CN102441167A - Pharmaceutical composition having apiolin and apiolin derivant as well as histone deaceylase inhibitors and application thereof - Google Patents
Pharmaceutical composition having apiolin and apiolin derivant as well as histone deaceylase inhibitors and application thereof Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition having apiolin and apiolin derivant as well as histone deaceylase inhibitors and an application in treating lung cancer, pancreatic cancer, colon cancer, liver cancer, prostatic cancer, kidney cancer, gastric cancer, brain tumor, sarcoma, ovarian cancer, breast cancer or glioma. The pharmaceutical composition provided by the invention has obvious synergistic effect, which improves the curative effect of medicine, reduces the dosage and also reduces the risk of side effect.
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 contain 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 of apigenin and apigenin analog derivative and Antibiotic FR 901228.
Background technology
World Health Organization's investigation report shows that global cancer condition is serious day by day, and 20 years from now on new patients' number will be increased to 1,500 ten thousand by present every year 1000 ten thousand, because of the number that cancer is dead also will be by increasing to 1,000 ten thousand 6,000,000 of every year.Primary hepatocarcinoma is one of human modal malignant tumor for occurring in the epithelial canceration of hepatocyte and stones in intrahepatic bile duct; 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; The cancer of pancreas pilosity is born in head of pancreas portion, and 90% derives from the ductus pancreaticus epithelial cell, and all the other are the digestive system common malignancy from pancreatic acini; Pulmonary carcinoma is one of common malignancy, comes from bronchiolar epitheliums at different levels, is divided into small cell lung cancer and nonsmall-cell lung cancer; Glioma is to originate from neurogliocyte, betides neuroectodermal tumor, and its principal character is the growth of tumor cell diffuse infiltrating, does not have clear and definite border, infinite multiplication and have the height aggressive.Although the neurosurgery skill is constantly perfect in recent years, radiotherapy is accurately located and the continuous research and development of chemotherapeutics, glioma patient more after still barely satisfactory; Carcinoma of prostate is most important a kind of in the male genitourinary system tumor, is human distinctive disease.Carcinoma of prostate is a senile disease, mostly at 50 years old with sequela.Along with the prolongation of human average life, the raising of diagnostic techniques and the change of life style, the sickness rate of carcinoma of prostate is in continuous rising, and it is extremely urgent therefore to study the treatment of prostate cancer medicine.
The antitumor drug that has gone on the market at present is more, and like alkylating agent medicine, antimetabolite, AGPM, immunomodulator etc., but medicine is because toxicity is bigger mostly, and patient does not tolerate.Lots of clinical facts have proved that malignant tumor can be effectively treated in the Chinese medicine or the combination of Chinese and Western medicine, can alleviate the toxic and side effects of chemicotherapy simultaneously.Utilization modern medicine means find that some bioactive natural products can effectively suppress the growth of tumor cell, have the effect of cell death inducing.Numerous antibiotic and the antitumor drug that uses at present or be directed to natural product, or get through its structure of modification.Therefore, safe bioactive natural product applies to clinically will have broad prospects with the treatment cancer.Along with the Study on Molecular Mechanism to the incidence and development of tumor is more and more clearer, the multiple malignant tumor of molecular targeted treatment has received to be paid close attention to widely and pays much attention to.The molecular targeted agents selectivity is high, wide spectrum is effective, and its safety is superior to the cytotoxicity chemotherapeutics, is the new direction of present oncotherapy field development.
Apigenin is a kind of flavone compound, extensively is present in the multiple fruits and vegetables, has various biological effects such as antitumor, antioxidation and antiinflammatory.Pass through pharmacological research in recent years and find that the apigenin antitumor action is obvious, can suppress growth of tumour cell, inducing apoptosis of tumour cell, and can suppress tumor vessel formation, invasion and attack and transfer, in addition, go back the signal transduction path of interfere tumor cell.Apigenin receives much concern in the application of anti-tumor aspect.
Antibiotic FR 901228 has the tumor cell proliferation of inhibition, cell cycle arrest, inducing cell differentiation and promotes apoptotic effect.Wherein SAHA goes on the market, and MS-275, LBH589, Trichostatin (TSA), FK228 and west reach multiple Antibiotic FR 901228 entering clinical researches such as aniline in addition.
Along with the progress of oncomolecularbiology, the molecular targeted treatment of tumor has become the focus of tumor research, in the treatment of kinds of tumors, has brought into play important effect.Yet the biological behaviour of most of tumor is not to be arranged by single signal transduction pathway, but a plurality of signal transduction pathway concurs, and Chinese medicine receives publicity with the effect advantage of the many target spots of its polygenes just day by day.Therefore reasonable joint medication; Has the incomparable superiority of single medicament; Drug combination carries out targeted therapy to many target spots will not only be intended to minimizing or delay chemical sproof appearance, reduction toxicity, and through multiple medicine the synergism that cancerous cell kills and wounds obtained better therapeutic.
