CN109419803A - Cell autophagy inhibitor and Afatinib pharmaceutical composition and its purposes in preparation tumour Synergistic preparations - Google Patents
Cell autophagy inhibitor and Afatinib pharmaceutical composition and its purposes in preparation tumour Synergistic preparations Download PDFInfo
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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Abstract
The invention belongs to pharmaceutical technology fields; it is related to a kind of cell autophagy inhibitor and Afatinib pharmaceutical composition and its purposes in preparation tumour Synergistic preparations; composition of medicine of the invention; its proliferation and inducing apoptosis of tumour cell that tumour cell is significantly inhibited by Afatinib; and cell autophagy occurs for induction tumour cell; cell autophagy plays the role of protecting tumour cell in Afatinib killing tumor cell, makes that cell autophagy is inhibited to achieve the effect that the killing that Afatinib is remarkably reinforced to tumour cell.The present invention can reduce the toxic side effect of Afatinib treatment dosage and medication generation and reduce drug resistant generation, while reduce treatment cost.The present invention is used for therapeutic intervention chronic myelogenous leukemia, liver cancer, breast cancer and non-small cell lung cancer, the tumour that especially EGFR mutation and HER2 mutation cause by joint or sequential usage mode.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to the pharmaceutical composition of new treatment tumour；Press down more particularly to a kind of autophagy
Purposes more particularly to the composition of medicine of the preparation with Afatinib pharmaceutical composition and its in preparation tumour Synergistic preparations pass through
It is administered in combination or non-small cell lung cancer that sequential administration is mutated in preparation treatment containing EGFR, breast cancer, liver cancer and chronic myelogenous
Purposes in the synergism medicine of leukaemia.
Background technique
It is second generation TKI class drug prior art discloses Afatinib (Afatinib), is polycyclic class drug, it can
It is potent it is irreversible be integrated on EGFR and Her2 protein, to block its corresponding signal path, it is suppressed that the life of cell
It is long, there is apparent curative effect to the tumour cell being mutated containing EGFR.
According to data, lung cancer is the highest tumor disease of Chinese disease incidence, and research reports lung cancer tumor cell in mirror
Lower form is divided into non-small cell lung cancer and Small Cell Lung Cancer, and in non-small cell lung cancer, and it is big to be divided into adenocarcinoma of lung, lung squamous cancer, lung
Cell cancer, wherein the disease incidence highest of adenocarcinoma of lung, and the pathogenic factor of adenocarcinoma of lung and smoking, air pollution, radiation, life are practised
It is used to related；According to statistics, there are about 40% patients with lung adenocarcinoma EGFR genetic mutation occurs, and the mutation of EGFR gene passes through RAS/
The accesses such as RAF and PI3K promote the growth of cell madness and cell that canceration occurs, and promote tumor vascular formation.
In clinical practice, such disease can be intervened using TKI class drug therapy, TKI class drug can be integrated to EGFR
On molecule, the conduction of its signal path is blocked, inhibits growth, the proliferation of tumour.Studies have shown that first generation TKI drug Ji is non-to be replaced
Buddhist nun can be obviously prolonged the life cycle of patient, but with prolonged use, drug resistance, which can occur, for tumour causes curative effect to reduce, with
Second generation TKI drug afatinib is developed afterwards, is had a good effect to the tumour cell of resistance to Gefitinib, so
And after long-time use, tumour cell still can generate drug resistance to afatinib.
Cell autophagy (autophagy) is also known as II type programmed death (type II programmed cell death),
The phenomenon that being " white I digests " (cellular degradation) common in eucaryote body, wherein can decompose intracellular
Impaired or extra organelle and albumen generate nucleic acid, and the small-molecule substances such as amino acid synthesize new protein for cell, and
It can maintain the stabilization of intracellular microenvironment.Development recently as molecular biology and gene technology and the depth to cell autophagy
Enter research, it is found that the development relationship of itself and a variety of diseases, especially tumour is close.
