apigenin analog derivative can be used or with the using in order of any priority simultaneously, as Bcl-2 inhibitor and apigenin and apigenin analog derivative can taken to patient simultaneously; Also can first apigenin and apigenin analog derivative be taken, then be taken to Bcl-2 inhibitor medicaments to patient, or first take apigenin and apigenin analog derivative, then take Bcl-2 inhibitor medicaments, 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 Bcl-2 inhibitor of the present invention and apigenin and apigenin analog derivative 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 Bcl-2 inhibitor and apigenin and apigenin analog derivative, its dosage form can be conventional tablet or capsule or controlled release, slow releasing preparation.In the pharmaceutical preparation of Bcl-2 inhibitor of the present invention and apigenin and apigenin analog derivative compositions, 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 does not have any restriction, Bcl-2 inhibitor and apigenin and apigenin analog derivative 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 apigenin and apigenin analog derivative and the combination of Bcl-2 inhibitor and has killed HepG2, HUH7 and PLC/PRF5 (hepatoma cell strain), A549 (lung cancer cell line), LNCaP (Prostatic cancer cell lines), DLD1 (colon cancer cell line), U2-OS (sarcoma cell strain), the test of D37 (neuroglial cytoma strain) and MDA-MB-468 (breast carcinoma cell strain), results suggest, apigenin of the present invention and apigenin analog derivative and Bcl-2 inhibitor combined therapy hepatocarcinoma, pulmonary carcinoma, carcinoma of prostate, colon cancer, sarcoma, glioma and breast carcinoma have significant cooperative effect, improved the curative effect of medicine, reduced 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: HepG2, HUH7 and PLC/PRF5 (hepatoma cell strain), A549 (lung cancer cell line), LNCaP (Prostatic cancer cell lines), DLD1 (colon cancer cell line), U2-OS (sarcoma cell strain), D37 (neuroglial cytoma strain) and MDA-MB-468 (breast carcinoma cell strain), all purchased from American Type Culture Collection (ATCC), Rockville, MD, USA.
Medicine: in following examples, institute's pharmaceutical composition is all prepared described in following method 1 or method 2; 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; Apigenin is purchased from Nanjing Zelang Pharmaceutical Technology Inc..
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 in 1-30.
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 in 31-54.
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 1-30 is by method 1 preparation, and the combination of 31-54 is by method 2 preparations.
Table 1
The ABT-263 of embodiment 1 different proportion and the combination Synergistic of apigenin promote the test of HepG2 cell death, in Table 2.
Table 2
At investigation related compound, cause in the test of hepatoma cell strain HepG2 cell death, finding, when using 30.0 μ M apigenins or lower concentration, 1.0 μ M ABT-263 or lower concentration separately, does not almost have cancer cell death; When both when low concentration share (25.0 μ M apigenin+0.75 μ M ABT-263) produce obvious synergism, cause 52% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+1.0 μ M ABT-263, produce more significant synergism, cause 82% cancer cell death.
The ABT-737 of embodiment 2 different proportions and the combination Synergistic of apigenin promote the test of HepG2 cell death, in Table 3.
Table 3
At investigation related compound, cause in the test of hepatoma cell strain HepG2 cell death, finding, when using 30.0 μ M apigenins or lower concentration, 1.5 μ M ABT-737 or lower concentration separately, does not almost have cancer cell death; When both when low concentration share (25.0 μ M apigenin+1.0 μ M ABT-737) produce obvious synergism, cause 46% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+1.5 μ M ABT-737, produce more significant synergism, cause 79% cancer cell death.
The ABT-263 of embodiment 3 different proportions and the combination Synergistic of apigenin promote the test of HUH7 cell death, in Table 4.
Table 4
At investigation related compound, cause in the test of hepatoma cell strain HUH7 cell death, finding, when using 25.0 μ M apigenins or lower concentration, 1.0 μ M ABT-263 or lower concentration separately, does not almost have cancer cell death; Even while using separately 30.0 μ M apigenin, only have 13% cancer cell death; When both when low concentration share (25.0 μ M apigenin+0.75 μ M ABT-263) produce very significantly synergism, cause 82% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+1.0 μ M ABT-263, produce more significant synergism, cause 99% cancer cell death.
The ABT-737 of embodiment 4 different proportions and the combination Synergistic of apigenin promote the test of HUH7 cell death, in Table 5.