Summary of the invention
To above technological deficiency; The present 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, is specially the application of pharmaceutical composition 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 that contains apigenin and apigenin analog derivative and Antibiotic FR 901228.
The present invention contains in the pharmaceutical composition of apigenin and apigenin analog derivative and Antibiotic FR 901228, and said apigenin and apigenin analog derivative are preferably apigenin, and its structural formula is formula I as follows.
In the pharmaceutical composition of the present invention, said component is not limited to apigenin itself, can also be its pharmaceutically useful salt, hydrate or derivant etc.
Among the present invention; Said Antibiotic FR 901228 can be the Antibiotic FR 901228 of any structure type; Like hydroximic acid, cyclic peptide, benzamides, fatty acid etc.; Specifically can for but be not limited to as, suberoylanilide hydroxamic acid (SAHA), Trichostatin (TSA), LBH589, MS-275, depsipeptide (FK228), aphidicolin (apicidin/aphacidin), depsipeptides, west reach aniline, sodium butyrate, phenylbutyrate sodium.
Antibiotic FR 901228 is preferably SAHA, LBH589 and MS-275 in the pharmaceutical composition of the present invention.
Wherein SAHA is JMC, 38,8,1995, and 1411-1413 and JMC, 48,15,2005, the chemical compound of the formula II that is put down in writing among the 5047-5051:
Wherein LBH-589 is by Novartis company research and development, and commodity are called panobinstat, and it is clinical to be in the II phase, and its structural formula is shown in the formula III:
Wherein MS-275 is the formula IV chemical compound of being put down in writing among the EP0847992:
In the pharmaceutical composition of the present invention, said component is not limited to said medicine itself, can also be the salt of their hydrate, analog, derivant and other organic or inorganic.
The present invention contains in the pharmaceutical composition of apigenin and apigenin analog derivative and Antibiotic FR 901228, and the mol ratio of apigenin and apigenin analog derivative and Antibiotic FR 901228 is 7.5-70.0: 0.005-7.0; Further the mol ratio of preferred said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 15.0-35.0: 0.01-3.5.
The pharmaceutical composition that the present invention contains apigenin and apigenin analog derivative and Antibiotic FR 901228 can be used to treat various tumors, and said 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 Antibiotic FR 901228 is used for preparing the application of the medicine of treating hepatocarcinoma, pulmonary carcinoma, carcinoma of prostate, colon cancer, glioma and cancer of pancreas.
In the application of pharmaceutical composition of the present invention in the medicine of preparation treatment hepatocarcinoma or colon cancer, the mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 20.0-35.0: 0.02-3.5.Wherein, when said Antibiotic FR 901228 was SAHA, the mol ratio of said apigenin and apigenin analog derivative and SAHA was 20.0-35.0: 1.5-3.5; Further the mol ratio of preferred said apigenin and apigenin analog derivative and SAHA is 25.0-35.0: 2.5-3.5; Best mol ratio for said apigenin and apigenin analog derivative and SAHA is 35.0: 3.5.Wherein, when said Antibiotic FR 901228 was LBH589, the mol ratio of said apigenin and apigenin analog derivative and LBH589 was 20.0-35.0: 0.02-0.03; Further the mol ratio of preferred said apigenin and apigenin analog derivative and LBH589 is 25.0-35.0: 0.025-0.03; Best mol ratio for said apigenin and apigenin analog derivative and LBH589 is 35.0: 0.03.Wherein, when said Antibiotic FR 901228 was MS-275, the mol ratio of said apigenin and apigenin analog derivative and MS-275 was 20.0-35.0: 0.25-1.0; Further the mol ratio of preferred said apigenin and apigenin analog derivative and MS-275 is 25.0-35.0: 0.5-1.0; Best mol ratio for said apigenin and apigenin analog derivative and MS-275 is 35.0: 1.0.