Currently, it is still unclear about effect of the cell autophagy in the generating process of tumour, therefore in oncotherapy
Effect show the complexity of " double-edged sword ", be both possible to inhibit the growth of tumour cell, and be possible to promote tumour thin
The increment of born of the same parents.Studies have shown that cell autophagy can provide under the adverse conditions such as amino acid starvation, anoxic, drug for tumour cell must
The nutritional ingredient wanted maintains the survival of tumour cell；Research also found that the single gram of drop antibody class drug such as Qu Tuozhu and western appropriate sound can
It induces tumour cell to generate cell autophagy protection tumour cell to kill from drug；5 fluorine urine uracil acts on liver cancer cells can
Induces Autophagy；Bai Lilu enjoys in west the generation for acting on the inducible cell autophagy of neuroglial cytoma, inhibits cell autophagy
Above-mentioned chemotherapeutics can be enhanced to the fragmentation effect of middle of the month oncocyte；And arsenic trioxide acts on malignant glioma cells
It can cause tumour cell that autophagy death, etc. occurs；This shows that different pharmaceutical acts on the cell of different tumor cell inductions
Autophagy is different；Recent study shows that the generation of autophagy and the drug resistance of tumour cell have substantial connection, therefore, probe into medicine
Object acts on cell autophagy effect and the regulatory mechanism of tumour cell initiation, is of great significance to the treatment of tumour.
By literature search etc., so far, there is not yet composition of medicine is made in relation to cell autophagy inhibitor and Afatinib
And the relevant report for treating adenocarcinoma of lung.
Summary of the invention
It is an object of the invention to be directed to the status of the prior art, a kind of composition of medicine of new treatment tumour, tool are provided
Body is related to a kind of composition of medicine and application thereof containing autophagy inhibitor and Afatinib, more particularly to the composition of medicine passes through joint
Non-small cell lung cancer, breast cancer, liver cancer and the chronic myelogenous leukemia etc. that administration or sequential use are mutated in preparation treatment EGFR
Purposes in tumour synergism medicine.
A kind of new composition of medicine for the treatment of tumour disclosed by the invention, by one or more safe doses cell oneself
The Afatinib composition of inhibitor and Formulas I structure is bitten, it is characterized in that, drug itself has auxiliary without obvious cytotoxicity or to tumour
Lethal effect is helped, but its curative effect can be enhanced by inhibiting cell autophagy to enhance Afatinib to the lethal effect of tumour cell.
In the present invention, cell autophagy inhibitor is selected from 3-MA (3-Methyladenine, 3-MA), chloroquine
(Chloroquine), LY294002, Bava Lip river mycin A1, ammonium chloride, hydroxychloroquine (hydroxychloroquine)；Wherein
It is preferred that chloroquine (Chloroquine) and 3-MA (3-Methyladenine, 3-MA).
In the present invention, shown in Afatinib its chemical structure such as formula (I), belong to second generation TKI class drug, is also possible to the
Two generation TKI other drugs.
In the present invention, it includes but is not limited to adenocarcinoma of lung that the composition of medicine, which is used to treat tumour, group of the invention
Composite medicine can also be applied to clinical intervention liver cancer, colon cancer, breast cancer etc..
The composition of medicine for the treatment of tumour provided by the invention, significantly inhibits the proliferation of tumour cell simultaneously by Afatinib
Inducing apoptosis of tumour cell, and induction tumour cell occur cell autophagy, in Afatinib killing tumor cell cell from
It bites and plays the role of protecting tumour cell, reach inhibition cell autophagy and killing of the Afatinib to tumour cell is remarkably reinforced
Effect.
