CN110090208A - Corylin is preparing Nrf2 inhibitor, is inhibiting the application of the drug of related disease, anticancer drug with Nrf2 - Google Patents
Corylin is preparing Nrf2 inhibitor, is inhibiting the application of the drug of related disease, anticancer drug with Nrf2 Download PDFInfo
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- CN110090208A CN110090208A CN201910334332.6A CN201910334332A CN110090208A CN 110090208 A CN110090208 A CN 110090208A CN 201910334332 A CN201910334332 A CN 201910334332A CN 110090208 A CN110090208 A CN 110090208A
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Abstract
The present invention relates to field of medicaments, and in particular to corylin is used to prepare Nrf2 inhibitor, inhibits the drug of related disease, the application in anticancer drug with Nrf2.The present invention provides a kind of new applications of corylin, it can lower Nrf2 protein expression level, reduce the anti-oxidation stress ability of Non-small cell lung carcinoma cell A549, chemotherapeutic drugs Cisplatin is improved to the apoptosis-promoting effect of A549, can be used as Nrf2 inhibits drug to use, and uses as anti-lung-cancer medicament；When corylin as drug in use, animal experiments show that, corylin has no significant effect animal liver and kidney.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to corylin has in preparation Nrf2 inhibitor, with Nrf2 inhibition
The application of the drug, anticancer drug of the disease of pass.
Background technique
Psoralea corylifolia is the ripening fruits of legumes psoraleae Psoralea corylifoliaL., has a variety of pharmacology living
Property, it is gradually paid close attention to by people in anti-tumor aspect.Studies have shown that the psoralen and isopsorapen in psoralea corylifolia can inhibit
The proliferation of gastric carcinoma cells BGG-823, Bakuchiol also have apparent inhibited proliferation, psoralea corylifolia to hepatoma Hep G 2 cells
B prime can not only inhibit squamous cell carcinoma of tongue Tca8113 cell Proliferation but also can induce the apoptosis of human hepatoma HepG2 cell.
Although psoralea corylifolia has good effects in anti-tumor aspect, specific mechanism of action does not illustrate completely yet.Li Peng
Profound (hydrant water supply system combines clinical research [D] the Traditional Chinese Medicine University Of Guangzhou of Tarceva treatment non-small cell lung cancer, 2016:15.) refers to
Out, psoralea corylifolia drug ingedient is by inhibiting the different approaches such as topoisomerase II, archaeal dna polymerase and cytotoxicity to play anti-tumor
Activity, psoralea corylifolia can induce the denaturation of tumour cell mitochondria, the decline of apoptosis suppressor gene Bcl2 expression promotes Apoptosis；
Wu Xia (the anti-non-small cell lung cancer Tumor Angiongesis research of Jianpi Bushen Huayu disintoxication [D] Traditional Chinese Medicine University Of Guangzhou, 2013:
7.) it points out, psoralea corylifolia plays antitumaous effect and relies primarily on psoralen, and psoralen, which has mice sarcoma cell, efficiently to be killed
Effect, principle are " psoralen forms complex compound with mice sarcoma cell DNA and molecule interlinks, so that DNA be inhibited to synthesize ".
Existing research shows that the activation of Nrf2-ARE signal path can promote the generation of lung cancer, develop and to chemicotherapy
It resists, reduce apoptosis of tumor cells and promote tumor cell proliferation, and accumulation of the Nrf2 in nucleus is to lead to tumour cell
The one of the major reasons of drug resistance are obtained, therefore, in the lung cancer therapy strategy of Nrf2-ARE signal pathway activated, very necessary hair
The Nrf2 of Zhan Xin inhibits drug.Corylin (Corylin) is isolated a kind of isoflavone compound from psoralea corylifolia,
Existing literature shows that corylin has treatment atherosclerosis (patent CN107737121A), cardiovascular disease, obesity, Ah
The effects of Zi Haimo disease, diabetes (CN105343051A), but corylin is based on as anticancer medicine and corylin
The inhibition of Nrf2 signal does not have technical solution proposition to the therapeutic effect of cancer.
Summary of the invention
The purpose of the present invention is to provide a kind of new applications of corylin, i.e., its be used to prepare Nrf2 inhibitor, with
Nrf2 inhibits the application of the drug of related disease, anticancer drug, with one or several in solving the above problems.