Table 5
At investigation related compound, cause in the test of hepatoma cell strain HUH7 cell death, finding, when using 25.0 μ M apigenins or lower concentration, 1.5 μ M ABT-737 or lower concentration separately, does not almost have cancer cell death; Even while using separately 30.0 μ M apigenin, only have 13% cancer cell death; When both when low concentration share (25.0 μ M apigenin+1.0 μ M ABT-737) produce very significantly synergism, cause 74% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+1.5 μ M ABT-737, produce more significant synergism, cause 99% cancer cell death.
The ABT-263 of embodiment 5 different proportions and the combination Synergistic of apigenin promote the test of PLC/PRF5 cell death, in Table 6.
Table 6
At investigation related compound, cause in the test of hepatoma cell strain PLC/PRF5 cell death, find when using 25.0 μ M apigenins or 1.0 μ M ABT-263 separately nearly 30% cancer cell death; When both share under low concentration, (20.0 μ M apigenin+0.75 μ M ABT-263) produces obvious synergism, causes 68% cancer cell death; When both share with the ratio of 25.0 μ M apigenin+1.0 μ M ABT-263, produce more significant synergism, cause 84% cancer cell death.
The ABT-737 of embodiment 6 different proportions and the combination Synergistic of apigenin promote the test of PLC/PRF5 cell death, in Table 7.
Table 7
At investigation related compound, cause in the test of hepatoma cell strain PLC/PRF5 cell death, find when using 25.0 μ M apigenins or 1.5 μ M ABT-737 separately nearly 30% cancer cell death; When both share under low concentration, (20.0 μ M apigenin+1.0 μ M ABT-737) produces obvious synergism, causes 67% cancer cell death; When both share with the ratio of 25.0 μ M apigenin+1.5 μ M ABT-737, produce more significant synergism, cause 85% cancer cell death.
The ABT-263 of embodiment 7 different proportions and the combination Synergistic of apigenin promote the test of A549 cell death, in Table 8.
Table 8
Cause in the test of lung cancer cell line A549 cell death investigating related compound, find almost there is no cancer cell death when use 30.0 μ M apigenins separately or lower concentration, 20% the cell death of also only having an appointment while using 1.0 μ M ABT-263 separately; When both share under low concentration, (25.0 μ M apigenin+0.75 μ M ABT-263) produces obvious synergism, causes approximately 69% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+1.0 μ M ABT-263, produce more significant synergism, cause 89% cancer cell death.
The ABT-737 of embodiment 8 different proportions and the combination Synergistic of apigenin promote the test of A549 cell death, in Table 9.
Table 9
Cause in the test of lung cancer cell line A549 cell death investigating related compound, find almost there is no cancer cell death when use 30.0 μ M apigenins separately or lower concentration, 15% the cell death of only having an appointment while using 1.5 μ M ABT-737 separately; When both when low concentration share (25.0 μ M apigenin+1.0 μ M ABT-737) produce obvious synergism, cause 72% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+1.5 μ M ABT-737, produce more significant synergism, cause 93% cancer cell death.
The ABT-263 of embodiment 9 different proportions and the combination Synergistic of apigenin promote the test of LNCaP cell death, in Table 10.
Table 10
Cause in the test of Prostatic cancer cell lines LNCaP cell death investigating related compound, find when use 30.0 μ M apigenins separately only have an appointment 20% cancer cell death, 10% the cell death of only having an appointment while using 1.0 μ MABT-263 separately; When both when low concentration share (25.0 μ M apigenin+0.75 μ M ABT-263) produce obvious synergism, cause 57% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+1.0 μ M ABT-263, produce more significant synergism, cause 88% cancer cell death.
The ABT-737 of embodiment 10 different proportions and the combination Synergistic of apigenin promote the test of LNCaP cell death, in Table 11.
Table 11
Cause in the test of Prostatic cancer cell lines LNCaP cell death investigating related compound, find when use 30.0 μ M apigenins separately only have an appointment 20% cancer cell death, be only no more than 15% cancer cell death while using 1.5 μ MABT-737 separately; When both when low concentration share (25.0 μ M apigenin+1.0 μ M ABT-737) produce obvious synergism, cause 56% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+1.5 μ M ABT-737, produce more significant synergism, cause 85% cancer cell death.
The ABT-263 of embodiment 11 different proportions and the combination Synergistic of apigenin promote the test of DLD1 cell death, in Table 12.