In the application of pharmaceutical composition of the present invention in the medicine of preparation treatment carcinoma of prostate, the mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 15.0-25.0: 0.02-2.5.Wherein, when said Antibiotic FR 901228 was SAHA, the mol ratio of said apigenin and apigenin analog derivative and SAHA was 15.0-25.0: 1.5-2.5; Further the mol ratio of preferred said apigenin and apigenin analog derivative and SAHA is 20.0-25.0: 2.0-2.5; Best mol ratio for said apigenin and apigenin analog derivative and SAHA is 25.0: 2.5.Wherein, when said Antibiotic FR 901228 was LBH589, the mol ratio of said apigenin and apigenin analog derivative and LBH589 was 15.0-25.0: 0.02-0.03; Further the mol ratio of preferred said apigenin and apigenin analog derivative and LBH589 is 20.0-25.0: 0.025-0.03; Best mol ratio for said apigenin and apigenin analog derivative and LBH589 is 25.0: 0.03.Wherein, when said Antibiotic FR 901228 was MS-275, the mol ratio of said apigenin and apigenin analog derivative and MS-275 was 15.0-25.0: 0.25-1.0; Further the mol ratio of preferred said apigenin and apigenin analog derivative and MS-275 is 20.0-25.0: 0.5-1.0; Best mol ratio for said apigenin and apigenin analog derivative and MS-275 is 25.0: 1.0.
In the application of pharmaceutical composition of the present invention in the gliomatous medicine of preparation treatment, the mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 20.0-35.0: 0.01-2.5.Wherein, when said Antibiotic FR 901228 was SAHA, the mol ratio of said apigenin and apigenin analog derivative and SAHA was 20.0-35.0: 1.5-2.5; Further the mol ratio of preferred said apigenin and apigenin analog derivative and SAHA is 25.0-35.0: 2.0-2.5; Best mol ratio for said apigenin and apigenin analog derivative and SAHA is 35.0: 2.5.Wherein, when said Antibiotic FR 901228 was LBH589, the mol ratio of said apigenin and apigenin analog derivative and LBH589 was 20.0-35.0: 0.01-0.02; Further the mol ratio of preferred said apigenin and apigenin analog derivative and LBH589 is 25.0-35.0: 0.015-0.02; Best mol ratio for said apigenin and apigenin analog derivative and LBH589 is 35.0: 0.02.
In the application of pharmaceutical composition of the present invention in the medicine of preparation treatment cancer of pancreas, the mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 15.0-25.0: 0.02-3.5.Wherein, when said Antibiotic FR 901228 was SAHA, the mol ratio of said apigenin and apigenin analog derivative and SAHA was 15.0-25.0: 1.5-3.5; Further the mol ratio of preferred said apigenin and apigenin analog derivative and SAHA is 20.0-25.0: 2.5-3.5; Best mol ratio for said apigenin and apigenin analog derivative and SAHA is 25.0: 3.5.Wherein, when said Antibiotic FR 901228 was LBH589, the mol ratio of said apigenin and apigenin analog derivative and LBH589 was 15.0-25.0: 0.02-0.03; Further the mol ratio of preferred said apigenin and apigenin analog derivative and LBH589 is 20.0-25.0: 0.025-0.03; Best mol ratio for said apigenin and apigenin analog derivative and LBH589 is 25.0: 0.03.
In the application of pharmaceutical composition of the present invention in preparation treatment lung cancer drugs, the mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 20.0-30.0: 0.015-2.5.Wherein, when said Antibiotic FR 901228 was SAHA, the mol ratio of said apigenin and apigenin analog derivative and SAHA was 20.0-30.0: 1.5-2.5; Further the mol ratio of preferred said apigenin and apigenin analog derivative and SAHA is 25.0-30.0: 2.0-2.5; Best mol ratio for said apigenin and apigenin analog derivative and SAHA is 30.0: 2.5.Wherein, when said Antibiotic FR 901228 was LBH589, the mol ratio of said apigenin and apigenin analog derivative and LBH589 was 20.0-30.0: 0.015-0.025; Further the mol ratio of preferred said apigenin and apigenin analog derivative and LBH589 is 25.0-30.0: 0.02-0.025; Best mol ratio for said apigenin and apigenin analog derivative and LBH589 is 30.0: 0.025.
The pharmaceutical composition that contains apigenin and apigenin analog derivative and Antibiotic FR 901228 is in the application of 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; In the scheme of the medicament of the present composition being processed administration simultaneously; Antibiotic FR 901228 and apigenin and apigenin analog derivative can be contained in in a kind of pharmaceutical preparation such as tablet or the capsule; Also can Antibiotic FR 901228 and apigenin and apigenin analog derivative be made preparation respectively; As make tablet or capsule respectively; And adopting the conventional mode in this area with their packings or combine, the patient takes according to the indication of package insert then simultaneously; In the scheme of the medicament of the present composition being processed administration successively; Can Antibiotic FR 901228 be made different preparations respectively with apigenin and apigenin analog derivative; And adopt the conventional mode in this area with their packings or combine; The patient takes according to the sequencing of package insert indication then; Or two kinds of compositions in the above-mentioned composition are processed a kind of preparation of controlled release, and a kind of composition in the first release composition and then the another kind of composition in the release composition, the patient only need take this controlled release composition preparation; In the scheme of the medicament that the present composition is prepared into the intersection administration; Can Antibiotic FR 901228 be made different preparations respectively with apigenin and apigenin analog derivative; And adopt the conventional mode in this area with their packings or combine; The patient takes according to the chi sequence of package insert indication then, the controlled release preparation that perhaps becomes Antibiotic FR 901228 and apigenin and apigenin analog derivative intersection to discharge this preparation of pharmaceutical compositions.