The present invention has carried out external intervention experiment:
Lung adenocarcinoma cell line H1975 and the H1650 cell of 2 plants of EFGFR mutation is chosen, various concentration gradient and time are set
Gradient gives Afatinib induction tumour cell, and mtt assay surveys cell activity, and as the result is shown, Afatinib can significantly inhibit swollen
The proliferation and inducing apoptosis of tumour cell of oncocyte, 20 μM of Afatinib reach the inhibiting rate of tumour cell effect 48h
60%-80% or so；Then the tumour cell through Afatinib effect 48h, cyto-ID dye are observed under laser confocal microscope
After color, the autophagy vesica quantity of tumor cells showed is apparently higher than control group, shows that Afatinib can induce tumour cell
Cell autophagy；In order to further prove the above results, significant albumen LC3II/ is bitten using the detection of Western-b1ot method is white
The expression of LC3-I, as the result is shown, the up-regulation of cell LC3-II/LC3-I ratio through Afatinib intervention, so show Ah
Method can induce tumour cell that cell autophagy occurs for Buddhist nun；Two kinds of autophagy inhibitor 3-MA, chloroquine are finally selected to inhibit cell certainly
It bites, the effect of mtt assay, Western-b1ot detection cell autophagy in Afatinib killing tumor cell, the result shows that, cell
Autophagy plays the role of protecting tumour cell in Afatinib killing tumor cell, by inhibiting cell autophagy that can generate obviously
Enhance Afatinib to the fragmentation effect of tumour cell；The present invention further demonstrates inhibition certainly using Nude mice model simultaneously
Bite the curative effect for improving afatinib.
Autophagy inhibitor by one or more of safe doses of the invention forms composition of medicine with Afatinib, passes through connection
It closes or sequential usage mode is for treating tumour, the ability of Afatinib killing tumor cell can be remarkably reinforced, can be used into one
In adjuvant treatment to the drug resistant tumor patient of Afatinib；The dosage of drug can be reduced using composition of medicine of the present invention, reversed
The drug resistance of tumour cell reduces the toxic side effect to human body.
Autophagy inhibitor by one or more of safe doses of the invention forms composition of medicine with Afatinib can be into one
Compound medicine is made for treating the tumor patients such as non-small cell lung cancer, breast cancer, liver cancer and chronic myelogenous leukemia in step.
Detailed description of the invention
Fig. 1, Fig. 2 show cell viability after various concentration Afatinib effect H1975 and H1650 cell different time.
Fig. 3 shows the change of cell related apoptosis protein content after various concentration Afatinib function cells different time
Change.
Fig. 4 shows that the Afatinib under laser confocal microscope induces tumour cell H975 and H1650 autophagosome
Generation result.
Fig. 5 shows that Western-blot detects autophagy GAP-associated protein GAP LC3-II/LC3-I expression.
Fig. 6, which is shown, inhibits cell autophagy enhancing Afatinib killing tumor cell effect.
Fig. 7 shows that western-blot detection inhibits the expression of autophagy GAP-associated protein GAP Lc3 after cell autophagy.
Fig. 8 shows that joint autophagy inhibitor CQ ratio is applied alone afatinib more and can inhibit the development of tumour.
Specific embodiment:
The experiment of 1 Afatinib inducing apoptosis of tumour cell of embodiment
After adenocarcinoma of lung H1975 and H1650 cell grows to the logarithm raw phase, with 5*105The concentration of cells/mL is transferred to cell
Culture, gives 0 μM, 2.5 μM, 5 μM, 10 μM, 20 μM of Afatinibs in culture plate, continuously cultivates 48h, and 10 μ L MTT reaction is added
Liquid, 37 DEG C are protected from light solution and educate 4h；It sufficiently reacts to generate after first is praised with intracellular succinic acid acidohydrogenase after MTT and 150 μ L DMSO is added
Dissolution first is praised, and the OD value of each group is measured at 570nm, is 100% progress cell viability percentage conversion with the OD of control group, and
Statistical analysis is carried out with graphpad, as a result as shown in figures 1 and 2；
It collects by 0 μM, 2.5 μM, 5 μM, 10 μM, 20 μM of Afatinib processing for 24 hours and by 10 μM of Afatinib processing
0h, 3h, 6h, 12h, H1975 and H1650 cell for 24 hours, with RIPA lysate crack extract total protein of cell, BCA kit into
Row protein quantification carries out protein electrophoresis by every 20 μ g protein content loading of hole and transferring film carries out Western blot, sent out with ECL chemistry
Light kit carries out chemiluminescence, as the result is shown, H1975 the and H1650 cell death related protein handled by Afatinib
The expression quantity of Cleaved-PARP increases at dose dependent and time dependence compared with the control group, due to Cleaved-PARP
Expression quantity and being positively correlated property of Apoptosis degree, the expression quantity of Cleaved-PARP is higher, Apoptosis it is more serious (as scheme
Shown in 3), the experimental results showed that, Afatinib can induce significantly H1975 and H1650 cell undergoes apoptosis；Experimental result
Show, Afatinib has the function of inducing apoptosis of tumour cell, and the effect increases at dosage and time dependence.
