CN102100688A - Application of zedoary cyclic diolefine in preparation of medicine for resisting neoplasm metastasis - Google Patents
Application of zedoary cyclic diolefine in preparation of medicine for resisting neoplasm metastasis Download PDFInfo
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- CN102100688A CN102100688A CN2009101550807A CN200910155080A CN102100688A CN 102100688 A CN102100688 A CN 102100688A CN 2009101550807 A CN2009101550807 A CN 2009101550807A CN 200910155080 A CN200910155080 A CN 200910155080A CN 102100688 A CN102100688 A CN 102100688A
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Abstract
The invention belongs to the field of pharmacy, and provides application of zedoary cyclic diolefine in preparation of a medicine for resisting neoplasm metastasis, and in particular relates to application in the preparation of medicines for resisting neoplasm metastasis, such as liver cancer, gastric cancer, carcinoma of urinary bladder, breast cancer, colon cancer, kidney cancer, esophagus cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, carcinoma of uterine cervix, thyroid cancer, prostatic cancer, oral cancer, lung cancer and the like. The zedoary cyclic diolefine plays a role in resisting the neoplasm metastasis through inhibiting the expression of proteins related to neoplasm cell metastasis.
Description
Technical field
The present invention relates to the application of Furanodiene. in the medicine of preparation anti metastasis.
Background technology
Invasion and attack, displacement behavior are the substitutive characteristics of malignant tumor.Cancerometastasis makes local patholoic change diffuse into many kitchen ranges of whole body property disease.When clinical diagnosis went out primary tumo(u)r, the cancerometastasis away from the position had taken place in about 50% patient, and existing operation, radiation and chemotherapy means are failed often in the treatment metastatic carcinoma, cause conditions of patients to worsen or death.Invasion and attack, transfer are the fatefulue the very cruxs of malignant tumor, and the invasion and attack of anti-curing oncoma, transfer are to reduce one of important channel of tumor case fatality rate.
Tumor invasion is meant that malignant cell breaks away from former position, breaks through the barrier that basement membrane and extracellular matrix constitute, the normal structure that invasion and attack are adjoined, final stymied tissue generation pathological changes and necrosis.Transfer is meant malignant cell by approach such as blood vessel, lymphatic vessels, away from organ in form the process of secondary tumor.The invasion and attack of tumor are processes that continuous steps is rapid with shifting.At first be the primary tumo(u)r fast breeding, the primary lesion new vessels generates; Tumor cell is invaded profit basement membrane, substrate, penetrates blood vessel or lymphatic vessel enters blood circulation; The tumor cell thromboembolism also rests in the blood capillary in site, distant place; Tumor cell passes blood vessel or lymphatic vessel, finally forms metastasis in target organ.
Furanodiene. (furanodiene, C
15H
20O) be a kind of natural component that is present in the zingiberaceous plant Rhizoma Curcumae (Curcumazedoaria (Berg) Rose).People such as Yu Xiao report that Furanodiene. can induce the human hepatoma HepG2 cell to be arrested in G
2/ M the phase, and by MAPK signal path and plastochondria-Caspase path generation apoptosis (CancerBiology ﹠amp; Therapy 6:7,1044-1050; 2007); In addition, also having the bibliographical information Furanodiene. to induce human leukemia HL-60 cell's apoptosis is to finish (Cancer Letters 271 158-166 by activating the TNFR1 signal path; 2008); Have not yet to see relevant for Furanodiene. at the report aspect the anti metastasis.
Summary of the invention
The invention provides the application of Furanodiene. in the medicine of preparation anti metastasis.
The present invention further provides the application of Furanodiene. in the medicine of the anti-hepatocarcinoma of preparation, gastric cancer, bladder cancer, breast carcinoma, colon cancer, renal carcinoma, esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, cervical cancer, thyroid carcinoma, carcinoma of prostate, oral cancer and lung cancer metastasis.
Beneficial effect:
1. external invasion and attack have the obvious suppression effect to Furanodiene. to liver, stomach, bladder, breast, colon, kidney, esophagus, gallbladder, ovary, pancreas, cervix uteri, thyroid, prostate, oral cavity and lung carcinoma cell.
