CN110051847A - The combination medicine of gossypol acetate and autophagy inhibitor - Google Patents
The combination medicine of gossypol acetate and autophagy inhibitor Download PDFInfo
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- CN110051847A CN110051847A CN201910340199.5A CN201910340199A CN110051847A CN 110051847 A CN110051847 A CN 110051847A CN 201910340199 A CN201910340199 A CN 201910340199A CN 110051847 A CN110051847 A CN 110051847A
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Abstract
The present invention relates to the combination medicines for treating tumour, and in particular to the combination medicine of gossypol acetate and autophagy inhibitor.Combination medicine provided by the invention shows good synergistic function, has the stronger effect for inhibiting tumour relative to single medical instrument.The present invention provides a kind of new, more effective therapeutic scheme for clinical treatment tumour disease, and potential applicability in clinical practice is good.
Description
Technical field
The present invention relates to the combination medicines for treating tumour, and in particular to gossypol acetate (gossypol acetic
Acid, GAA) and autophagy inhibitor combination medicine.
Background technique
Cancer is a kind of principal disease for causing human death, and the annual whole world is about 7,000,000 because of number of cancer deaths.It is existing
Stage, a big chunk cancer patient was just place when first medical due to the deficiency of early diagnosis of cancer and screening technology
In advanced tumor, the chance that operation excision is cured is lost.Chemotherapy and radiotherapy are still that the main of late tumor at this stage is controlled
Treatment means.However, this treatment method offer limited effectiveness, most patients finally can recur, and furthermore this kind of method has non-
Often big side effect, greatly reduces life in patients.
Neoplasm targeted therapy is the functional molecular for tumor specific expression, and the inhibitor for designing and developing targeting includes
Antibody, small molecule, bio-carrier etc..Such targeting molecule can specific growth, movement and the chemotherapy for inhibiting tumour cell
The functions such as resistance, and do not have destruction to normal histocyte.Therefore, targeted therapy can greatly extend patient's
Life span and life quality.Therefore new neoplasm targeted therapy drug is developed to be of great significance.
Gossypol acetate (GAA) is the widely distributed natural products being present in cottonseed, and existing research shows acetic acid before this
Gossypol has certain antitumor action, but its mechanism of action is still imperfectly understood, all at this stage using GAA as BCL2 egg
The clinical test of white inhibitor all ends in failure.The mechanism of action for exploring GAA, constructs novel GAA pharmaceutical composition, for
The clinical expansion of GAA is of great significance.
Summary of the invention
In order to solve the above technical problem, the present invention provides a kind of gossypol acetate (gossypol acetic acid, GAA)
With the combination medicine of autophagy inhibitor.The drug combination can significantly inhibit growth of tumour cell, and have synergistic make
With.
For this purpose, in a first aspect, the present invention provides application of the LRPPRC negative regulator agent in induction tumour cell autophagy.
Wherein, the LRPPRC negative regulator agent is LRPPRC degradation agent, preferably gossypol acetate.
Second aspect, the present invention provide the agent of LRPPRC negative regulator with autophagy inhibitor answering in the preparation of antitumor drugs
With.
Wherein, the LRPPRC negative regulator agent is LRPPRC degradation agent, preferably gossypol acetate.
The third aspect, the present invention provide the agent of LRPPRC negative regulator in preparing autophagy inhibitor anti-tumor activity synergist
Using.
Wherein, the LRPPRC negative regulator agent is LRPPRC degradation agent, preferably gossypol acetate.
Fourth aspect, the present invention provide a kind of drug comprising a) agent of LRPPRC negative regulator and b) autophagy inhibitor.
Wherein, the LRPPRC negative regulator agent is LRPPRC degradation agent, preferably gossypol acetate.
Wherein, the autophagy inhibitor is selected from 3- methyladenosine, wortmannin, LY294002, hydroxychloroquine sulfate, Ba Fu
Lip river mycin A1, methicillin, one or more of phenylacetylene sulfonamide, preferably bar bifilomycin A1 or sulfuric acid hydroxyl chlorine
Quinoline.
Further, drug of the present invention further includes pharmaceutically acceptable carrier or excipient.
5th aspect, the present invention provide the drug and are preparing the application in following products:
1) eucaryote tumor cell proliferation inhibitor；2) prevent and/or treat the drug of tumor disease.
Wherein, the tumour cell is cancer cell, and the cancer cell is preferably that lung carcinoma cell, breast cancer cell, mammary gland are led
Pipe cancer cell, liver cancer cells, esophageal cancer cell, colorectal cancer cell and prostate gland cancer cell, preferably lung adenocarcinoma cell, lung squamous cancer
Cell, breast cancer cell, breast duct cancer cell.
