CN109966499A - Synergistic anti-breast cancer diversion medicaments composition and application thereof - Google Patents
Synergistic anti-breast cancer diversion medicaments composition and application thereof Download PDFInfo
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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Abstract
It include NAC1 inhibitor the invention discloses synergistic anti-breast cancer diversion medicaments composition；Angiogenesis inhibitor class compound；Acceptable carrier or excipient in pharmacy, health care conduct and learning or bromatology.Angiogenesis inhibitor class compound is combined the medication of NAC1 inhibitor by the present invention, compared with exclusive use angiogenesis inhibitor class compound, has the function of significantly improving anti-breast cancer transfer effect.The discovery belongs to great progress in the research for the treatment of Metastasis in Breast Cancer, and potential applicability in clinical practice is good.
Description
Technical field
The invention belongs to biotechnologys and medical domain, and in particular to a kind of to have anti-breast cancer to shift synergistic function
Pharmaceutical composition includes NAC1 inhibitor and angiogenesis inhibitor class compound, is inhibiting tumour, especially breast cancer
Transfer aspect has significant synergistic effect.
Background technique
Breast cancer is one of the most common malignant tumors in women, its disease incidence is in rise year by year in the world in recent years
Trend.The whole world has about 1,200,000 women to suffer from breast cancer every year, Died Patients about 500,000, and disease incidence accounts for annual various malignant tumours
7%~10%.To advanced stage, the cancer cell inside patient body generally can all occur to shift and spread, mammary gland breast cancer development
Cancer DISTANT METASTASES IN is the extremely difficult treatment if transfer occurs the main reason for leading to death.Bevacizumab
(bevacizumab) it is first anti-angiogenic drugs for being approved by the FDA in the United States listing for 2 months 2004, can be used for metastatic cream
The first-line treatment of gland cancer.In treatment of metastatic breast cancer, bevacizumab can be significantly improved progression free survival phase (PFS), however
These researchs do not significantly improve overall survival phase (OS).Studies have reported that anti-angiogenic therapy is possible to make to swell unintentionally
Tumor more has invasion and is more likely to spread.Should research shows that: in the tumour of Anti-angiogenic therapy anoxic zones increase
5 times, to have activated a series of reaction of hypoxia inducibles of tumour cell class；And it was found that this kind of tumour cell has similar do
Cell characteristics, in this way these cells are easier to survive.
BTB/POZ family gene NACC1 gene Codocyte transcription factor NAC1 (nucleus accumbens-1, volt every
Core 1) expression, be positioned at human chromosome area Ch19p13.2, be a newly discovered new carcinogen.NAC1 is more
(such as oophoroma, cervical carcinoma, carcinoma of endometrium, breast cancer etc.) universal high expression in kind of gynecological tumor, and normal tissue not
It is shown in Table and reaches.BTB structural domain (also referred to as POZ structural domain) is the important feature domain of mediating proteins interaction, the BZB structure of NAC1
Domain (1-129 amino acid sequence) is formed necessary to NAC1 dimer complex, and the NAC1 dimer complex of formation can be with
Participate in a variety of biological function regulations: such as anti-apoptotic, rush proliferation, promoting invasion transfer, anti-aging.
There is experiment to show that NAC1 can also go out nuclear translocation by blocking HDAC4, stable nucleus HIF-1 α albumen promotes anoxic ring
Tumour cell glycolysis activates under border；It may additionally facilitate the self-renewing of tumour and embryonic stem cell.Since NAC1 is specificity
Ground is expressed in tumour cell height, and takes part in the maintenance of hypoxia inducible reaction and stem cell properties, therefore for the molecule
Small molecule compound can cancel the reaction of hypoxia inducible caused by its Anti-angiogenic therapy and stem cell properties maintain, and will have
An oncotherapy new strategy may be opened up with angiogenesis inhibitor class drug combination.
Summary of the invention
It is an object of the present invention to provide anti-breast cancer diversion medicaments compositions of a kind of synergy and application thereof.
The technical scheme is that
A kind of anti-breast cancer diversion medicaments composition of synergy, which is characterized in that contain:
(1) NAC1 inhibitor；
(2) angiogenesis inhibitor class compound；
(3) acceptable carrier or excipient in pharmacy, health care conduct and learning or bromatology.
Further, the NAC1 inhibitor is compound 2- (4- tert-butyl benzene oxygroup)-N- (2- { [(4- tert-butyl benzene
Oxygroup) acetyl group] amino } ethyl) acceptable salt or ester or derivative in acetamide or its pharmacy, health care conduct and learning or bromatology
Object or their mixture.
Further, the angiogenesis inhibitor class compound is bevacizumab, VEGF Trap, Lei Molu mono-
Anti-, any one in endostatin research, small molecule tyrosine kinase inhibitors.Such as Sorafenib, Sutent, A Xi
For Buddhist nun, Bu Linibu, pa azoles for Buddhist nun, Ah pa for Buddhist nun etc., more preferable bevacizumab.