According to an aspect of the invention, there is provided corylin is preparing the application in Nrf2 inhibitor, wherein Psoralen
The peaceful structural formula of rouge is as follows:
Experiment shows that the corylin of various concentration is able to suppress the activity of the luciferase of ARE dependence, and inhibits energy
Power rises with the increase of corylin dosage, prompts corylin to be able to suppress the relevant oxidative stress transduction of Nrf2-ARE logical
Road.
According to another aspect of the present invention, the medicament that corylin inhibits related disease in preparation with Nrf2 is provided
The application of aspect, wherein corylin structural formula is as follows:
In some embodiments, drug is made of corylin and pharmaceutically acceptable excipient.
In some embodiments, drug is capsule, granule, tablet, pill or oral solution.
In some embodiments, disease is cancer.Specifically, cancer is lung cancer.Experiment shows that corylin can be lowered
Nrf2 protein expression level reduces the anti-oxidation stress ability of Non-small cell lung carcinoma cell A549.
According to another aspect of the present invention, it provides corylin and cis-platinum is used to prepare the purposes of lung-cancer medicament,
In, corylin structural formula is as follows:
In some embodiments, drug is by the corylin and cis-platinum and pharmaceutically acceptable excipient group
At.
In some embodiments, drug is capsule, granule, tablet, pill or oral solution.
In some embodiments, anticancer refers specifically to anti-lung cancer.
The present invention is that applicant is based on more than 50 Chinese herbal medicines, therefrom screens, extracts, studies and complete, passes through test
It was found that corylin exclusive use is suitable with DDP to the inhibiting effect of human lung carcinoma cell line A549 subcutaneous transplantation tumor, join with cis-platinum
Closing to use inhibits tumor effect stronger, thus provides a kind of new application of corylin, can lower Nrf2 protein expression water
It is flat, the anti-oxidation stress ability of Non-small cell lung carcinoma cell A549 is reduced, improves chemotherapeutic drugs Cisplatin to the rush apoptosis of A549
Effect can be used as Nrf2 and drug inhibited to use, and uses as anticancer especially lung-cancer medicament；When corylin is as drug
In use, animal experiments show that, corylin has no significant effect animal liver and kidney.
Detailed description of the invention
Fig. 1 is the uciferase activity comparison diagram of various concentration corylin；
Fig. 2 is the electrophoretic image that corylin influences Nrf2, HO-1, AKR1 protein expression；
Fig. 3 is that each test group inhibits Xenografts in nude mice growing state；
Fig. 4 is each test group Mouse Liver kidney HE slice map.
Specific embodiment
With reference to the accompanying drawing and test to corylin provided by the present invention for Nrf2 inhibitory effect, treatment and its
Inhibition has related disorders, anti-lung cancer effect to be described in further detail.
One, inhibiting effect of the corylin to Nrf2
1, test material
1) cell is tested
Transfect Antioxidant responsive element-luciferase plasmids human breast cancer cell cell line (MDA-MB-231-ARE-
Luc), Arizona, USA University Medical institute pharmacology and toxicity system provide.
2) test medicinal material: corylin is purchased from Hiroad standing grain medical sci-tech Development Co., Ltd.
3) test reagent
DMSO is purchased from Sigma company, and fetal calf serum is purchased from Hyclone development company, and DMEM high glucose medium is purchased from
In Gibco company, phosphate buffer (PBS) is purchased from Hyclone development company, and luciferase immue quantitative detection reagent box is purchased from
In ThermoFisher company.
4) test apparatus
20/20 chemiluminescence detector of automated cell calculating instrument model Countstar IC100, GloMax is purchased from
Promega company.
2, test method
48 orifice plate culture MDA-MB-231-ARE-Luc cell lines are added different dense when convergence degree reaches 50%-70%
It spends gradient corylin (DMSO dissolution), receives cell for 24 hours.Illustrate to dilute lysate 5X PLB (passive according to kit
Lysis buffer), remove cell culture fluid, washes one time with PBS to remove remaining culture medium, 80ul 1X is added in every hole
PLB.Culture plate is shaken into 20min in room temperature on shaking table, cracks cell sufficiently.20ul cell pyrolysis liquid, 50ul in EP pipe
Luciferase assay reagent, pipette tips beat 2-3 times up and down, measure in light-emitting appearance, read, and carry out after recording data
Statistical analysis.
