CN109432091A - The new application of FDI-6 - Google Patents
The new application of FDI-6 Download PDFInfo
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- CN109432091A CN109432091A CN201811528303.5A CN201811528303A CN109432091A CN 109432091 A CN109432091 A CN 109432091A CN 201811528303 A CN201811528303 A CN 201811528303A CN 109432091 A CN109432091 A CN 109432091A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/04—Antineoplastic agents specific for metastasis
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Abstract
The invention belongs to pharmaceutical fields, disclose the purposes of the new application of FDI-6, especially FDI-6 in the drug of preparation treatment colon cancer.Test result shows that FDI-6 can significantly inhibit the proliferation of colon cancer cell and inhibit the occurrence and development of hepatic metastasis of colonic carcinoma, shows that FDI-6 can be used for the treatment of colon cancer.
Description
Technical field
The invention belongs to pharmaceutical fields, and in particular to the new application of FDI-6, especially FDI-6 treat colon cancer in preparation
Drug in purposes and be related to molecular targeted therapy and DNA methylation regulatory mechanism.
Background technique
In worldwide, the morbidity and mortality of colorectal cancer are in the 3rd of malignant tumour, with 40~50
Year age group disease incidence highest.Colon cancer is the malignant cell due to losing normal growth mechanism on colonic mucosa epithelium or body of gland
The malignant tumour for being constantly proliferated and generating, predilection site are followed successively by sigmoid colon, caecum and colon ascendens, transverse colon, colon descendens.Knot
Intestinal cancer general form is in polypoid, ulcer type etc..Colon cancer can go in ring development along intestinal wall, indulge diameter along intestinal tube and spread up and down or to intestines
The infiltration of wall deep layer can also expand in addition to through lymphatic vessel, blood flow transfer and local Invasion to intraperitoneal plantation or along suture, cut sides
Dissipate transfer.Patients with chronic colitis, polyp of colon patient, male overweight person etc. are Susceptible population.In recent years, with our people
Improvement of living standard, the change of dietary structure, the disease incidence of colon cancer has the tendency that rising year by year and rejuvenation.
The primary treatments of colon cancer have operation, radiotherapy and chemotherapy etc. at present.It can be under early carcinoma scope
The lesion of radical cure can take scope minimally-invasive treatment, and middle and advanced stage method of therapy for cancer is based on performing the operation, is aided with chemotherapy, is immunized and controls
The integration scenario for the treatment of, Chinese medicine and other supportive treatments reduces recurrence rate to improve Resection Rate, improves survival rate.Colon
Cancer early stage, colon was difficult to detect this in the deep of human body, common detection means mostly without apparent specific findings or symptom
Microscopic lesions in a narrow worldlet, and many people are unwilling to receive bring pain when enteroscopy, so early stage
Malignant tumour be difficult to make a definite diagnosis, most of malignant intestinal tumours that can be made a definite diagnosis, after all having evolved in uncontrollable
Phase.Although operation excision effect is best, operation risk is big and Postoperative recurrent rate is higher, and especially patients with terminal is because of cancer
Disease transfer may lost operative chance.Because the cause of disease and pathogenesis of colon cancer not yet illustrate at present, clinical treatment colon cancer
Drug can not be eradicated effectively.Therefore, researchers wish the occurrence and development mechanism that colon cancer is probed into from molecular level, are its target
New thinking is provided to prevention and treatment.
Summary of the invention
In a specific embodiment, the present invention handles MC38 mouse knot according to different time using various concentration FDI-6
Colon-cancer cell, MTT detect the proliferative capacity of group of cells, as a result, it has been found that, with the increase of FDI-6 concentration for the treatment of and prolonging for time
Long, FDI-6 can significantly inhibit the proliferation of colon cancer cell.Therefore the present invention provides FDI-6 inhibits colon cancer cell in preparation
Purposes in the drug of proliferation.
In a specific embodiment, the present invention is small by scratch Healing Experiments detection various concentration FDI-6 processing MC38
Influence of the mouse colon cancer cell to group of cells transfer ability, as a result, it has been found that with the increase of FDI-6 concentration for the treatment of, FDI-6 can
The transfer ability for significantly inhibiting colon cancer cell shows that FDI-6 is inhibited to colon metastasis of cancer.Therefore the present invention provides
Purposes of the FDI-6 in the drug that preparation inhibits colon metastasis of cancer.