2 Afatinib of embodiment induces the experiment of tumour cell autophagy
10 μM of Afatinibs have been handled to H1975 the and H1650 cell and cellular control unit Cyto-ID autophagy phase of 48h
By being observed under the laser confocal microscope of 560nm in excitation wavelength after the albumen LC3-II protein staining reagent dyeing of pass,
As a result as shown in Figure 4: having handled in the cytoplasm of the H1975 and H1650 cell of 48h and existed more by 10 μM of Afatinibs
Green fluorescence spot, and green fluorescence spot number depend on autophagy body associated protein Lc3-II expression, therefore with
Control group is compared, and Afatinib can significantly induce the LC3-II expression quantity of H1975 and H1650 cell to raise, i.e., induction of two plants
Autophagy occurs for tumour cell；
It collects by 0 μM, 2.5 μM, 5 μM, 10 μM, 20 μM of Afatinib processing for 24 hours and by 10 μM of Afatinib processing
0h, 3h, 6h, 12h, H1975 and H1650 cell for 24 hours, with RIPA lysate crack extract total protein of cell, BCA kit into
Row protein quantification carries out protein electrophoresis by every 20 μ g protein content loading of hole and transferring film carries out Western blot, sent out with ECL chemistry
Light kit carries out chemiluminescence, as the result is shown, H1975 the and H1650 cell autophagy GAP-associated protein GAP handled by Afatinib
The expression quantity of LC3II increases at dose dependent and time dependence compared with the control group, due to the expression quantity and autophagy of LC3II
The being positively correlated property of quantity of body, the expression quantity of LC3II is higher, and cell autophagy is also more active (as shown in Figure 4), experimental result table
Bright, Afatinib can induce H1975 and H1650 cell that cell autophagy occurs significantly.
Embodiment 3 inhibits the apoptosis of tumor cells experiment of cell autophagy enhancing Afatinib induction
There is alkalescent based on chloroquine itself while there is the characteristic of lysosome, the acidic environment of lysosome can be destroyed,
The activity for inhibiting monoacylglycerol lipase, the enzymes such as phospholipase A2, prevent the substances such as the long-lived proteins in autophagosome packet from
Autophagy vesica is caused to be accumulated in the cell by lysosomal degradation；With 3-MA is the inhibition of Group III phosphatidyl-inositol 3-kinase
Agent is converted to Lc3II by inhibiting Beclinl-PI3KC3 compound to form suppressed FCM LC3-I, makes Lc3-II/Lc3-I's
Ratio decline, the decline of the ratio mean that the formation of autophagosome is suppressed；
This experiment using 2.5 μM Afatinib intervene H1975 and H1650 cell, and before administration 2h be added 3-MA or
CQ inhibits cell autophagy, and continuous culture is rear for 24 hours, and directly by 10 μ L MTT reaction solutions are added, 37 DEG C are protected from light solution and educate, to MTT and into the cell
Succinic acid acidohydrogenase sufficiently react generate first praise after be added 150 μ L DMSO dissolution first praise, in 570nm at measurement each group OD
Value carries out cell viability percentage conversion with the OD of control group for 100%, and carries out statistical analysis with graphpad, as a result
As shown in Figure 6: compared with the control group, the cell viability of the H1975 and H1650 cell by 2.5 μM of Afatinib interventions has aobvious
Work property decline (p < 0.01), the cell viability of the H1975 and H1650 cell of addition autophagy inhibitor 3-MA and CQ and simple Ah method
Cell viability for H1975 with the H1650 cell of Buddhist nun's intervention is compared, and is had conspicuousness reduction, is proved that autophagy inhibitor and A Fa replace