Wherein, the tumor disease includes lung cancer, breast cancer, breast ductal cancer, liver cancer, the cancer of the esophagus, colorectal cancer and preceding
Column gland cancer, preferably adenocarcinoma of lung, lung squamous cancer, breast cancer, breast ductal cancer.
Medication name or product name used herein only indicate its active constituent, are not construed as the limit to the medicament sources
System.
Term " carrier " or " excipient " can be any conventional carrier and excipient in pharmaceutical field.Specific carrier
Selection with excipient will depend on the administration mode for being used to treat particular patient or disease type and state.For specific administration
The preparation method of the said synthetic processes of mode is completely in the knowledge of drug field technical staff.For example, can make
For pharmaceutically acceptable carrier or excipient include the carrier of pharmaceutical field routine, excipient, diluent, filler, solvent,
Supporting agent, adhesive, wetting agent, disintegrating agent, sorbefacient, surfactant, absorption carrier and lubricant etc..When necessary,
It can also include flavouring agent, preservative and sweetener etc..
Early-stage study shows that LRPPRC (the triangular shape pentapeptide rich in leucine repeats motif protein) is a kind of mitochondria egg
It is white, its mutation and cytochrome C oxidase defect (cytochrome C oxidase deficiency) and Leigh synthesis
The generation for levying (Leigh Syndrome) is closely related；Beclin-1 albumen has the function of Induces Autophagy, and LRPPRC
Albumen can form compound with Beclin-1, to inhibit the autophagy process of cell.
Meanwhile the LRPPRC specific small molecule inhibitor gossypol acetate (GAA) that the present invention screens, it is studied through the present invention
It was found that GAA in conjunction with LRPPRC, can not only inhibit the nucleic acid binding function of LRPPRC albumen, but also can directly degrade
LRPPRC albumen, Induces Autophagy.And cell autophagy can protect cell and spend adverse circumstance, therefore inventor speculates, presses down simultaneously
The anticancer effect of GAA can be enhanced in autophagy process processed.It is had shown that through further research of the invention, the connection of GAA and autophagy inhibitor
With growth, the clonality that can significantly inhibit cancer cell, and stronger inhibitory effect is shown than single medicine use, there is association
The same sex.
Compared with prior art, the invention has the following advantages that
(1) the present invention provides the combination medicines of GAA and autophagy inhibitor, and effect is aobvious when for inhibiting tumour growth
It writes, and is significantly better than the two and is used alone, synergistic effect can be played by illustrating that the two is used in combination.
(2) GAA and autophagy inhibitor are proved to can be used for clinical treatment respectively, highly-safe, therefore the present invention is to face
Bed treatment tumor disease provides a kind of new, more effective therapeutic scheme, and potential applicability in clinical practice is good.
Detailed description of the invention
By reading the following detailed description of the preferred embodiment, various other advantages and benefits are common for this field
Technical staff will become clear.The drawings are only for the purpose of illustrating a preferred embodiment, and is not considered as to the present invention
Limitation.And throughout the drawings, the same reference numbers will be used to refer to the same parts.In the accompanying drawings:
Fig. 1 is the western blot detection of LC3B-I, LC3B-II and LRPPRC albumen in lung adenocarcinoma cell line A549
Figure, wherein using the hybridization signal of Actin albumen as the internal reference for measuring applied sample amount.
Fig. 2 is the confocal microscope imaging results figure of lung adenocarcinoma cell line A549.
Fig. 3 is tri- kinds of lung cancer cell line H460, lung adenocarcinoma cell line A549, lung cancer cell line H1299 cancer cells through handling
Versus cell vigor figure afterwards, figure A are to handle through GAA and HCQ, and figure B is to handle through GAA and Bafilomycin A1.
Fig. 4 is that the western blot of LRPPRC albumen in the tumor mass of adenocarcinoma of lung PDX model detects figure, wherein with Actin
The hybridization signal of albumen is as the internal reference for measuring applied sample amount.
Fig. 5 is the knurl growth curve of adenocarcinoma of lung PDX model.
Specific embodiment
The illustrative embodiments of the disclosure are more fully described below with reference to accompanying drawings.Although showing this public affairs in attached drawing
The illustrative embodiments opened, it being understood, however, that may be realized in various forms the disclosure without the reality that should be illustrated here
The mode of applying is limited.It is to be able to thoroughly understand the disclosure on the contrary, providing these embodiments, and can be by this public affairs
The range opened is fully disclosed to those skilled in the art.The person that is not specified actual conditions in embodiment, according to molecular biology
It is carried out with immunologic conventional laboratory conditions.Reagents or instruments used without specified manufacturer, being can be by commercially available purchase
Buy the conventional products of acquisition.