3, test result
Test result is as described in Figure 1, and data are as shown in table 1, and shown by comparison: the corylin of various concentration can
The activity for the luciferase for inhibiting ARE to rely on, and rejection ability rises with the increase of corylin dosage, prompts corylin
The relevant oxidative stress Signal Transduction Pathways of Nrf2-ARE are able to suppress, and studies have shown that Nrf2-ARE is cellular oxidation stress reaction
Critical path, play an important role antitumor, anti-inflammatory, liver diseases, neurotrosis etc. are many-sided.
Influence of 1 the compounds of this invention of table to the ARE uciferase activity relied on
| Concentration (umol/L) | Fluorescent value (A.U) |
| 1 | 6.28±0.11 |
| 2.5 | 3.2±0.21 |
| 5 | 2.31±0.19 |
| 10 | 1.69±0.22 |
| 15 | 0.39±0.04 |
| 20 | 0.24±0.01 |
Table 1 the result shows that, corylin can effectively inhibit ARE rely on uciferase activity, inhibition level is with dosage
It increases and is incremented by.
Two, corylin lowers Nrf2 protein level
1, test material
1) cell is tested
Non-small cell lung carcinoma cell line A549, the regeneration of Guangdong Provincial Medicine Research Institute are provided with translational medicine center.
2) test medicinal material: corylin is purchased from Hiroad standing grain medical sci-tech Development Co., Ltd.
3) test reagent
DMSO is purchased from Sigma company, and fetal calf serum is purchased from Hyclone development company, and DME M high glucose medium is purchased from
In Gibco company, phosphate buffer (PBS) is purchased from Hyclone development company, and NP-40 cell pyrolysis liquid is purchased from green cloud
Its company, BCA determination of protein concentration kit are purchased from ThermoFisher company；Anti-GAPDH antibody
(ab8245)、Anti-Nrf2antibo dy(ab62352)、Anti-HO-1antibody(ab52947)、Anti-
AKR1C1antibody(ab192785)、Goat Anti-Rabbit IgG(ab6721)。
4) test apparatus
20/20 chemiluminescence detector of automated cell calculating instrument model Countstar IC100, GloMax is purchased from
Promega company.
2, test method
A549 cell inoculation 6 orifice plates reach 50%-70% or so to convergence degree and various concentration DMSO dissolution psoralea corylifolia are added
Rather, cell is collected in processing afterwards for 24 hours, discards culture medium, and PBS is cleaned one time, adds appropriate trypsin digestion and cell, and culture medium terminates
Digestion collects cell suspension into centrifuge tube.1100rpm, 5min centrifugation, abandon supernatant, and cleaning 2 times is resuspended (every time with PBS
1100rpm, 5min).
The NP-40 lysate that 1ml has diluted is added in every pipe, and sufficiently piping and druming uniformly, is placed in and cracks 30-45min on ice.Low temperature
4 DEG C of centrifuge pre-coolings, the sufficiently rear 12000g of cell cracking, 15min centrifugation carefully draw supernatant with liquid-transfering gun, mounted in new EP
It is marked in pipe, carries out protein quantification detection according to BCA kit operation instruction, calculate WB loading volume, protein sample adds 4
× loading buffer, 100 DEG C of heating 5min albuminous degenerations are placed in -20 DEG C and save backup.
PAGE gel is configured, the gel slab solidified is assembled into electrophoresis tank, internal layer fills it up with fresh electrophoresis liquid, outer layer
Add appropriate electrophoresis liquid not have gel slab following, extracts comb vertically upward.By BCA it is quantitative after calculate volume each group successively on
Sample.Add 5ul albumen Maker on the comb hole of sample both sides.