Further, in a specific embodiment, the present invention using intrasplenic injection MC38 cell and then cuts off spleen
Method establishes hepatic metastasis of colonic carcinoma model.Mouse after modeling is randomly divided into 3 groups: physiological saline group, FDI-6 group and positive drug without
Fluorouracil (5-FU) group.25mg/kg FDI-6 or 5-FU, physiological saline group is injected intraperitoneally according to mouse weight daily in administration group
Then the physiological saline of injection equivalent, successive administration put to death animal after 28 days daily, took hepatic tissue, and observation liver morphology weighs note
Liver organization weight is recorded, a portion see under hematoxylin-eosin (hematoxylin-eosin, HE) dyeing, microscope
Pathological characteristics are examined, another part leach protein carries out the expression of western blot detection FOXM1, DNMT1 and MMP9 etc..Liver
Form is the results show that hepatic metastasis of colonic carcinoma+apparent lump of physiological saline group mouse liver surface exhibits；FDI-6 administration group liver
It is dirty to have no obvious lump, but have a small amount of white point；5-FU group liver also has no obvious lump, but is in obvious tumefaction, has certain white
Point.HE coloration result shows that hepatic metastasis of colonic carcinoma+physiological saline group mouse liver cell form is seriously damaged, and nucleocytoplasmic ratio is obvious
Increase, cell arrangement is chaotic, and liver rope and sinus hepaticus structure have disappeared.And FDI-6 administration group liver cell form is normal, it can be bright
It is aobvious to differentiate liver rope and sinus hepaticus structure.Western blot testing result shows, FDI-6 administration group and physiological saline group carry out pair
Than the expression of FOXM1, DNMT1 and MMP9 are all substantially reduced, and show that FDI-6 can significantly lower FOXM1, DNMT1 and MMP9
Expression.
In conclusion the present invention proves that FDI-6 has the proliferation of colon cancer and transfer by In vitroandin vivotrial for the first time
Inhibiting effect can be used for treating colon cancer；At the same time, FDI-6 can lower dnmt rna DNMT1, to regulate and control
DNA methylation.Therefore the purposes and regulating DNA methylation that the present invention provides FDI-6 in the drug of preparation treatment colon cancer
This mechanism.
Wherein, the drug includes FDI-6.
Further, the drug further includes pharmaceutically acceptable auxiliary material.
The drug can be any dosage form of current medicine field, it is preferred that the drug be pill, capsule, tablet,
Pulvis, granule or oral solution.
Each pharmaceutical dosage form can be actually needed according to the dosage form chooses suitably acceptable auxiliary material to prepare, this belongs to this field
Conventional dosage form technology of preparing.
As shown from the above technical solution, the purposes the present invention provides FDI-6 in the drug of preparation treatment colon cancer.Examination
It tests the results show that proliferation, migration and the inhibition hepatic metastasis of colonic carcinoma that FDI-6 can significantly inhibit colon cancer cell are sent out
Exhibition shows that FDI-6 can be used for the treatment of colon cancer, and methylates this mechanism there are regulating DNA.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
Fig. 1 shows the influence that FDI-6 is proliferated MC38 mouse colonic cell；Wherein left figure is FDI-6 pairs of various concentration
The influence of MC38 mouse colonic cell proliferation；Right figure is that FDI-6 handles cell different time to MC38 mouse colonic cell
The influence of proliferation；
Fig. 2 shows the influence that FDI-6 migrates MC38 mouse colonic cell；Wherein upper figure is various concentration FDI-6 processing
The influence that cell 0h migrates MC38 mouse colonic cell；The following figure is that FDI-6 processing cell is thin to MC38 mouse junction cancer for 24 hours
The influence of born of the same parents' migration；
Fig. 3 shows that influence of the FDI-6 to mouse junction cancer hepatic metastases mouse is substantially seen and HE colored graph, wherein figure A is physiology
Salt water group hepatic metastasis of colonic carcinoma tissue is substantially seen, and figure B is that FDI-6 group hepatic metastasis of colonic carcinoma tissue is substantially seen, and schemes C for 5-FU group knot
Intestinal cancer hepatic metastases tissue is substantially seen；Figure D is physiological saline group hepatic metastasis of colonic carcinoma tissue HE colored graph (10 ×), and figure E is FDI-6
Group hepatic metastasis of colonic carcinoma tissue HE colored graph (10 ×), figure F are 5-FU group hepatic metastasis of colonic carcinoma tissue HE colored graph (10 ×)；Figure
G is physiological saline group hepatic metastasis of colonic carcinoma tissue HE colored graph (40 ×), schemes H for FDI-6 group hepatic metastasis of colonic carcinoma tissue HE dye
Chromatic graph (40 ×), figure I are 5-FU group hepatic metastasis of colonic carcinoma tissue HE colored graph (40 ×)；
Fig. 4 shows the expression of results of FOXM1, DNMT1 and MMP9 in Western blot detection hepatic metastasis of colonic carcinoma hepatic tissue
Figure；
Fig. 5 shows FOXM1, DNMT1, PCNA, KI67 and MMP9 group by colon cancer database GSE24514 colon cancer and cancer
Differential expression in knitting.