Embodiment 1GAA degradation LRPPRC induces cell autophagy
The present embodiment is tested by western blot and immunofluorescence experiment, and the degradable LRPPRC of verifying GAA induces thin
Born of the same parents' autophagy.Experimental procedure is as follows:
Western blot experiment:
It after lung adenocarcinoma cell line A549 is digested, is inoculated in the culture dish of φ 100mm, carries out concentration respectively using GAA
Gradient and time gradient are tested:
(1) concentration gradient is tested: being used (0 μM, 1 μM, 5 μM, 10 μM) processing cell of GAA of various concentration respectively, is cultivated 48h
Afterwards, it collects, lytic cell, takes 40 μ g Tot Prots with western blot experiment is carried out, detect LC3 expressing quantity.
(2) time gradient is tested: being handled cell with 10 μM of final concentration of GAA, is acted on 8h, 16h, for 24 hours respectively.It collects, split
Cell is solved, 40 μ g Tot Prots are tested for western blot, detect LC3 albumen.When autophagy does not occur, LC3 master
To exist in the form of LC3B-I, after autophagy occurs, exist in the form of LC3B-II.Western blot testing result is shown in figure
1。
Immunofluorescence experiment:
After lung adenocarcinoma cell line A549 is digested, it is inoculated in laser co-focusing culture dish, after culture for 24 hours, adds final concentration
For 10 μM of GAA, while blank control group (DMSO of 10 μM of addition) is set, cultivates 48h, is consolidated after washing with 4% paraformaldehyde
Determine 5min, then is washed with after the penetrating 5min of 0.1%Triton x-100 with PBS buffer solution.1:200 dilutes LC3 antibody (abcam
Company, article No. ab192890) incubated cell slide afterwards, 4 DEG C be incubated overnight after washed with PBS buffer solution.It is glimmering that 1:200 dilutes FITC
The secondary antibody of signal thoroughly after washing, acquires green florescent signal with laser confocal microscope.Fluorescence imaging result is shown in Fig. 2.
As shown in Figure 1, after GAA is handled, the expression quantity of LRPPRC is remarkably decreased.Further pass through immunofluorescence experiment,
As shown in Figure 2, after GAA is handled, the graininess coloring of autophagy marker LC3 is dramatically increased, and illustrates that GAA processing can reduce
The expression quantity of LRPPRC, further Induces Autophagy.
Embodiment 2GAA and cell autophagy inhibitor, which are combined, inhibits cell activity in cellular level
GAA is combined with hydroxychloroquine sulfate (HCQ) and Bafilomycin A1 (Baf-A1) by the present embodiment respectively, is tested
Cell activity can be inhibited in cellular level by demonstrate,proving GAA and the combination of cell autophagy inhibitor.Experimental procedure is as follows:
GAA and hydroxychloroquine sulfate (HCQ) combination are tested:
After tri- kinds of lung cancer cell line H460, lung adenocarcinoma cell line A549, lung cancer cell line H1299 cancer cell digestion, point
It is not inoculated in 96 orifice plates, 2000, every hole cell, handles (10 μM) with GAA respectively afterwards for 24 hours, (5 μM) of HCQ processing or both
Combination handles (10 μM of GAA, 5 μM of HCQ), using 10 μM of DMSO processing as blank control group (NC group).MTS method is used after 48h
The absorbance in each hole is detected, is normalized with the absorbance value of NC group.It detects obtained cell activity value and sees Fig. 3
(A)。
GAA and Bafilomycin A1 (Baf-A1) combination are tested:
After tri- kinds of lung cancer cell line H460, lung adenocarcinoma cell line A549, lung cancer cell line H1299 cancer cell digestion, point
Be not inoculated in 96 orifice plates, 2000, every hole cell, for 24 hours afterwards respectively with GAA handle (10 μM), Baf-A1 (100nM) processing or
Both persons combination handles (10 μM of GAA, Baf-A1 100nM), using 10 μM of DMSO processing as blank control group (NC group).
The absorbance for detecting each hole after 48h with MTS method, is normalized with the absorbance value of NC group.Detect obtained cell
Activity value is shown in Fig. 3 (B).
According to Fig. 3, compared with GAA is used alone or inhibitor is used alone, GAA and HCQ (figure A) or
After Bafilomycin A1 combination (figure B), tumor inhibitory effect is dramatically increased.Illustrate that GAA can be mentioned with autophagy inhibitor combination
High cancer resistant effect.
Embodiment 3GAA and cell autophagy inhibitor are combined inhibits tumour to increase on PDX model
The present embodiment tests tumor suppression associated with GAA and autophagy inhibitor HCQ and imitates on lung cancer patient PDX model
Fruit.Experimental procedure is as follows:
(1) it is total to carry out homogenized extraction tissue for the tumor mass cutting tissue for the adenocarcinoma of lung PDX model for being LU0378 to number
Albumen takes the total protein of 40 μ g to test for western blot, detects the expression of LRPPRC albumen.Western blot
Testing result is shown in Fig. 4.