Further, the weight ratio between the NAC1 inhibitor and angiogenesis inhibitor class compound is 1:
1000 to 1000:1, preferred weight ratio 1:500-500:1, more preferable weight ratio are 1:100-100:1, and further preferably weight ratio is
1:50-50:1。
Further, the NAC1 inhibitor accounts for the l-95wt% of composition total weight, preferably 5-90wt%, more preferably
10-80wt%.
Further, the dosage form of the composition is tablet, capsule, powder agent, granule, suspension or injection.?
When the composition is unit dosage form or multi-form, the content of the NAC1 inhibitor is 0.05-50000mg/ agent, preferably 0.1-
10000mg/ agent, more preferable 0.5-5000mg/ agent.
Further, the medication sequence of the composition is first then to be pressed down using Tumor Angiongesis with NAC1 inhibitor
Preparation class compound.
Breast cancer cell is the tumour cell for expressing people NAC1, and people's NAC1 expression quantity of breast cancer cell is higher than normal cell
30%~50%.Above-mentioned composition can be applied to preparation for treating the transcellular drug of anti-breast cancer.
The invention has the advantages that the anti-breast cancer diversion medicaments composition of synergy of the present invention, can effectively press down
NAC1 processed, control, the treatment for alleviating or curing disease, such as Metastasis in Breast Cancer etc..
Detailed description of the invention
Fig. 1 shows the anti-breast cancer lung transfer effect of synergistic anti-breast cancer diversion medicaments composition；
Fig. 2 and 3 shows the variation of lung's metastatic nodules and disease of synergistic anti-breast cancer diversion medicaments composition
Manage testing result；
Fig. 4 shows the anti-breast cancer hind leg Bone tumour effect of synergistic anti-breast cancer diversion medicaments composition；
Fig. 5 shows that synergistic anti-breast cancer diversion medicaments composition can significantly extend Metastasis in Breast Cancer model mice
Life cycle.
Specific embodiment
In order to make the foregoing objectives, features and advantages of the present invention clearer and more comprehensible, further below with reference to embodiment
Illustrate technical solution of the present invention.But the present invention is not limited to listed embodiments, should also be included in of the presently claimed invention
Other any well known changes in interest field.
" one embodiment " or " embodiment " referred to herein, which refers to, may be included at least one implementation of the invention
A particular feature, structure, or characteristic." in one embodiment " that different places occur in the present specification not refers both to same
A embodiment, nor the individual or selective embodiment mutually exclusive with other embodiments.
In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, such as Sambrook etc.
People, " molecular cloning: laboratory manual " (New York, CSH Press, New York:Cold Spring Harbor
Laboratory Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.
Unless otherwise stated, otherwise percentage and number are calculated by weight.Unless otherwise defined, as used herein all
Professional and scientific terms have the same meanings as commonly understood by one of ordinary skill in the art.In addition, any similar or equal to described content
Deng method and material all can be applied in the present invention.The preferred methods and materials described herein are for illustrative purposes only.
Cell line
MDA-MB-231 cell line: it is purchased from ATCC, this is the metastatic breast cancer cell line of positive expression NAC1 a kind of.
The cultural method of MDA-MB-231 cell line is as follows: by cell inoculation in the DMEM for containing 10% calf serum
In (InVitrogen company) culture solution, it is placed in 37 degrees Celsius, routine culture in the CO2 incubator that volume fraction is 5%, experiment
First no medicine culture two weeks.
Embodiment
1, the foundation and intervention of mouse model are shifted
Tail vein injection breast carcinoma cell strain MDA-MB-231 prepares Metastasis in Breast Cancer mouse model, and observes NAC1 inhibitor
The effect of joint bevacizumab.The MDA-MB-231 cell of fluorescent marker passes on.Cell is collected in the cell log phase, is made into concentration
It is 1 × 106/ 100 microlitres of cell suspension, 0.1ml cell suspension is injected under SCID caudal vein, and (cell number is 1.0 × 106
A/only).It is randomly divided into 4 groups, every group 5.Negative control group (intravenous injection physiological saline group), NAC1 inhibitor administration group (tail
Vein note, 25mg/kg), bevacizumab administration group (intraperitoneal injection, 5mg/kg), NAC1 inhibitor+bevacizumab is administered in combination
Group.MDA-MB-231 cell lung and bone are turned the results show that NAC1 inhibitor can significantly increase bevacizumab in 25mg/kg
It moves.
