CN115054592A - Application of compound in preparation of medicine for treating proliferative hepatocellular carcinoma - Google Patents
Application of compound in preparation of medicine for treating proliferative hepatocellular carcinoma Download PDFInfo
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- CN115054592A CN115054592A CN202210787815.3A CN202210787815A CN115054592A CN 115054592 A CN115054592 A CN 115054592A CN 202210787815 A CN202210787815 A CN 202210787815A CN 115054592 A CN115054592 A CN 115054592A
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The invention relates to an application of a compound in preparing a medicine for treating proliferative hepatocellular carcinoma, belonging to the technical field of biological medicines. The invention provides application of a compound Elesclomol in preparation of a medicine for treating hepatocellular carcinoma. And an application of Elesclomol in preparing a medicine for treating diseases related to hepatocellular carcinoma metastasis. The hepatocellular carcinoma is a proliferative hepatocellular carcinoma with high malignancy and poor prognosis.
Description
Technical Field
The invention relates to an application of a compound in preparing a medicine for treating proliferative hepatocellular carcinoma, belonging to the technical field of biological medicines.
Background
Primary liver cancer is the common malignant tumor at the 4 th place in China and the 2 nd cause of death due to tumor, wherein 85% -90% of primary liver cancer is hepatocellular carcinoma. Hepatocellular carcinoma is a malignant tumor with high heterogeneity, including intratumoral heterogeneity, and many other aspects. The heterogeneity of hepatocellular carcinoma is manifested in various levels of gene mutation, gene expression, and posttranslational modification, and hepatocellular carcinoma can be classified into subtypes having different biological and clinical characteristics based on these differences. Proteomics based on mass spectrometry technology can quantitatively detect the protein level of the whole cells or tissues, and therefore can more directly reflect the biological characteristics of tumors. In the previous research of the inventor team, liver cancer patients are divided into 3 subtypes by an unsupervised clustering algorithm based on proteins which are differentially expressed in cancer and paracancer tissues: metabolic, immune microenvironment, proliferative; wherein the proliferative form has a high degree of malignancy and a worst prognosis [ Cell,2019,179(2): 561-. Therefore, there is an urgent need in the art to develop new drugs to prolong the survival time of patients with proliferative hepatocellular carcinoma.
Disclosure of Invention
The invention aims to solve the technical problem of how to obtain a novel medicament for prolonging the survival time of a proliferative hepatocellular carcinoma patient.
In order to solve the problems, the invention provides an application of Elesclomol (CAS No.: 488832-69-5) in preparing a medicine for treating hepatocellular carcinoma.
Preferably, the hepatocellular carcinoma is a proliferative hepatocellular carcinoma with a high degree of malignancy and a poor prognosis.
Preferably, the proliferative hepatocellular carcinoma exhibits an increased level of proliferation-associated proteins.
Preferably, the proliferation-associated protein comprises CBX4, DDX21, JMJD6, LIG1, MCM2, MCM6, MKI67, MSH2, NDRG1, PARP1, PCNA, pool 3, POLR1E, PRMT3, PYCR2, RAD1, RHEB, SQSTM1, TOP2A or XRCC 1.
The invention provides an application of Elesclomol (CAS No.: 488832-69-5) in preparing a medicine for treating hepatocellular carcinoma, wherein the dosage form of the medicine comprises tablets, powder, granules, capsules, oral liquid, injection or sustained release agents.
The invention provides an application of Elesclomol (CAS No.: 488832-69-5) in preparing a medicine for treating diseases related to hepatocellular carcinoma metastasis.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a new medicine for prolonging the survival time of a proliferative hepatocellular carcinoma patient; provides a medicine with clinical application prospect for the treatment of proliferative hepatocellular carcinoma.
Drawings
FIG. 1 is a schematic diagram showing the inhibitory activity of different drugs on different proliferative liver cancer primary cells (HCC703, HCC3434, HCC 4739);
FIG. 2 is a graph of Elesclomol inhibiting the growth of proliferative liver cancer.
Wherein Elesclomol inhibits JHH-7 with an IC50 of 37.9nM in panel A; elesclomol inhibited SNU-423 in panel B with an IC50 of 17.5 nM; elesclomol (40nM) inhibits JHH-7 cell viability in panel C; elesclomol (20nM) inhibited SNU-423 cell viability in panel D.
FIG. 3 is a graph of Elesclomol inhibiting the growth of proliferative liver cancer.
Graph A is a statistical graph of the proportion of EdU-positive cells for JHH-7 (.: P < 0.05); panel B is a statistical plot of the fraction of EdU-positive cells for SNU-423 (P < 0.05);
FIG. 4 is a graph of Elesclomol's ability to inhibit clonogenic and migratory activities of JHH-7 cells.
Wherein, A graph and D graph are the scratch test for detecting the influence of Elesclomol on JHH-7 cell migration ability; b and E are graphs obtained by detecting the influence of Elesclomol on the migration capacity of JHH-7 cells through a Transwell experiment; panel C and F are plate cloning experiments to examine the effect of Elesclomol on the clonogenic capacity of JHH-7 cells. (P <0.05, P < 0.01);
FIG. 5 is a graph of Elesclomol's ability to inhibit clonogenic and migratory activities of SNU-423 cells.
Wherein, A graph and D graph are scratch experiments for detecting the influence of Elesclomol on the cell migration capacity of SNU-423; b and E are graphs obtained by detecting the influence of Elesclomol on the cell migration capacity of SNU-423 through a Transwell experiment; panels C and F are plate cloning experiments to examine the effect of Elesclomol on the clonogenic capacity of SNU-423 cells. (. P <0.05, P <0.01)
Detailed Description
In order to make the invention more comprehensible, preferred embodiments are described in detail below with reference to the accompanying drawings:
as shown in figures 1-5, the technical scheme adopted by the invention is to provide the application of Elesclomol (CAS No.: 488832-69-5) in preparing a medicine for treating hepatocellular carcinoma.