Specific embodiment
The invention discloses the new applications of FDI-6.Those skilled in the art can use for reference present disclosure, be suitably modified technique
Parameter is realized.In particular, it should be pointed out that all similar substitutions and modifications are apparent for a person skilled in the art
, they are considered as being included in the present invention.Method and product of the invention is described by preferred embodiment, phase
Pass personnel can obviously not depart from the content of present invention, method described herein is being modified or suitably changed in spirit and scope
With combine, carry out implementation and application the technology of the present invention.
For a further understanding of the present invention, below in conjunction with the embodiment of the present invention, to the technical side in the embodiment of the present invention
Case is clearly and completely described, it is clear that and described embodiments are only a part of the embodiments of the present invention, rather than all
Embodiment.Based on the embodiments of the present invention, those of ordinary skill in the art institute without making creative work
The every other embodiment obtained, shall fall within the protection scope of the present invention.
Unless otherwise specified, reagent involved in the embodiment of the present invention is commercial product, can pass through business canal
Road purchase obtains.
Embodiment 1,
In vitro culture MC38 mouse colonic cell, is randomly divided into 4 groups, is administered using FDI-6: 0, at 10,20 and 30 μM
Cell 12h and 20 μM of processing cells 0,3,6,12 and for 24 hours are managed, MTT detects the proliferative capacity of group of cells, as a result such as Fig. 1.
Wherein MTT method is that cell dissociation after-blow breaks into cell suspension, and every hole cell number is 5 × 103It is a to be inoculated with into 96 well culture plates, often
Group sets 3-6 multiple holes, and after FDI-6 agent-feeding treatment, every hole is added sterile MTT liquid and is protected from light effect 4h, and every hole adds DMSO to shake
OD value is surveyed after dissolution, calculates proliferation rate.The result is shown in Figure 1.
The results show that it is thin that FDI-6 can significantly inhibit colon cancer with the increase of FDI-6 concentration for the treatment of and the extension of time
The proliferation of born of the same parents.
Embodiment 2,
In vitro culture MC38 mouse colonic cell, is randomly divided into 4 groups, is administered using FDI-6: 0, at 10,20 and 30 μM
Cell is managed, scratch Healing Experiments detect the transfer ability of group of cells, as a result such as Fig. 2.Wherein scratch Healing Experiments method is thin
Born of the same parents digest after-blow and break into cell suspension, and every hole cell number is 5 × 105It is a to be inoculated with into 6 well culture plates, after FDI-6 agent-feeding treatment,
With the vertical scratch of 100 μ l pipette tips, take pictures under microscope；After for 24 hours afterwards observe cell migration situation, take pictures under microscope.As a result see
Fig. 2.
The results show that FDI-6 can significantly inhibit the transfer ability of colon cancer cell with the increase of FDI-6 concentration for the treatment of.
Embodiment 3,
The consistent about 6-8 weeks male C57BL/6 mouse by week old using intrasplenic injection MC38 cell, and then cuts off spleen
Method establish hepatic metastasis of colonic carcinoma model.Mouse after modeling is randomly divided into 3 groups: physiological saline group, FDI-6 group and positive drug
Without fluorouracil (5-FU) group.25mg/kg FDI-6 or 5-FU, physiological saline is injected intraperitoneally according to mouse weight daily in administration group
Then the physiological saline of injection equivalent, successive administration put to death animal after 28 days to group daily, took hepatic tissue, and observation liver morphology weighs
Liver organization weight is recorded, a portion is fixed through formalin, paraffin embedding, slice, carries out hematoxylin-eosin
(hematoxylin-eosin, HE) dyeing, microscopically observation pathological characteristics, another part leach protein carry out western
Blot detects the expression of FOXM1, DNMT1 and MMP9 etc..It is specific as follows:
One, experimental method
(1) method of intrasplenic injection MC38 cell and then excision spleen establishes hepatic metastasis of colonic carcinoma model method are as follows: takes hero
Property C57BL/6 Strains of Mouse about 6-8 week old, by yellow Jackets 0.06ml/20g intraperitoneal injection anaesthetize, about 5min waits for fiber crops
Liquor-saturated action, skin degerming, transverse incision (being about 0.5-1cm) cut off skin, into abdomen after in abdomen left-external side find willow leaf shape spleen.