In the application of the pharmaceutical composition of apigenin and apigenin analog derivative and Antibiotic FR 901228 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; Antibiotic FR 901228 in the said compositions and apigenin and apigenin analog derivative can use or with the using in order of any priority simultaneously, as can Antibiotic FR 901228 and apigenin and apigenin analog derivative being taken to the patient simultaneously; Also can earlier apigenin and apigenin analog derivative taken, taken then to the Antibiotic FR 901228 medicine to the patient; Or take apigenin and apigenin analog derivative earlier, take the Antibiotic FR 901228 medicine then; The interval of taking for both does not have special demands, but the interval of preferably taking two kinds of medicines is no more than one day; Perhaps two kinds of medicines replace administration.
Among the present invention; Can Antibiotic FR 901228 of the present invention and the conventional method of apigenin and apigenin analog derivative employing this area be prepared into the pharmaceutical preparation that is suitable for gastrointestinal administration or parenteral administration; The pharmaceutical preparation that the present invention preferably processes gastrointestinal administration with Antibiotic FR 901228 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 Antibiotic FR 901228 of the present invention and apigenin and apigenin analog derivative compositions; According to different dosage forms and preparation specification; The content of said compositions in preparation can be counted 1-99% for quality, is preferably 10%-90%; The adjuvant that preparation uses can adopt the conventional adjuvant in this area, reacts or the curative effect that do not influence medicine of the present invention is a prerequisite with the discord present composition; The method for preparing of said preparation can adopt the conventional method for preparing in this area to prepare.
Among the present invention; The preparation of compositions method does not have any restriction; Antibiotic FR 901228 and apigenin and apigenin analog derivative can directly mix makes preparation then; Or respectively and/or corresponding auxiliary material mix and to make preparation respectively, and then packaging together, or mix and then mix and make preparation with corresponding auxiliary material respectively according to the conventional mode in this area.
The dosage of the pharmaceutical composition among the present invention can carry out suitable variation according to the dosage form difference of administration object, route of administration or medicine, but is prerequisite to guarantee that this pharmaceutical composition can reach effective blood drug level in mammalian body.
The present invention has carried out the test that apigenin and apigenin analog derivative and Antibiotic FR 901228 combination kill HepG2 (hepatoma cell strain), H460 (lung cancer cell line), LNCaP (prostate gland cancer cell strain), DLD1 (colon cancer cell line), D37 (neuroglial cytoma strain) and Panc-1 (pancreas cancer cell strain) respectively; Results suggest; Apigenin of the present invention and apigenin analog derivative and Antibiotic FR 901228 combined therapy hepatocarcinoma, pulmonary carcinoma, carcinoma of prostate, colon cancer, glioma and cancer of pancreas have significant cooperative effect; Improved the curative effect of medicine; Reduce dosage, reduced the generation of side effect.
The specific embodiment
In conjunction with following examples the present invention is done further elaboration, but the present invention is not limited to this.
Embodiment
Reagent and method:
Cell: HepG2 (hepatoma cell strain), H460 (lung cancer cell line), LNCaP (prostate gland cancer cell strain), DLD1 (colon cancer cell line), D37 (neuroglial cytoma strain) and Panc-1 (pancreas cancer cell strain); All available from American Type Culture Collection (ATCC); Rockville; MD, USA.
Medicine: apigenin is available from Nanjing Zelang Pharmaceutical Technology Inc.; SAHA, LBH589 and MS-275 all are synthesized into by document, and the synthesized reference document of SAHA is: J.Med.Chem., 1995,38,1411-1413; The synthesized reference document of MS-275 is: J.Med.Chem., 1999,42,3001-3003; The synthesized reference document of LBH589 is: WO2002022577.
Institute's pharmaceutical composition is all by following method 1 or 2 said preparations of method in following examples;
Method 1: each component of accurate weighing corresponding pharmaceutical compositions, dissolve respectively with dimethyl sulfoxide, be made into the stock solution of 10mM separately; Preserve down at-20 ℃; Be diluted to suitable concentration with fresh culture medium during use, the solution of each component of 1 microlitre of respectively asking for then mixes subsequent use.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, so that do not influence cell activity.