Correctly connect each interface of electrophoresis tank after end of the sample, constant pressure 110V electrophoresis about 1h, to protein sample close to running out of point
Stop electrophoresis when from glue.Soak is taken out in transferring film buffer, cuts the filter paper and pvdf membrane of suitable size.Filter paper soaks
Buffer, pvdf membrane are placed in methanol and activate, and are successively put on transferring film instrument electrode plate according to the sequence of filter paper, film, glue, filter paper,
It drives bubble out of, seals electrode plate clip, assemble constant pressure 90V transferring film 1h after transferring film instrument.
It configures confining liquid (5% skimmed milk power), pvdf membrane is placed in shaking table in confining liquid and is incubated at room temperature 1h.According to being detected
The molecular size range of albumen cuts pvdf membrane, and by specification confining liquid dilutes antibody, pvdf membrane is placed in primary antibody dilution and is shaken
4 DEG C of closings of bed are overnight.TBST carries out secondary antibody incubation after washing film after primary antibody is incubated for, and being incubated for after 1h, which terminates TBST, washes film.Configuration
Film is placed in develop in chemiluminescence imaging system after good developer solution and is exposed.
3, test result
As a result as shown in Fig. 2, corylin starts to show obviously to inhibit to make in 10uM to Nrf2 in A549 cell line
With, and with the increase of dosage, inhibiting effect is also become apparent from, also, Nrf2 regulate and control as nuclear factor HO-1,
The protein level of the downstream genes such as AKR1CI is significantly reduced.Show corylin can the Nrf2 intracellular to A549 play suppression
Production is used.
Three, corylin and its combination with cisplatin transplant the therapeutic effect of nude mice to human lung cancer cell A549
1, test material
1) experimental animal
6 week old BALB/c male nude mouses, weight 18-22g are provided by Traditional Chinese Medicine University Of Guangzhou's Experimental Animal Center.
2) cell is tested
Non-small cell lung carcinoma cell line A549, the regeneration of Guangdong Provincial Medicine Research Institute are provided with translational medicine center.
3) test medicinal material: corylin is purchased from Hiroad standing grain medical sci-tech Development Co., Ltd.
4) test reagent
Cisplatin for injection (DDP, freeze-dried type) is purchased from Qilu Pharmaceutical Co., Ltd.；Corn oil is purchased from Guangdong Changxing food
Trade Co., Ltd, 0.9% sodium chloride injection are purchased from Beijing Co., Ltd, Double-Crane Pharmaceutical Co., Ltd, and DMSO is purchased from Sigma company,
Fetal calf serum source Hyclone development company, DMEM high glucose medium are purchased from Gibco company, and phosphate buffer (PBS) is purchased from
In Hyclone development company, trypsase-EDTA digestive juice is purchased from Gibco company.
5) test apparatus: automated cell calculating instrument model Countstar IC100.
2, test method
By after A549 cell recovery as being cultivated in 37 DEG C of cell incubators, when cell grow to about 90% or more converge when biography
In generation, is inoculated into new culture bottle according to a biography three or biography four, and passage expands culture to suitable modeling quantity repeatedly.
Culture medium in culture bottle is risen and is discarded, appropriate pancreatin digestive juice, microscopic observation cell rounding is added after PBS cleaning
Or appropriate culture medium is added when falling off and terminates digestion, centrifuge tube is sucked after piping and druming, low-speed centrifugal 5min is discarded supernatant, and PBS is added
Cleaning 2-3 times carries out cell count, and according to cell quantity 107/100ul PBS diluting cells suspension, whole process is on ice
It carries out.
Then the syringe being pre-chilled in advance with 1ml draws the cell suspension mixed and squeezes into oxter on the right side of nude mice, every mouse
100ml cell suspension.80mm is grown to lotus knurl3Mouse is grouped and is marked at random.
4 groups are randomly divided into, every group at least 5, the molten DMSO of corn oil, the molten corylin of corn oil are injected intraperitoneally respectively
(10mg/kg), the water-soluble cis-platinum of physiology salt (2mg/kg) and corylin combination with cisplatin, every other day injection treatment is primary, weight
It is 5 times multiple.The weight of every mouse is weighed every time and observes tumour growth state, with the longest diameter (a) of vernier caliper measurement tumour
Most short diameter (b), according to V=1/2ab2It calculates gross tumor volume and records.
Nude mice materials are put to death in last time administration afterwards every other day.