2. Furanodiene. can suppress the expression of hepatocarcinoma, gastric cancer and lung carcinoma cell metastasis related protein.
3. Furanodiene. can suppress the neoplasm metastasis of people's hepatocarcinoma tumor strain nude mouse orthotopic implantation model.
The specific embodiment
The invention will be further elaborated by the following examples, but the present invention is not imposed any restrictions.
Furanodiene. is that extraction separation reaches 99.7% pure product through structure evaluation and purity in the Rhizoma Curcumae.
The preparation of preparation example 1 Furanodiene.
Get the exsiccant rhizome 1kg of Rhizoma Curcumae, distill, obtain the 385g oil water mixture altogether by the steam distillation device, extract with ether and petroleum ether, separate oil reservoir, abandon or adopt water layer, and concentrate, obtain Rhizoma Curcumae volatile oil 46.5g, separate, the petroleum ether eluting with silicagel column, every bottle of 100ml collects, merge 26～42 components, take out and desolvate, obtain yellow crystals 15.6g, going up silicagel column again separates, the petroleum ether eluting, every bottle of 30ml merges 16～28 components, take out and desolvate, obtain white crystals 10.7g, the purity that HPLC analyzes this sample reaches 99.7%, and high resolution mass spectrum is analyzed cation and detected the quasi-molecular ion peak [M+H] that shows sample
+Be 217.1583, infer that its molecular weight is 216.1505, inspection element coupling, it is elementary composition to be C
15H
20O, error is less than 5ppm, and the molecular formula that promptly shows this sample is C
15H
20O.The magnetic resonance detection demonstration, at δ 7.228ppm, δ 4.996ppm, δ 4.691ppm, δ 3.378ppm, δ 3.107ppm, δ 2.211ppm, δ 2.104ppm, δ 1.874ppm, δ 1.760ppm, δ 1.559ppm, there is absorption group peak at δ 1.200ppm place, resolves by detailed ownership, proves that this separator is a Furanodiene..
Preparation example 2 Furanodiene. preparation of soft capsule
2.4g Furanodiene.
0.24mg soybean phospholipid
0.24mg methyl parahydroxybenzoate
Add injection soybean oil dissolving said components and be settled to 24ml
Preparation: get injection soybean oil 1000ml, 150 ℃ of dry heat sterilizations 1 hour, put and be chilled to 25 ℃, take out part fluid and add above-mentioned principal agent and adjuvant, stirring is dissolved it fully, is settled to 24ml at last, filter with the exsiccant No. 6 molten funnels that hang down, embedding is in soft capsule, and ultraviolet sterilization 60 minutes contains the soft capsule of Furanodiene. 200mg in making every.
Experimental example 1 Furanodiene. is to the inhibitory action of the external invasion and attack of tumor cell
Experiment material: Bel-7402 hepatoma cell strain, the BGC-823 stomach cancer cell line, the A549 lung cancer cell line, 5637 bladder cancer cell lines, the MCF-7 breast carcinoma cell strain, the Caco-2 colon cancer cell line, the OS-RC-2 renal cancer cell line, the strain of Eca-109 esophageal cancer cell, GBC-SD carcinoma of gallbladder cell strain, the strain of HO8910 ovarian cancer cell, the PANC-1 pancreas cancer cell strain, the strain of Hela cervical cancer cell, the strain of SW579 thyroid carcinoma cell, the strain of PC-3 prostate gland cancer cell, the strain of KB cancer cell of oral cavity: Chinese Academy of Sciences's Shanghai cell bank provides, and conventional cultivation the in our company clinical pharmacology research department gone down to posterity; Cell Invasion Assay KIT (ECM550), Chemicon company; DMEM, RPMI-1640 culture medium, Gbico company; Hyclone (FBS), Hangzhou Ilex purpurea Hassk.[I.chinensis Sims biological engineering material company; DMSO, Sigma company.