With all cells in RPMI 1640 culture medium that contain 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2Damp condition cultivate down, in the previous day of dosing, on six orifice plates, carry out cell inoculation 2 * 10
5/ hole adds the pharmaceutical composition solution of preparation as stated above then in cell, make each component reach its working concentration, specifically sees 1-27 in the table.
After the drug treating, measure cell death through trypan blue (Trypan Blue), cell turns into 10 minutes through carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Get into the culture medium because dead cell comes off from incubator,, and then, mix with the trypan blue dyestuff with culture medium suspended sediment again through all cells of centrifugal collection under 1200 rev/mins.After the dyeing, count with optical microscope and hematimeter.Dyed the blue dead cell of counting by dyestuff.500 cells of picked at random are counted, and dead cell is recently expressed with the percentage that accounts for the grand total cell.
Method 2: each component of accurate weighing corresponding pharmaceutical compositions, dissolve respectively with dimethyl sulfoxide, be made into the stock solution of 10mM separately, preserve down at-20 ℃.Be diluted to suitable concentration with fresh culture medium during use, the solution for standby of each component of 1 microlitre of respectively asking for then.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, so that do not influence cell activity.
With all cells in RPMI 1640 culture medium that contain 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2Damp condition cultivate down, in the previous day of dosing, on six orifice plates, carry out cell inoculation 2 * 10
5/ hole adds each component solution of the pharmaceutical composition of preparation as stated above with any order then in cell, make each component reach its working concentration, specifically sees 28-45 in the table.
After the drug treating, measure cell death through trypan blue (Trypan Blue), cell turns into 10 minutes through carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Get into the culture medium because dead cell comes off from incubator,, and then, mix with the trypan blue dyestuff with culture medium suspended sediment again through all cells of centrifugal collection under 1200 rev/mins.After the dyeing, count with optical microscope and hematimeter.Dyed the blue dead cell of counting by dyestuff.500 cells of picked at random are counted, and dead cell is recently expressed with the percentage that accounts for the grand total cell.
Tabulate down in the drug regimen shown in 1, the combination of 1-27 is by method 1 preparation, and the combination of 28-45 is by method 2 preparations.
Table 1
The SAHA of embodiment 1 different proportion and the combination Synergistic of apigenin promote the test of HepG2 cell death, see table 2.
Table 2
Cause in the test of hepatoma cell strain HepG2 cell death at the investigation related compound, finding does not almost have cancer cell death, has only 18% cancer cell death when using 3.5 μ M SAHA separately when using 35.0 μ M apigenins or lower concentration separately; When both when low concentration share (25.0 μ M apigenins+2.5 μ M SAHA) then produce than the obvious synergistic effect, cause 46% cancer cell death; When both share with the ratio of 35.0 μ M apigenins+3.5 μ M SAHA, then produce significant more synergism, cause 89% cancer cell death.
The LBH589 of embodiment 2 different proportions and the combination Synergistic of apigenin promote the test of HepG2 cell death, see table 3.
Table 3
Cause in the test of hepatoma cell strain HepG2 cell death investigating related compound, even only have an appointment 10% cancer cell death when finding when use 35.0 μ M apigenins or lower concentration separately, almost not have cancer cell death to use 0.03 μ M LBH589 separately; When both when low concentration share (25.0 μ M apigenins+0.025 μ M LBH589) then produce than the obvious synergistic effect, cause 61% cancer cell death; When both share with the ratio of 35.0 μ M apigenins+0.03 μ M LBH589, then produce significant more synergism, cause 93% cancer cell death.
The MS-275 of embodiment 3 different proportions and the combination Synergistic of apigenin promote the test of HepG2 cell death, see table 4.
Table 4
Cause in the test of hepatoma cell strain HepG2 cell death at the investigation related compound, finding does not almost have cancer cell death when using 35.0 μ M apigenins or lower concentration, 1.0 μ M MS-275 or lower concentration separately; When both when low concentration share (25.0 μ M apigenins+0.5 μ MMS-275) then produce than the obvious synergistic effect, cause 40% cancer cell death; When both share with the ratio of 35.0 μ M apigenins+1.0 μ M MS-275, then produce significant more synergism, cause 78% cancer cell death.
The SAHA of embodiment 4 different proportions and the combination Synergistic of apigenin promote the test of DLD1 cell death, see table 5.