The administering drug combinations of Buddhist nun can enhance the drug effect of Afatinib, and only the cell viability of the experimental group of inhibiting 3-MA and CQ with it is right
According to group compared to no significant difference, illustrate that inhibitor itself grows without obvious inhibiting effect cell；Therefore, the experimental results showed that,
The cell activity for the H1975 and H1650 cell that autophagy inhibitor and the administering drug combinations of Afatinib are reduced is not inhibitor
Caused by synergistic effect with drug, but due to enhancing killing of the Afatinib to H1975 and H1650 cell after inhibiting autophagy
Effect；
The Experiment on Function that the present embodiment further progress cell autophagy plays in Afatinib induction tumour cell, and adopt
With the expression of Western-blot detection autophagy GAP-associated protein GAP LC3: by each group H1975 and H1650 cell in 6 porocyte plates
Interior continuous culture 48h, using 2.5 μM Afatinibs intervene H1975 and H1650 cell, and before administration 2h be added 3-MA or
The cell autophagy of CQ inhibition H1975 and H1650 cell；Each group H1975 and H1650 cell is cracked after being collected by centrifugation with RIPA
Total protein of cell is extracted in liquid cracking, carries out protein electrophoresis by every 20 μ g protein content loading of hole after BCA is quantitative and transferring film carries out
Western blot carries out chemiluminescence with ECL chemical luminescence reagent kit, the results show that the Afatinib by 2.5 μM is handled
The expression quantity of LC3II of H1975 and H1650 cell be above control group, the LC3II of Afatinib and 10 μM of CQ combination groups
The LC3II expression quantity of expression quantity Gao Yu Unit Afatinib group, Afatinib and 2mM 3-MA combination group, which is lower than, is applied alone Ah method to replace
Buddhist nun, the experimental results showed that the cell autophagy for the H1975 and H1650 cell that CQ and 3-MA can effectively inhibit Afatinib to induce.
4 Nude mice model of embodiment further verifies the curative effect for inhibiting autophagy that can improve afatinib
By H1975 cell kind in culture dish, 37 DEG C of feeding casees are put in, cell is made constantly to cultivate amplification.It is closed to cell quantity
After suitable, with trypsin digestion cell, gained cell is collected in centrifuge tube, 1200rpm/min is centrifuged 10min, gently absorbs
Clearly, with 1640 culture medium by gained cell mass be made cell density be 1 × 107/ml suspension, by centrifuge tube be placed on ice to
With；It is drawn 100 μ L cell suspensions with the syringe of 1ml and is injected in nude mice front right-leg and subcutaneously located, 5 groups of total co-injection, every group 9
Nude mice observes the tumour growth situation of mouse daily, until mouse tumor volume reaches 200mm3When, every group is selected 6 at random
It is only used as group member.And start administration (control group: administration mode: stomach-filling, dosage be containing 0.5% carboxymethyl cellulose and
The 100 μ L/d of physiological saline of 0.2% Tween 80；CQ group, administration mode；Intraperitoneal injection, dosage CQ, 50mg/kg/d；
Afatinib group: administration mode: stomach-filling, dosage afatinib, 20mg/kg/d；Administering drug combinations group: administration mode: stomach-filling+abdomen
Chamber injection, dosage CQ, 50mg/kg/d CQ+afatinib, 20mg/kg/d；Positive controls: administration mode: intraperitoneal injection,
Dosage is cis-platinum, 10mg/kg/d).The weight and measuring and calculating mouse tumor volume size of mouse are weighed within every 3 days, until suffer from tumor mouse
Terminate to test when dead, it is conventional to dissect mouse, tumour is taken out, knurl weight and gross tumor volume are measured；As a result, it was confirmed that inhibiting autophagy that can mention
The curative effect of high afatinib.