In vitro culture MC38 cell grows to logarithmic phase to cell, and it is 2 × 10 that digestion, which counts cell to density,5A cell/ml, with life
Reason salt water is resuspended in 150uL volume.Spleen point is carefully pressed from both sides out with tweezers, is slowly pulled out spleen point and is placed on the gauze of wetting.From
Oncocyte liquid 0.1ml is slowly injected into spleen by spleen junior inserting needle；After pulling out needle, cotton swab presses pinprick, gently rubs spleen
5min makes cell enter liver through splenic vein.After the pale protuberance in area to be injected disappears, pedicle of spleen is ligatured, spleen is cut off, checked without bleeding,
Successively interrupted suture muscle, skin close abdomen.Mouse revival to be anaesthetized observes mouse situation daily and is grouped administration.
(2) HE colouring method are as follows: take tissue block to carry out paraffin embedding, slice, dewax each 10 minutes through dimethylbenzene I, II；It will
Slice is sequentially placed into the alcoholic solutions at different levels such as 100%, 95%, 85%, 75% each 10 minutes, tap water flushing 5 minutes, 1 ×
PBS 5 minutes；0.3%H2O237 DEG C after warm bath 30 minutes, 1 × PBS is washed 5 minutes again；Dyeing: hematoxylin is disseminated 2 minutes, from
Water is rinsed 10 minutes, and 1% acidic alcohol breaks up 5 seconds, and tap water rinses 10 minutes, and eosin stains 2 minutes, tap water rinsed 10
Minute；It is sliced in 75%, 85%, 95%, 100% alcoholic solutions at different levels each 5 minutes, 1/2 dimethylbenzene 5 minutes, dimethylbenzene I,
Each 5 minutes in II, gummy mounting is finally used, microscopically observation takes pictures and acquires picture.
(3) Western blot detection method are as follows: the animal tissue (50mg or so) for taking soya bean size is shredded with scissors,
400 μ l lysates (RIPA:PMSF=100:1) are added.EP pipe is placed in and is homogenized on ice with homogenizer low speed, keeps tissue abundant
Cracking.4 DEG C of 12 000rpm centrifugation 30min. takes supernatant.The every hole of 96 orifice plates adds 3 μ l of albumen sample, 17 μ l, BCA liquid of deionized water
200 μ l (50:1), and two blank control groups are set, 37 DEG C are incubated for 30 minutes.Enzyme-linked immunization surveys OD value (570nm), according to OD
Value calculates protein concentration；Boiled egg is white, loading, gel electrophoresis, transferring film, closing, successively incubates primary antibody and corresponding secondary antibody, development.
Two, experimental result
(1) liver morphology: examining mouse liver, the results show that hepatic metastasis of colonic carcinoma+physiological saline group mouse liver
The apparent lump of surface exhibits (Fig. 3 A)；FDI-6 administration group liver has no obvious lump, but has a small amount of white point (Fig. 3 B)；5-FU
Group liver also has no obvious lump, but is in obvious tumefaction, there is certain white point (Fig. 3 C).
(2) HE coloration result: hepatic metastasis of colonic carcinoma+physiological saline group mouse liver cell form is seriously damaged, caryoplasm
Than significantly increasing, cell arrangement is chaotic, and liver rope and sinus hepaticus structure have disappeared (Fig. 3 D and G).And FDI-6 administration group liver cell shape
State is normal, can obviously differentiate liver rope and sinus hepaticus structure finds out (Fig. 3 E and H).The visible a small amount of cancer nests of 5-FU administration group, cell
Arrangement is substantially neat, and cell nucleocytoplasmic ratio slightly increases (Fig. 3 F and I).
(3) Western blot testing result: can analyze by experiment, and FDI-6 administration group and physiological saline group carry out
Comparison, the expression of FOXM1, DNMT1 and MMP9 are all substantially reduced.Show that FDI-6 is able to suppress the table of FOXM1, DNMT1 and MMP9
It reaches, is able to suppress the occurrence and development (Fig. 4) of colon cancer.