Table 12
Cause in the test of colon cancer cell line DLD1 cell death investigating related compound, find when use 30.0 μ M apigenins separately only have an appointment 20% cancer cell death, almost there is no cancer cell death while using 2.0 μ MABT-263 or lower concentration separately; When both when low concentration share (25.0 μ M apigenin+1.5 μ M ABT-263) produce obvious synergism, cause 62% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+2.0 μ M ABT-263, produce more significant synergism, cause 94% cancer cell death.
The ABT-737 of embodiment 12 different proportions and the combination Synergistic of apigenin promote the test of DLD1 cell death, in Table 13.
Table 13
Cause in the test of colon cancer cell line DLD1 cell death investigating related compound, find when use 30.0 μ M apigenins separately only have an appointment 20% cancer cell death, almost there is no cancer cell death while using 3.0 μ MABT-737 or lower concentration separately; When both when low concentration share (25.0 μ M apigenin+2.0 μ M ABT-737) produce obvious synergism, cause 51% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+3.0 μ M ABT-737, produce more significant synergism, cause 82% cancer cell death.
The ABT-263 of embodiment 13 different proportions and the combination Synergistic of apigenin promote the test of U2-OS cell death, in Table 14.
Table 14
Cause in the test of sarcoma cell strain U2-OS cell death investigating related compound, find when use separately 30.0 μ M apigenins only have an appointment 25% cancer cell death, use only have an appointment 10% cancer cell death of 2.0 μ MABT-263 separately; When both when low concentration share (25.0 μ M apigenin+1.5 μ M ABT-263) produce obvious synergism, cause 57% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+2.0 μ M ABT-263, produce more significant synergism, cause 91% cancer cell death.
The ABT-737 of embodiment 14 different proportions and the combination Synergistic of apigenin promote the test of U2-OS cell death, in Table 15.
Table 15
Cause in the test of sarcoma cell strain U2-OS cell death investigating related compound, find when use separately 30.0 μ M apigenins only have an appointment 25% cancer cell death, use only have an appointment 15% cancer cell death of 3.0 μ MABT-737 separately; When both when low concentration share (25.0 μ M apigenin+2.0 μ M ABT-737) produce obvious synergism, cause 49% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+3.0 μ M ABT-737, produce more significant synergism, cause 84% cancer cell death.
The ABT-263 of embodiment 15 different proportions and the combination Synergistic of apigenin promote the test of D37 cell death, in Table 16.
Table 16
Cause in the test of neuroglial cytoma strain D37 cell death investigating related compound, find when use 30.0 μ M apigenins separately or lower concentration, almost there is no cancer cell death, use separately only have an appointment 20% cancer cell death of 0.75 μ M ABT-263; When both when low concentration share (25.0 μ M apigenin+0.5 μ M ABT-263) produce obvious synergism, cause 50% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+0.75 μ M ABT-263, produce more significant synergism, cause 90% cancer cell death.
The ABT-737 of embodiment 16 different proportions and the combination Synergistic of apigenin promote the test of D37 cell death, in Table 17.
Table 17
Cause in the test of neuroglial cytoma strain D37 cell death investigating related compound, find when use 30.0 μ M apigenins separately or lower concentration, almost there is no cancer cell death, use separately only have an appointment 20% cancer cell death of 1.0 μ M ABT-737; When both share under low concentration, (25.0 μ M apigenin+0.75 μ M ABT-737) produces obvious synergism, causes 52% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+1.0 μ M ABT-737, produce more significant synergism, cause 82% cancer cell death.
The ABT-263 of embodiment 17 different proportions and the combination Synergistic of apigenin promote the test of MDA-MB-468 cell death, in Table 18.
Table 18
Cause in the test of breast carcinoma cell strain MDA-MB-468 cell death investigating related compound, find when use separately 30.0 μ M apigenins only have an appointment 20% cancer cell death, use only have an appointment 15% cancer cell death of 3.0 μ M ABT-263 separately; When both when low concentration share (25.0 μ M apigenin+2.0 μ M ABT-263) produce obvious synergism, cause 46% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+3.0 μ M ABT-263, produce more significant synergism, cause 81% cancer cell death.
The ABT-737 of embodiment 18 different proportions and the combination Synergistic of apigenin promote the test of MDA-MB-468 cell death, in Table 19.