Claims (8)
1. cell autophagy inhibitor and Afatinib pharmaceutical composition, which is characterized in that inhibited by one or more cell autophagies
The Afatinib of agent and Formulas I structure composition,
2. cell autophagy inhibitor according to claim 1 and Afatinib pharmaceutical composition, which is characterized in that described is thin
Born of the same parents' autophagy inhibitor is selected from 3-MA (3-Methyladenine, 3-MA), chloroquine (Chloroquine),
LY294002, Bava Lip river mycin A1, ammonium chloride or hydroxychloroquine (hydroxychloroquine).
3. cell autophagy inhibitor according to claim 1 and Afatinib pharmaceutical composition, which is characterized in that described is thin
Born of the same parents' autophagy inhibitor is chloroquine (Chloroquine) or 3-MA (3-Methyladenine, 3-MA).
4. cell autophagy inhibitor according to claim 1 and Afatinib pharmaceutical composition, which is characterized in that described Ah
Method is second generation tyrosine kinase inhibitor (Tyrosine kinase inhibitor, TKI) for Buddhist nun (afatinib), can be strong
It imitates and irreversible is integrated to ATP binding pocket in EGFR molecule.
5. cell autophagy inhibitor according to claim 1 and Afatinib pharmaceutical composition, which is characterized in that the medicine
Compound medicine is made in compositions.
6. cell autophagy inhibitor as described in claim 5 and Afatinib pharmaceutical composition, which is characterized in that described answers
Cell autophagy inhibitor in recipe object and Afatinib using combine or sequential administration by the way of.
7. Claims 1-4 any the cell autophagy inhibitor and Afatinib pharmaceutical composition are being used to prepare tumour
Purposes in Synergistic preparations, the tumour are the non-small cell lung cancer of EGFR genetic mutation, breast cancer, liver cancer or chronic myelogenous
Leukaemia.
8. purposes according to claim 7, which is characterized in that the cell autophagy inhibitor and Afatinib pharmaceutical composition
Object improves Afatinib antitumous effect.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111150848A (en) * | 2020-01-21 | 2020-05-15 | 中国药科大学 | PLAGL2 and application thereof in liver cancer |
| CN113797339A (en) * | 2020-06-11 | 2021-12-17 | 复旦大学 | Pharmaceutical composition of pyoluteorin and autophagy inhibitor and application |
| CN114984242A (en) * | 2022-05-17 | 2022-09-02 | 刘天龙 | Method for treating tumors by ubiquitin-proteasome pathway and autophagy double inhibition |
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| CN104324035A (en) * | 2013-07-23 | 2015-02-04 | 复旦大学 | Composition of autophagy inhibitor and lapatinib, and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104324035A (en) * | 2013-07-23 | 2015-02-04 | 复旦大学 | Composition of autophagy inhibitor and lapatinib, and application thereof |
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| XU X等: "Blocking autophagy improves the anti-tumor activity of afatinib in lung adenocarcinoma with activating EGFR mutations in vitro and in vivo", 《SCIENTIFIC REPORTS》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111150848A (en) * | 2020-01-21 | 2020-05-15 | 中国药科大学 | PLAGL2 and application thereof in liver cancer |
| CN111150848B (en) * | 2020-01-21 | 2022-02-15 | 中国药科大学 | PLAGL2 and application thereof in liver cancer |
| 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 |
| CN114984242A (en) * | 2022-05-17 | 2022-09-02 | 刘天龙 | Method for treating tumors by ubiquitin-proteasome pathway and autophagy double inhibition |
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