(2) after the tumor mass of the adenocarcinoma of lung PDX model of LU0378 being cut kind immune deficiency nude mouse it is subcutaneous, to tumor
Body grows to 100mm3Afterwards, it is divided into 3 groups.One group is placebo treatment group, one group for GAA processing (gastric infusion 30mg/kg, one day
Once), one group for GAA (gastric infusion 30mg/kg, once a day) combine HCQ (intraperitoneal injection 70mg/kg, one day one
It is secondary) processing.The once every three days measurement of knurl product draws knurl growth curve and sees Fig. 5.
As seen from Figure 4, the adenocarcinoma of lung PDX model tormulation LRPPRC that number is LU0378.As shown in Figure 5, individually apply
GAA plays the role of that tumour is inhibited to increase, and GAA and HCQ combination have stronger inhibitory effect.
Embodiment 4GAA and autophagy inhibitor combination have synergistic effect
Using standard in combination formula of index Q=E (A+B)/(E (A)+E (B)-E (A) × E (B)), (E (A+B) is two
Medicine is combined inhibiting rate, and E (A) is the inhibiting rate of A prescription, and E (A) is the inhibiting rate of B prescription) carry out GAA and HCQ cooperate with effect
It should count, be defined as synergistic effect when Q value is greater than 1.15.E (GAA)=0.49, E (HCQ) in lung adenocarcinoma cell line A549
=0.21, E (GAA+HCQ)=0.74, Q=1.22, are shown as synergistic effect.
It should be noted that embodiment 1-4 is verified by taking adenocarcinoma of lung, lung carcinoma cell as an example, it is of course also possible to take mammary gland
The cells such as cancer, colon and rectum carcinoma, the cancer of the esophagus, lung squamous cancer, cancer of pancreas, gastric cancer, the present embodiment is it is not limited here.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
In the technical scope disclosed by the present invention, any changes or substitutions that can be easily thought of by anyone skilled in the art,
It should be covered by the protection scope of the present invention.Therefore, protection scope of the present invention should be with the protection model of the claim
Subject to enclosing.
Claims (10)
- Application of the 1.LRPPRC negative regulator agent in induction tumour cell autophagy.
- The agent of 2.LRPPRC negative regulator and autophagy inhibitor application in preparation of anti-tumor drugs.
- The agent of 3.LRPPRC negative regulator is preparing the application in autophagy inhibitor anti-tumor activity synergist.
- 4. application as described in any one of claims 1-3, wherein the LRPPRC negative regulator agent is LRPPRC degradation agent, preferably Gossypol acetate.
- 5. a kind of drug comprising a) agent of LRPPRC negative regulator and b) autophagy inhibitor.
- 6. drug as claimed in claim 5, wherein the agent of LRPPRC negative regulator is LRPPRC degradation agent, preferably gossypol acetate.
- 7. drug as claimed in claim 5, which is characterized in that the autophagy inhibitor is selected from 3- methyladenosine, wet graceful mould Element, LY294002, hydroxychloroquine sulfate, bar bifilomycin A1, methicillin, one of phenylacetylene sulfonamide or several Kind, preferably bar bifilomycin A1 or hydroxychloroquine sulfate.
- 8. drug described in claim 6 or 7 is preparing the application in following products: 1) eucaryote Cytostatic to tumor cell Agent；2) prevent and/or treat the drug of tumor disease.
- 9. application as claimed in claim 8, which is characterized in that the tumour cell is cancer cell, and the cancer cell is preferably Lung carcinoma cell, breast cancer cell, breast duct cancer cell, liver cancer cells, esophageal cancer cell, colorectal cancer cell and prostate cancer Cell, preferably lung adenocarcinoma cell, Lung Squamous Carcinoma Cells, breast cancer cell, breast duct cancer cell.
- 10. application as claimed in claim 8, which is characterized in that the tumor disease includes lung cancer, breast cancer, breast duct Cancer, liver cancer, the cancer of the esophagus, colorectal cancer and prostate cancer, preferably adenocarcinoma of lung, lung squamous cancer, breast cancer, breast ductal cancer.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113797339A (en) * | 2020-06-11 | 2021-12-17 | 复旦大学 | Pharmaceutical composition of pyoluteorin and autophagy inhibitor and application |
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2019
- 2019-04-25 CN CN201910340199.5A patent/CN110051847A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113797339A (en) * | 2020-06-11 | 2021-12-17 | 复旦大学 | Pharmaceutical composition of pyoluteorin and autophagy inhibitor and application |
| CN113797339B (en) * | 2020-06-11 | 2024-01-16 | 复旦大学 | Pharmaceutical composition of pyocin and autophagy inhibitor and application thereof |
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