Table 5
Cause in the test of colon cancer cell line DLD1 cell death investigating related compound, find when use 35.0 μ M apigenins separately, to have approximately 25% cancer cell death, 10% the cancer cell death of only having an appointment when using 3.5 μ MSAHA separately; When both when low concentration share (25.0 μ M apigenins+2.5 μ M SAHA) then produce the obvious synergistic effect, cause 52% cancer cell death; When both share with the ratio of 35.0 μ M apigenins+3.5 μ M SAHA, then produce significant more synergism, cause 87% cancer cell death.
The LBH589 of embodiment 5 different proportions and the combination Synergistic of apigenin promote the test of DLD1 cell death, see table 6.
Table 6
Cause in the test of colon cancer cell line DLD1 cell death investigating related compound, find when use 35.0 μ M apigenins separately, to have approximately 25% cancer cell death, have only 10% cancer cell death when using 0.03 μ MLBH589 separately; When both when low concentration share (25.0 μ M apigenins+0.025 μ M LBH589) then produce the obvious synergistic effect, cause 62% cancer cell death; When both share with the ratio of 35.0 μ M apigenins+0.03 μ M LBH589, then produce significant more synergism, cause 91% cancer cell death.
The MS-275 of embodiment 6 different proportions and the combination Synergistic of apigenin promote the test of DLD1 cell death, see table 7.
Table 7
Cause in the test of colon cancer cell line DLD1 cell death investigating related compound, find when use 35.0 μ M apigenins separately, to have approximately 25% cancer cell death, almost do not have cancer cell death when using 1.0 μ MMS-275 or lower concentration separately; When both when low concentration share (25.0 μ M apigenins+0.5 μ M MS-275) then produce the obvious synergistic effect, cause 40% cancer cell death; When both share with the ratio of 35.0 μ M apigenins+1.0 μ M MS-275, then produce significant more synergism, cause 82% cancer cell death.
The SAHA of embodiment 7 different proportions and the combination Synergistic of apigenin promote the test of LNCaP cell death, see table 8.
Table 8
Cause in the test of prostate gland cancer cell strain LNCaP cell death investigating related compound, find when use 20.0 μ M apigenins or 2.5 μ M SAHA separately, almost do not have cancer cell death, 20% the cancer cell death of only having an appointment when using 25.0 μ M apigenins separately; When both when low concentration share (20.0 μ M apigenins+2.0 μ M SAHA) then produce the obvious synergistic effect, cause 62% cancer cell death; When both share with the ratio of 25.0 μ M apigenins+2.5 μ M SAHA, then produce significant more synergism, cause 99% cancer cell death.
The LBH589 of embodiment 8 different proportions and the combination Synergistic of apigenin promote the test of LNCaP cell death, see table 9.
Table 9
Cause in the test of prostate gland cancer cell strain LNCaP cell death investigating related compound, find when use 20.0 μ M apigenins or 0.03 μ M LBH589 separately, almost do not have cancer cell death, 20% the cancer cell death of only having an appointment when using 25.0 μ M apigenins separately; When both when low concentration share (20.0 μ M apigenins+0.025 μ M LBH589) then produce the obvious synergistic effect, cause 49% cancer cell death; When both share with the ratio of 25.0 μ M apigenins+0.03 μ M LBH589, then produce significant more synergism, cause 99% cancer cell death.
The MS-275 of embodiment 9 different proportions and the combination Synergistic of apigenin promote the test of LNCaP cell death, see table 10.
Table 10
Cause in the test of prostate gland cancer cell strain LNCaP cell death investigating related compound, find when use 20.0 μ M apigenins or 1.0 μ M MS-275 separately, almost do not have cancer cell death, 20% the cancer cell death of only having an appointment when using 25.0 μ M apigenins separately; When both when low concentration share (20.0 μ M apigenins+0.5 μ M MS-275) then produce the obvious synergistic effect, cause 64% cancer cell death; When both share with the ratio of 25.0 μ M apigenins+1.0 μ M MS-275, then produce significant more synergism, cause 99% cancer cell death.
The SAHA of embodiment 10 different proportions and the combination Synergistic of apigenin promote the test of D37 cell death, see table 11.
Table 11
Cause in the test of neuroglial cytoma strain D37 cell death 10% the cancer cell death of finding when use 35.0 μ M apigenins or 2.5 μ M SAHA separately, only to have an appointment investigating related compound; When both when low concentration share (25.0 μ M apigenins+2.0 μ M SAHA) then produce the obvious synergistic effect, cause 40% cancer cell death; When both share with the ratio of 35.0 μ M apigenins+2.5 μ M SAHA, then produce significant more synergism, cause 68% cancer cell death.
The LBH589 of embodiment 11 different proportions and the combination Synergistic of apigenin promote the test of D37 cell death, see table 12.