Experimental technique: Furanodiene. (according to preparation example 1 gained) is mixed with the storage liquid of 200mg/L with DMSO, and-20 ℃ store for future use.Face with preceding and be diluted to required final concentration with culture fluid.Collect the tumor cell of exponential phase, (final concentration is 0.2,0.4,0.8mg/L with containing blank solvent and Furanodiene. respectively, trial test shows that this series concentration do not have influence to tumor cell proliferation) the RPMI-1640 culture fluid with cell suspension, make 1 * 10
6The single cell suspension of/ml is operated according to Cell InvasionAssay Kit description.Cell dyes behind the inner cultivation of cell 48h, the cell that acetate dissolution cell below has penetrated, and lysate is transferred in 96 orifice plates, and microplate reader detects the 560nm absorbance (A of place
560) value, with A
560The cell number of value representative invasion and attack is established 3 parallel holes for every group; Statistical method: t-test.
Experimental result: after Furanodiene. was handled separate sources cancerous cell 48h respectively, the cell invasion ability of 0.2mg/L group was lower than cellular control unit, but difference not statistically significant (P＞0.05); 0.4mg/L be starkly lower than matched group (P＜0.05 or P＜0.01) with the cell invasion ability of 0.8mg/L group, see Table 1.
Table 1 Furanodiene. is to the influence (OD value) of separate sources tumor cell invasion ability (x ± s)
Compare a P＜0.05, b P＜0.01 with matched group
Experiment conclusion: Furanodiene. can suppress the external invasive ability of separate sources tumor cell.
Experimental example 2 Furanodiene .s are to the influence of tumor metastasis related protein vegf expression
Experiment material: Bel-7402 hepatoma cell strain, BGC-823 stomach cancer cell line, A549 lung cancer cell line: Chinese Academy of Sciences's Shanghai cell bank provides, and conventional cultivation the in our company clinical pharmacology research department gone down to posterity; VEGF Enzyine Linked Immunosorbent Assay, bio-engineering research institute is built up in Nanjing; The RPMI-1640 culture medium, Gbico company; Hyclone (FBS), Hangzhou Ilex purpurea Hassk.[I.chinensis Sims biological engineering material company; DMSO, Sigma company.
Experimental technique: Furanodiene. (according to preparation example 1 gained) is mixed with the storage liquid of 200mg/L with DMSO, and-20 ℃ store for future use.Face with preceding and be diluted to required final concentration with culture fluid.Get the tumor cell that is in exponential phase, with every bottle 5 * 10
6Individual being inoculated in the Tissue Culture Flask, 37 ℃, 5%CO
2After cultivating 24h, replacing is with the blank solution and the Furanodiene. sample solution of culture fluid dilution, final concentration is respectively 0.2,0.4,0.8mg/L, after continue cultivating 48h, draw cells and supernatant, centrifugal remove cell debris and impurity after, the vegf protein concentration determination is carried out according to detection kit description method in the supernatant, survey the A value in microplate reader 450nm place, obtain the standard curve equation according to the A value of standard substance, and calculate VEGF concentration in the cell conditioned medium; Statistical method: t-test.
Experimental result: Furanodiene. is to the influence of separate sources tumor cell secretion VEGF: ELISA result shows, after Furanodiene. acts on above three kinds of tumor cell 48h, can obviously reduce the amount of VEGF in the cell culture fluid supernatant, 0.4mg/L, 0.8mg/L group compares with matched group, there is significant difference (P＜0.05 or P＜0.01), sees Table 2.
Table 2 Furanodiene. is to influence (x ± s) (pg/ml) of separate sources tumor cell vegf expression
Compare a P＜0.05, b P＜0.01 with matched group
Experiment conclusion: Furanodiene. can be brought into play the antineoplastic invasion transferance by the expression that suppresses Bel-7402, BGC-823 and A549 tumor cell VEGF.