3, test result
As shown in figure 3, compared to the control group, corylin group, cis-platinum group are able to suppress the growth of Xenografts in nude mice,
And compared with corylin list medicine group, cis-platinum list medicine group, administering drug combinations group becomes apparent the inhibiting effect of transplantable tumor.This shows
Corylin can be improved chemotherapeutic drugs Cisplatin to the inhibiting effect of A549.
Influence of 2 the compounds of this invention of table to human lung carcinoma cell line A549 subcutaneous transplantation tumor size
| Group | Dosage | Knurl accumulates (mm3) | Tumour inhibiting rate (%) |
| Blank | 0 | 309±38.91 | |
| DDP | 2mg/kg | 99.16±1.8 | 67.91 |
| Corylin group | 10mg/kg | 99.41±2.42 | 67.83 |
| Corylin+DDP group | - | 68.87±5.69 | 77.71 |
The results are shown in Table 2 for influence of each group to human lung carcinoma cell line A549 subcutaneous transplantation tumor size, illustrates corylin
Exclusive use is suitable with DDP to the inhibiting effect of human lung carcinoma cell line A549 subcutaneous transplantation tumor, is swollen with cisplatin combined using inhibition
Tumor effect is stronger.
It is prompted by above-mentioned test, corylin can be used for preparing Nrf2 inhibitor, have related disorders (outstanding with Nrf2 inhibition
It is lung cancer) drug, anti-lung-cancer medicament (if being used in conjunction with existing drug, can reach better anti-lung cancer effect), institute herein
The drug said refers to, main active is corylin, then again plus pharmaceutically acceptable excipient composition capsule,
Granule, tablet, pill or oral solution.
Four, corylin tests mouse lesions of liver and kidney
1, test material
1) experimental animal
6 week old BALB/c male nude mouses, weight 18-22g are provided by Traditional Chinese Medicine University Of Guangzhou's Experimental Animal Center, qualified
Card number 11400700340882.
2) medicinal material and reagent are tested
Corylin is purchased from Hiroad standing grain medical sci-tech Development Co., Ltd；Corn oil is purchased from Guangdong Changxing food trade
Co., Ltd, DMSO are purchased from Sigma company, and phosphate buffer (PBS) is purchased from Hyclone development company, the purchase of HE dye liquor
From in Google's biology, dehydrated alcohol, dimethylbenzene are purchased from Tianjin great Mao chemical reagents corporation；
3) test apparatus:
Inverted phase contrast microscope (CKX41 Olympus), automated cell calculating instrument (Countstar IC100)；Biology peace
Full cabinet (BSC-1000IIAC)；Full-automatic dyeing mounting industrial workstation (LEICAST5020), tissue embedding machine
(HisTOSTAR), Full automatic closed tissue processor (SHANDON PATACENTRE), paraffin slicing machine (LEICA
RM2245)。
2, test method
Hematoxylin-eosin (Hematoxylin-eosin, HE) dyeing: carrying out the slice of paraffin sample with paraffin slicing machine,
3.5 μm of thickness, serial section, dyeing procedure is that roasting piece is 20 minutes dry, dimethylbenzene 2 times × 10 minutes, dehydrated alcohol 2 times × 2
Minute, 95% ethyl alcohol 1 minute, 80% ethyl alcohol 1 minute, 70% ethyl alcohol 1 minute, washing 1 minute, haematoxylin 8 minutes, haematoxylin 10
Minute, it washes 2 times × 1 minute, 0.5% hydrochloride alcohol 10 seconds, washes 10 minutes, 2 minutes, Yihong, wash 1 minute, 80% ethyl alcohol
5 seconds, 85% ethyl alcohol 5 seconds, 90% ethyl alcohol 5 seconds, 95% ethyl alcohol 1 minute, dehydrated alcohol 2 times × 2 minutes, dehydrated alcohol 3 minutes, two
Toluene 2 times × 2 minutes, neutral gum mounting was directly used after terminating dyeing.
3, test result
As a result as shown in figure 4, showing that corylin has no significant effect animal liver and kidney.Wherein, the visible sinus hepaticus of liver section,
Liver rope morphosis is complete, and liver has no nucleus oedema, and cytoplasm is without lesion；The visible glomerulus of Kidney sections is complete, and number
Amount is consistent with control group, and cytoplasm, nucleus have no pathological change form.