Table 12
Cause in the test of neuroglial cytoma strain D37 cell death 10% the cancer cell death of finding when use 35.0 μ M apigenins or 0.02 μ M LBH589 separately, only to have an appointment investigating related compound; When both when low concentration share (25.0 μ M apigenins+0.015 μ M LBH589) then produce the obvious synergistic effect, cause 44% cancer cell death; When both share with the ratio of 35.0 μ M apigenins+0.02 μ M LBH589, then produce significant more synergism, cause 72% cancer cell death.
The SAHA of embodiment 12 different proportions and the combination Synergistic of apigenin promote the test of Panc-1 cell death, see table 13.
Table 13
Cause in the test of pancreas cancer cell strain Panc-1 cell death the cancer cell death of the 15%-20% that finds when use 25.0 μ M apigenins or 3.5 μ M SAHA separately, only to have an appointment investigating related compound; When both when low concentration share (20.0 μ M apigenins+2.5 μ M SAHA) then produce the obvious synergistic effect, cause 56% cancer cell death; When both share with the ratio of 25.0 μ M apigenins+3.5 μ M SAHA, then produce significant more synergism, cause 94% cancer cell death.
The LBH589 of embodiment 13 different proportions and the combination Synergistic of apigenin promote the test of Panc-1 cell death, see table 14.
Table 14
Cause in the test of pancreas cancer cell strain Panc-1 cell death 20% the cancer cell death of finding when use 25.0 μ M apigenins or 0.03 μ M LBH589 separately, only to have an appointment investigating related compound; When both when low concentration share (20.0 μ M apigenins+0.025 μ M LBH589) then produce the obvious synergistic effect, cause 49% cancer cell death; When both share with the ratio of 25.0 μ M apigenins+0.03 μ M LBH589, then produce significant more synergism, cause 82% cancer cell death.
The SAHA of embodiment 14 different proportions and the combination Synergistic of apigenin promote the test of H460 cell death, see table 15.
Table 15
Cause in the test of lung cancer cell line H460 cell death investigating related compound, find when use 30.0 μ M apigenins separately, to have approximately 25% cancer cell death, 15% the cancer cell death of only having an appointment when using 2.5 μ M SAHA separately; When both when low concentration share (25.0 μ M apigenins+2.0 μ M SAHA) then produce the obvious synergistic effect, cause 46% cancer cell death; When both share with the ratio of 30.0 μ M apigenins+2.5 μ M SAHA, then produce significant more synergism, cause 69% cancer cell death.
The LBH589 of embodiment 15 different proportions and the combination Synergistic of apigenin promote the test of H460 cell death, see table 16.
Table 16
Cause in the test of lung cancer cell line H460 cell death investigating related compound, find when use 30.0 μ M apigenins separately, to have approximately 25% cancer cell death, 20% the cancer cell death of only having an appointment when using 0.025 μ MLBH589 separately; When both when low concentration share (25.0 μ M apigenins+0.02 μ M LBH589) then produce the obvious synergistic effect, cause 46% cancer cell death; When both share with the ratio of 30.0 μ M apigenins+0.025 μ M LBH589, then produce significant more synergism, cause 73% cancer cell death.
Although the foregoing description describes in detail technical scheme of the present invention; But technical scheme of the present invention is not limited to above embodiment; Under the situation that does not break away from thought of the present invention and aim, any change that technical scheme of the present invention is done all will fall into claims of the present invention institute restricted portion.
Claims (15)
1. a pharmaceutical composition is characterized in that, said composition contains apigenin and apigenin analog derivative and Antibiotic FR 901228.
2. pharmaceutical composition according to claim 1; It is characterized in that; The mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 7.5-70.0: 0.005-7.0, and the mol ratio of preferred said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 15.0-35.0: 0.01-3.5.
3. pharmaceutical composition according to claim 2 is characterized in that, said apigenin and apigenin analog derivative are apigenin; Said Antibiotic FR 901228 is that SAHA, MS-275, LBH589, FK228, TSA, aphidicolin, depsipeptides or west reach aniline.
4. the application of the arbitrary described pharmaceutical composition of claim 1-3 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.
5. application according to claim 4 is characterized in that, in the application in the medicine of preparation treatment hepatocarcinoma or colon cancer, the mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 20.0-35.0: 0.02-3.5.
6. application according to claim 5; It is characterized in that; In the application in the medicine of preparation treatment hepatocarcinoma or colon cancer, when said Antibiotic FR 901228 was SAHA, the mol ratio of said apigenin and apigenin analog derivative and SAHA was 25.0-35.0: 2.5-3.5; When said Antibiotic FR 901228 was LBH589, the mol ratio of apigenin and apigenin analog derivative and LBH589 was 25.0-35.0: 0.025-0.03; When said Antibiotic FR 901228 was MS-275, the mol ratio of apigenin and apigenin analog derivative and MS-275 was 25.0-35.0: 0.5-1.0.