Fig. 1-Fig. 5 specifically is seen, as shown in Figure 1, existing using NAC1 inhibitor+bevacizumab administering drug combinations group mouse
When preceding surrounding, compared with negative control group, NAC1 inhibitor administration group, bevacizumab administration group, no significant difference, but
After four weeks, the metastatic cells amount using the mouse of negative control group and NAC1 inhibitor administration group obviously rises, and cuts down list using shellfish
The metastatic cells amount of the mouse of anti-administration group is lower than the mouse using negative control group and NAC1 inhibitor administration group, but still
There is apparent rising, and low-down transfer is still able to maintain using NAC1 inhibitor+bevacizumab administering drug combinations group mouse
Rate.As shown in Fig. 2, it is few using the Pulmonary artery tubercle number of NAC1 inhibitor+bevacizumab administering drug combinations group mouse, it connects
Nearly zero, and the Pulmonary artery tubercle number of the mouse of other three groups of administration groups is using NAC1 inhibitor+bevacizumab joint
20-40 times of the Pulmonary artery tubercle number of the mouse of administration group.As shown in figure 3, lung pathologies using NAC1 the results show that pressed down
The lung tumors transport zone (T) of preparation+bevacizumab administering drug combinations group mouse significantly reduces, and other three groups of administration groups
The lung tumors transport zone (T) of mouse increased significantly.As shown in figure 4, using NAC1 inhibitor+bevacizumab administering drug combinations group
Mouse in preceding surrounding, compared with negative control group, NAC1 inhibitor administration group, bevacizumab administration group, no significant difference,
But after 4th week, using the Bone tumour of the mouse of negative control group, NAC1 inhibitor administration group and bevacizumab administration group
Cell concentration obviously rises, and especially after the 7th week, ascensional range is very big, and uses NAC1 inhibitor+bevacizumab joint
The mouse of administration group is still able to maintain the low-down rate of transform.As shown in figure 5, using NAC1 inhibitor+bevacizumab combine to
The survival rate of the mouse of medicine group after 90 days is 100%, and uses the mouse of negative control group survival rate is adopted for 0 after 90 days
With the mouse of NAC1 inhibitor administration group, survival rate is 20% after 90 days, and falling to survival rate quickly is 0.List is cut down using shellfish
Survival rate is 40% to the mouse of anti-administration group after 90 days, and falling to survival rate quickly is 20%.
It follows that NAC1 inhibitor+bevacizumab administering drug combinations group can significantly extend cream compared with other three groups of modes
The life cycle of gland cancer metastasis model mouse.
In conclusion the invention discloses a kind of anti-breast cancer transfers for targeting the antitumor synergy of people's nucleus accumbens septi 1
Angiogenesis inhibitor class compound is combined the medication of NAC1 inhibitor, with exclusive use by medical composition and its use
Angiogenesis inhibitor class compound compares, and has the function of significantly improving anti-breast cancer transfer effect.The discovery exists
It treats and belongs to great progress in the research of Metastasis in Breast Cancer, potential applicability in clinical practice is good.
It should be noted that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to preferable
Embodiment describes the invention in detail, those skilled in the art should understand that, it can be to technology of the invention
Scheme is modified or replaced equivalently, and without departing from the spirit and scope of the technical solution of the present invention, should all be covered in this hair
In bright scope of the claims.
Claims (10)
1. a kind of anti-breast cancer diversion medicaments composition of synergy, which is characterized in that contain:
(1) NAC1 inhibitor；
(2) angiogenesis inhibitor class compound；
(3) acceptable carrier or excipient in pharmacy, health care conduct and learning or bromatology.
2. a kind of anti-breast cancer diversion medicaments composition of synergy according to claim 1, it is characterised in that: described
NAC1 inhibitor is compound 2- (4- tert-butyl benzene oxygroup)-N- (2- { [(4- tert-butyl benzene oxygroup) acetyl group] amino } ethyl)
Acceptable salt or ester or derivative or their mixture on acetamide or its pharmacy, health care conduct and learning or bromatology.
3. a kind of anti-breast cancer diversion medicaments composition of synergy according to claim 1, it is characterised in that: described
Angiogenesis inhibitor class compound is bevacizumab, VEGF Trap, Lei Molu monoclonal antibody, endostatin research, small molecule
Any one in tyrosine kinase inhibitor.
4. a kind of anti-breast cancer diversion medicaments composition of synergy according to claim 1, it is characterised in that: described
Weight ratio between NAC1 inhibitor and angiogenesis inhibitor class compound is 1:50-50:1.
5. a kind of anti-breast cancer diversion medicaments composition of synergy according to claim 1, it is characterised in that: described
NAC1 inhibitor accounts for the 10-80wt% of composition total weight.
6. a kind of anti-breast cancer diversion medicaments composition of synergy according to claim 1, it is characterised in that: described
The dosage form of composition is tablet, capsule, powder agent, granule, suspension or injection.
7. a kind of anti-breast cancer diversion medicaments composition of synergy according to claim 1, it is characterised in that: in institute
When to state composition be unit dosage form or multi-form, the content of the NAC1 inhibitor is 0.5-5000mg/ agent.
8. a kind of anti-breast cancer diversion medicaments composition of synergy according to claim 1, it is characterised in that: described
The medication sequence of composition is first then to use angiogenesis inhibitor class compound with NAC1 inhibitor.
9. a kind of anti-breast cancer diversion medicaments composition of synergy is in preparation for treating the transcellular medicine of anti-breast cancer
Purposes in object.
10. purposes according to claim 9, it is characterised in that: the breast cancer cell is that the tumour of expression people NAC1 is thin
People's NAC1 expression quantity of born of the same parents, the breast cancer cell are higher than normal cell 30%~50%.
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