Embodiment 4,
Gene expression profile (gene expression omnibus, GEO) is done by collecting colon cancer database clinical sample
Analysis, screening DNA transmethylase DNMT1, promotion sensitivity gene FOXM1 and proliferation marker proliferating cell nuclear antigen
(Proliferating Cell Nuclear Antigen, PCNA), KI67 and Metastatic Marker matrix metalloproteinase
(matrix metalloprotein, MMP) 9 differential expression in colon cancer and cancer beside organism, and carry out DNMT1 and these
Gene two-by-two between correlation analysis.
We have collected GSE24514 colon cancer database, as a result, it has been found that: compared to Carcinoma side normal tissue (NT), DNMT1,
Significantly high expression (Fig. 5) is presented in FOXM1, PCNA, KI67 and MMP9 in colon cancer (CC) tissue.Wherein, FOXM1 with
DNMT1, PCNA and KI67 correlation (table 1), and P < 0.05 two-by-two.
The correlation analysis (GSE24514) of table 1 FOXM1, DNMT1, PCNA and KI67 in colon cancer tissue
Infuse *: the significant correlation on 0.05 horizontal (bilateral), * *: the significant correlation on 0.01 horizontal (bilateral).
Claims (7)
- Purposes of the 1.FDI-6 in the drug of preparation treatment colon cancer.
- Purposes of the 2.FDI-6 in the drug that preparation inhibits Colon Cancer Cells.
- Purposes of the 3.FDI-6 in the drug that preparation inhibits hepatic metastasis of colonic carcinoma.
- 4.FDI-6 is preparing the purposes in DNA methylation regulating medicine.
- 5. purposes according to any one of claims 1-4, the drug is molecular targeted therapy.
- 6. purposes according to any one of claims 1-4, the drug also includes pharmaceutically acceptable auxiliary material.
- 7. purposes according to any one of claims 1-4, the drug is pill, capsule, tablet, pulvis, particle Agent or oral solution.
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| CN201811528303.5A CN109432091A (en) | 2018-12-13 | 2018-12-13 | The new application of FDI-6 |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811528303.5A CN109432091A (en) | 2018-12-13 | 2018-12-13 | The new application of FDI-6 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005076979A2 (en) * | 2004-02-06 | 2005-08-25 | Wyeth | Diagnosis and therapeutics for cancer |
| WO2018026776A2 (en) * | 2016-08-04 | 2018-02-08 | City Of Hope | Foxm1 modulators and uses thereof |
| CN107913409A (en) * | 2016-11-21 | 2018-04-17 | 中山大学肿瘤防治中心 | It is a kind of to combine the composition for suppressing tumour |
| CN108210494A (en) * | 2018-03-23 | 2018-06-29 | 南华大学 | The application of FOXM1 inhibitor FDI-6 anti-hepatic fibrosis |
-
2018
- 2018-12-13 CN CN201811528303.5A patent/CN109432091A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005076979A2 (en) * | 2004-02-06 | 2005-08-25 | Wyeth | Diagnosis and therapeutics for cancer |
| WO2018026776A2 (en) * | 2016-08-04 | 2018-02-08 | City Of Hope | Foxm1 modulators and uses thereof |
| CN107913409A (en) * | 2016-11-21 | 2018-04-17 | 中山大学肿瘤防治中心 | It is a kind of to combine the composition for suppressing tumour |
| CN108210494A (en) * | 2018-03-23 | 2018-06-29 | 南华大学 | The application of FOXM1 inhibitor FDI-6 anti-hepatic fibrosis |
Non-Patent Citations (4)
| Title |
|---|
| GIOVANNI MARSICO ET AL.: "Small molecule inhibition of FOXM1: How to bring a novel compound into genomic context", 《GENOMICS DATA》 * |
| MICHAEL V. GORMALLY ET AL.: "："Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition", 《NATURE COMMUNICATIONS》 * |
| 刘亚男等: "叉头结构域抑制物6(FDI-6)通过下调细胞核FoxM1增加喉癌细胞凋亡并抑制其侵袭和迁移", 《细胞与分子免疫学杂志》 * |
| 金成等: "FoxM1与EMT相关蛋白E-cadherin在结肠癌中的表达及其相关性研究", 《实用预防医学》 * |
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Application publication date: 20190308 |