7. application according to claim 4 is characterized in that, in the application in the medicine of preparation treatment carcinoma of prostate, the mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 15.0-25.0: 0.02-2.5.
8. application according to claim 7; It is characterized in that; In the application in the medicine of preparation treatment carcinoma of prostate, when said Antibiotic FR 901228 was SAHA, the mol ratio of said apigenin and apigenin analog derivative and SAHA was 20.0-25.0: 2.0-2.5; When said Antibiotic FR 901228 was LBH589, the mol ratio of apigenin and apigenin analog derivative and LBH589 was 20.0-25.0: 0.025-0.03; When said Antibiotic FR 901228 was MS-275, the mol ratio of apigenin and apigenin analog derivative and MS-275 was 20.0-25.0: 0.5-1.0.
9. application according to claim 4 is characterized in that, in the application in the gliomatous medicine of preparation treatment, the mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 20.0-35.0: 0.01-2.5.
10. application according to claim 9; It is characterized in that; In the application in the gliomatous medicine of preparation treatment, when said Antibiotic FR 901228 was SAHA, the mol ratio of said apigenin and apigenin analog derivative and SAHA was 25.0-35.0: 2.0-2.5; When said Antibiotic FR 901228 was LBH589, the mol ratio of apigenin and apigenin analog derivative and LBH589 was 25.0-35.0: 0.015-0.02.
11. application according to claim 4 is characterized in that, in the application in the medicine of preparation treatment cancer of pancreas, the mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 15.0-25.0: 0.02-3.5.
12. application according to claim 11; It is characterized in that; In the application in the medicine of preparation treatment cancer of pancreas, when said Antibiotic FR 901228 was SAHA, the mol ratio of said apigenin and apigenin analog derivative and SAHA was 20.0-25.0: 2.5-3.5; When said Antibiotic FR 901228 was LBH589, the mol ratio of apigenin and apigenin analog derivative and LBH589 was 20.0-25.0: 0.025-0.03.
13. application according to claim 4 is characterized in that, in the application in preparation treatment lung cancer drugs, the mol ratio of said apigenin and apigenin analog derivative and Antibiotic FR 901228 is 20.0-30.0: 0.015-2.5.
14. application according to claim 13; It is characterized in that; In the application in preparation treatment lung cancer drugs, when said Antibiotic FR 901228 was SAHA, the mol ratio of said apigenin and apigenin analog derivative and SAHA was 25.0-30.0: 2.0-2.5; When said Antibiotic FR 901228 was LBH589, the mol ratio of apigenin and apigenin analog derivative and LBH589 was 25.0-30.0: 0.02-0.025.
15. application according to claim 4 is characterized in that, apigenin in the said pharmaceutical composition and apigenin analog derivative and Antibiotic FR 901228 are used or using in order with any priority simultaneously.
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| US10287353B2 (en) | 2016-05-11 | 2019-05-14 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-1 inhibitors |
| US10385130B2 (en) | 2016-05-11 | 2019-08-20 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-1 inhibitors |
| US10385131B2 (en) | 2016-05-11 | 2019-08-20 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-L1 inhibitors |
| US11535670B2 (en) | 2016-05-11 | 2022-12-27 | Huyabio International, Llc | Combination therapies of HDAC inhibitors and PD-L1 inhibitors |
| WO2020034916A1 (en) * | 2018-08-17 | 2020-02-20 | 深圳微芯生物科技股份有限公司 | Combination of histone deacetylase inhibitor and protein kinase inhibitor and pharmaceutical use thereof |
| CN110833544A (en) * | 2018-08-17 | 2020-02-25 | 深圳微芯生物科技股份有限公司 | Combination of histone deacetylase inhibitor and protein kinase inhibitor and pharmaceutical application thereof |
| RU2770754C1 (en) * | 2018-08-17 | 2022-04-21 | Шэньчжэнь Чипскрин Байосайенсиз Ко., Лтд. | Combination of a histone deacetylase inhibitor and a protein kinase inhibitor and pharmaceutical application thereof |
| CN114681455A (en) * | 2018-08-17 | 2022-07-01 | 深圳微芯生物科技股份有限公司 | Combination of histone deacetylase inhibitor and protein kinase inhibitor and pharmaceutical application thereof |
| CN110833544B (en) * | 2018-08-17 | 2022-08-09 | 深圳微芯生物科技股份有限公司 | Combination of histone deacetylase inhibitor and protein kinase inhibitor and pharmaceutical application thereof |
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