Table 19
Cause in the test of breast carcinoma cell strain MDA-MB-468 cell death investigating related compound, find when use separately 30.0 μ M apigenins only have an appointment 20% cancer cell death, use only have an appointment 15% cancer cell death of 5.0 μ M ABT-737 separately; When both when low concentration share (25.0 μ M apigenin+3.0 μ M ABT-737) produce obvious synergism, cause 41% cancer cell death; When both share with the ratio of 30.0 μ M apigenin+5.0 μ M ABT-737, produce more significant synergism, cause 79% 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 (9)
1. a pharmaceutical composition that is used for the treatment of cancer, is characterized in that, said composition contains apigenin and Bcl-2 inhibitor, and the mol ratio of described apigenin and Bcl-2 inhibitor is 17.5-30.0:0.25-5.0; Described Bcl-2 inhibitor is ABT-263 or ABT-737;
Described cancer is pulmonary carcinoma, colon cancer, hepatocarcinoma, carcinoma of prostate, sarcoma, breast carcinoma or glioma;
Wherein, in being used for the treatment of the pharmaceutical composition of hepatocarcinoma, the mol ratio of described apigenin and Bcl-2 inhibitor is 20.0-30.0:0.35-1.5;
When described hepatocarcinoma is PLC/PRF5 type hepatocarcinoma, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and ABT-263 is 20.0-25.0:0.75-1.0; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and ABT-737 is 20.0-25.0:1.0-1.5;
In being used for the treatment of the pharmaceutical composition of breast carcinoma, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and ABT-263 is 25.0-30.0:2.0-3.0; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and ABT-737 is 25.0-30.0:3.0-5.0.
2. pharmaceutical composition according to claim 1, is characterized in that, when described hepatocarcinoma is HepG2 or HUH7 type hepatocarcinoma, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and ABT-263 is 25.0-30.0:0.75-1.0; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and ABT-737 is 25.0-30.0:1.0-1.5.
3. pharmaceutical composition according to claim 1, is characterized in that, in being used for the treatment of the pharmaceutical composition of pulmonary carcinoma, carcinoma of prostate, the mol ratio of described apigenin and Bcl-2 inhibitor is 20.0-30.0:0.35-1.5.
4. pharmaceutical composition according to claim 3, it is characterized in that, in being used for the treatment of the pharmaceutical composition of pulmonary carcinoma, carcinoma of prostate, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and ABT-263 is 25.0-30.0:0.75-1.0; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and ABT-737 is 25.0-30.0:1.0-1.5.
5. pharmaceutical composition according to claim 1, is characterized in that, in being used for the treatment of the pharmaceutical composition of colon cancer, sarcoma, the mol ratio of described apigenin and Bcl-2 inhibitor is 20.0-30.0:1.0-3.0.
6. pharmaceutical composition according to claim 5, is characterized in that, in being used for the treatment of the pharmaceutical composition of colon cancer, sarcoma, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and ABT-263 is 25.0-30.0:1.5-2.0; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and ABT-737 is 25.0-30.0:2.0-3.0.
7. pharmaceutical composition according to claim 1, is characterized in that, in being used for the treatment of gliomatous pharmaceutical composition, the mol ratio of described apigenin and Bcl-2 inhibitor is 20.0-30.0:0.25-1.0.
8. pharmaceutical composition according to claim 7, is characterized in that, in being used for the treatment of gliomatous pharmaceutical composition, when described Bcl-2 inhibitor is ABT-263, the mol ratio of described apigenin and ABT-263 is 25.0-30.0:0.5-0.75; When described Bcl-2 inhibitor is ABT-737, the mol ratio of described apigenin and ABT-737 is 25.0-30.0:0.75-1.0.
9. pharmaceutical composition according to claim 1, is characterized in that, the apigenin in described pharmaceutical composition and Bcl-2 inhibitor are used or using in order with any priority simultaneously.
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| US20160158189A1 (en) * | 2013-07-17 | 2016-06-09 | Deutsches Krebsforschungszentrum | Sensitization of cancer cells to apoptosis induction by flavaglines and 5-hydroxy-flavones |
| CN115381810A (en) * | 2021-05-25 | 2022-11-25 | 中南大学 | Application of apigenin derivative in preparation of anti-renal cancer drugs |
| WO2023105103A1 (en) | 2022-06-17 | 2023-06-15 | Mesoestetic Pharma Group, S.L | Synergistic skin depigmenting cosmetic composition |
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