Above-described is only some embodiments of the present invention.For those of ordinary skill in the art, not
Under the premise of being detached from the invention design, various modifications and improvements can be made, these belong to protection model of the invention
It encloses.
Claims (10)
1. corylin is preparing the application in Nrf2 inhibitor, the corylin structural formula is as follows:
2. application of the corylin in the drug that preparation inhibits related disease with Nrf2, wherein the corylin structure
Formula is as follows:
3. application according to claim 2, which is characterized in that the drug is by the corylin and pharmaceutically acceptable
Excipient composition.
4. application according to claim 2, which is characterized in that the drug is capsule, granule, tablet, pill
Or oral solution.
5. according to the described in any item applications of claim 2~4, which is characterized in that the disease is cancer.
6. application according to claim 5, which is characterized in that the cancer is lung cancer.
7. corylin and cis-platinum are preparing the application in anticancer drug, wherein corylin structural formula is as follows:
。
8. application according to claim 7, which is characterized in that the drug is by the corylin and cis-platinum and pharmacy
Upper acceptable excipient composition.
9. application according to claim 7, which is characterized in that the drug is capsule, granule, tablet, pill
Or oral solution.
10. according to the described in any item applications of claim 7~9, which is characterized in that the anticancer refers to anti-lung cancer.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910334332.6A CN110090208B (en) | 2019-04-24 | 2019-04-24 | Application of psoralen in preparation of Nrf2 inhibitor, medicine for treating diseases related to Nrf2 inhibition and anticancer medicine |
| PCT/CN2019/092968 WO2020215481A1 (en) | 2019-04-24 | 2019-06-26 | Applications of psoralen in preparing nrf2 inhibitor, medicament for nrf2 inhibition-related diseases, and anticancer medicament |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910334332.6A CN110090208B (en) | 2019-04-24 | 2019-04-24 | Application of psoralen in preparation of Nrf2 inhibitor, medicine for treating diseases related to Nrf2 inhibition and anticancer medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110090208A true CN110090208A (en) | 2019-08-06 |
| CN110090208B CN110090208B (en) | 2021-11-23 |
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|---|---|---|---|
| CN201910334332.6A Active CN110090208B (en) | 2019-04-24 | 2019-04-24 | Application of psoralen in preparation of Nrf2 inhibitor, medicine for treating diseases related to Nrf2 inhibition and anticancer medicine |
Country Status (2)
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|---|---|
| CN (1) | CN110090208B (en) |
| WO (1) | WO2020215481A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101007050A (en) * | 2007-01-11 | 2007-08-01 | 浙江大学 | Extract of an traditional Chinese medicine containing isopsoralen, preparation method and use thereof |
| CN108283635A (en) * | 2018-04-19 | 2018-07-17 | 中国药科大学 | Corylin is used as the medical usage of HSP90AB1 inhibitor |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI556818B (en) * | 2015-08-07 | 2016-11-11 | 長庚大學 | Activator of mammalian sirt1 |
-
2019
- 2019-04-24 CN CN201910334332.6A patent/CN110090208B/en active Active
- 2019-06-26 WO PCT/CN2019/092968 patent/WO2020215481A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101007050A (en) * | 2007-01-11 | 2007-08-01 | 浙江大学 | Extract of an traditional Chinese medicine containing isopsoralen, preparation method and use thereof |
| CN108283635A (en) * | 2018-04-19 | 2018-07-17 | 中国药科大学 | Corylin is used as the medical usage of HSP90AB1 inhibitor |
Non-Patent Citations (3)
| Title |
|---|
| CHIN-CHUAN CHEN等: "Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair", 《CELL DEATH AND DISEASE》 * |
| CHI-YUAN CHEN等: "Corylin Suppresses Hepatocellular Carcinoma Progression via the Inhibition of Epithelial-Mesenchymal Transition, Mediated by Long Noncoding RNA GAS5", 《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》 * |
| 冯书云等: "靶向Rad51与肿瘤治疗的研究进展", 《现代生物医学进展》 * |
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| CN110090208B (en) | 2021-11-23 |
| WO2020215481A1 (en) | 2020-10-29 |
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