Experimental example 3 Furanodiene .s are to the inhibiting effect on tumor metastasis of people's hepatocarcinoma tumor strain nude mouse metastasis model
Experiment material: supply test agent: by the Furanodiene. soft capsule (content) of preparation example 2 preparations, and provide the blank solvent of the soft capsule of preparing by preparation example 2 to contrast simultaneously, prepare by people's livelihood Pharmaceutical centers for making of pharmaceutical preparations.Laboratory animal: the BALB/c nude mice, female, age in 4-5 week, 28; Provide by Shanghai Si Laike Experimental Animal Center, raise clinical pharmacology Animal Lab., 25 ℃ of room temperatures, the drinking-water of freely ingesting in people's livelihood Pharmaceutical product development department.The Bel-7402 hepatoma cell strain: Chinese Academy of Sciences's Shanghai cell bank provides, and conventional cultivation the in our company clinical pharmacology research department gone down to posterity.
Experimental technique: the Bel-7402 cell dilution is become 2 * 10
7The cell suspension of concentration.Nude mice is sterilized with povidone iodine and alcohol swab successively with after the pentobarbital sodium 80mg/kg intraperitoneal anesthesia of 10g/L, laterally does the otch about 1.5cm at the margo interior hepatis position, carefully inserts the cell suspension of slowly injecting 0.05ml in the liver with syringe then.The suture operation otch is used the iodophor disinfection wound surface, and the penicillin of lumbar injection 100,000 units.Divide four groups (matched group, 200,100,50mg/kg administration group) beginning administration at random by body weight after two weeks of inoculation, continuous 30 days, when finishing, experiment puts to death animal, observe each internal organs tumor growth situation under the anatomic microscope, calculate the neoplasm metastasis incidence rate.
Experimental result: matched group shifts incidence rate: 80% (8/10), and it mainly moves internal organs is gastrointestinal, spleen, kidney.Low dose group shifts incidence rate: 50% (3/6), and it mainly shifts internal organs is gastrointestinal, spleen, kidney.Middle dosage group shifts incidence rate: 50% (3/6), and mainly shifting internal organs is gastrointestinal.The transfer incidence rate of high dose group: 16.7% (1/6), the transfer internal organs are gastrointestinal.
Experiment conclusion: Furanodiene. can suppress the neoplasm metastasis of nude mice in-situ inoculating hepatocarcinoma Bel-7402 cell.
Claims (2)
1. the application of Furanodiene. in the medicine of preparation anti metastasis.
2. application according to claim 1, wherein said tumor is selected from hepatocarcinoma, gastric cancer, bladder cancer, breast carcinoma, colon cancer, renal carcinoma, esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, cervical cancer, thyroid carcinoma, carcinoma of prostate, oral cancer and pulmonary carcinoma.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1884271A (en) * | 2005-06-23 | 2006-12-27 | 烟台大学 | Zedoary cyclo-diolefine and its derivatives preparation method and use |
| CN101219135A (en) * | 2007-01-08 | 2008-07-16 | 杭州民生药业集团有限公司 | Application of zedoary root cyclic diolefine in preparing medicament for treating tumour disease and disease caused by virus |
| CN101538259A (en) * | 2009-04-17 | 2009-09-23 | 杭州民生药业集团有限公司 | Crystal form A of zedoary root cyclic diolefine, preparation method thereof and application thereof in preparing anti-tumor drugs |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1884271A (en) * | 2005-06-23 | 2006-12-27 | 烟台大学 | Zedoary cyclo-diolefine and its derivatives preparation method and use |
| CN101219135A (en) * | 2007-01-08 | 2008-07-16 | 杭州民生药业集团有限公司 | Application of zedoary root cyclic diolefine in preparing medicament for treating tumour disease and disease caused by virus |
| CN101538259A (en) * | 2009-04-17 | 2009-09-23 | 杭州民生药业集团有限公司 | Crystal form A of zedoary root cyclic diolefine, preparation method thereof and application thereof in preparing anti-tumor drugs |
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Address after: 311100 No. 36, Linping Avenue, Yuhang economic and Technological Development Zone, Zhejiang, Hangzhou Applicant after: Hangzhou Minsheng Pharmaceutical Co., Ltd. Address before: 310011, No. 108 Tong Road, Yuhang, Zhejiang, Hangzhou (high tech Zone) Applicant before: Hangzhou Minsheng Pharmaceutical Co., Ltd. |
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Application publication date: 20110622 |