The hepatocellular carcinoma is a proliferative hepatocellular carcinoma having a high degree of malignancy and a poor prognosis.
The proliferative hepatocellular carcinoma is characterized by an increase in the level of a protein involved in proliferation.
The above proliferation-related proteins include CBX4, DDX21, JMJD6, LIG1, MCM2, MCM6, MKI67, MSH2, NDRG1, PARP1, PCNA, POLE3, POLR1E, PRMT3, PYCR2, RAD1, RHEB, SQSTM1, TOP2A or XRCC 1.
The invention provides an application of Elesclomol (CAS No.: 488832-69-5) in preparing a medicine for treating hepatocellular carcinoma, wherein the dosage form of the medicine comprises tablets, powder, granules, capsules, oral liquid, injection or sustained release agents.
The invention provides an application of Elesclomol (CAS No.: 488832-69-5) in preparing a medicine for treating diseases related to hepatocellular carcinoma metastasis.
The invention provides an application of an active ingredient Elesclomol (CAS No.: 488832-69-5) or a preparation containing the active ingredient, wherein the active ingredient Elesclomol (CAS No.: 488832-69-5) or a pharmaceutically acceptable salt thereof; and the preparation of the active ingredient is used for preparing an inhibitor for treating hepatocellular carcinoma; and/or a medicament for treating and/or preventing and relieving the relevant diseases caused by the hepatocellular carcinoma.
The relevant disease caused by hepatocellular carcinoma is hepatocellular carcinoma metastasis.
Such inhibitors or drugs include: oral and non-oral formulations.
The compound or the pharmaceutically acceptable salt thereof is used for preparing a proliferative hepatocellular carcinoma medicament.
In the earlier research, 3 subtypes (metabolic type, immune microenvironment type and proliferative type) of liver cancer primary cells are classified based on protein markers, the proliferative liver cancer primary cells with the worst prognosis are selected for screening high-throughput clinical drugs, the relative cell activity is less than 0.3, and the proliferative liver cancer primary cells are taken as the standard of drugs for effectively inhibiting the growth of liver cancer, wherein Elesclomol is the drug with the strongest inhibition capacity in 3 proliferative liver cancer primary cells. Subsequently, proliferative liver cancer cell lines JHH-7 and SNU-423 were selected, and the effects of Elesclomol on proliferation, clonality and migratory ability of hepatocellular carcinoma were investigated by cell function tests. The results show that elesclomal can inhibit proliferation, clonogenic and migratory capacity of proliferative hepatocellular carcinoma in vitro.
Examples
Applying primary cells to study compounds effective against proliferative hepatocellular carcinoma;
1. hepatocellular carcinoma primary cell proteomics:
taking a tissue sample beside the cancer as an internal standard sample, taking a primary cell sample as a sample to be detected, adding a sample lysate, performing shake decomposition at 4 ℃, centrifuging at 11000rpm for 30min, and collecting a supernatant protein lysate. After protein denaturation and reductive alkylation, trypsin is added into the protein solution, and the mixture is subjected to enzyme digestion on a shaking table overnight. Desalting and gradient eluting the peptide fragment with C18, and vacuum concentrating to dry. TMT labeling was performed using a TMT10plex labeling kit, and the protocol was performed according to the instructions provided with the kit. From each sample 50. mu.g of polypeptide was added to 50. mu.L of 100mM TEAB, and different labeling reagents were added. After reacting at room temperature for 1h, 5% hydroxylamine was added and concentrated to dryness in vacuo. The labeled peptide fragment was desalted and gradient eluted with C18 after redissolving in 0.1% TFA, and concentrated to dryness in vacuo for LC-MS analysis.
2. Protein marker typing of hepatocellular carcinoma cells:
and performing library searching analysis on the identified peptide fragments by using MaxQuant software. To correct for errors caused by loading variations, proteomic results were normalized using a median center algorithm and subjected to a log2 transformation. The missing values for proteins identified in more than half of the samples were filled in using the KNN algorithm. According to the proliferation, immunity and metabolism related protein markers found in previous studies, proliferation, immunity and metabolism scoring of hepatocellular carcinoma cells was performed using ssgsea (single Sample Gene Set analysis) method. And (3) establishing a hepatocellular carcinoma typing model by using a support vector machine algorithm and taking proteomics ssGSEA scoring and typing in a previous study as a training set, and typing the hepatocellular carcinoma cells according to the typing model.
3. Drug screening was performed on proliferating hepatocellular carcinoma primary cells:
when the cells were grown to 90% density, 0.25% pancreatin was digested, washed once with PBS, centrifuged and the supernatant discarded. Adding complete culture medium, and blowing and beating uniformly at density of 2 × 10 4 and/mL. Cells were plated evenly onto 384-well plates using an automated liquid sorter. Drug was transferred to Cell culture plates using the Cell Explorer high throughput screening workstation at a concentration of 200 μ M clinical compound library, with 0.1 μ L of drug added per well to a final concentration of 400 nM. After the drug treatment, 10. mu.L of CellTiter-Glo reagent was added to each well, and the luminescence intensity was measured after shaking for 1 min. Relative cell activity was calculated by normalizing the cell activity of the other drugs added to each plate with the cell activity of DMSO added as a reference.
4. Cell function test:
CCK-8 cell proliferation assay: cells were added at a density of 3,000/well in 96-well plates. Cells were allowed to adhere by overnight culture. The cells were treated with the addition of the drug. The culture medium was discarded and CCK-8 solution diluted with medium was added. After the reaction was carried out for 30min at 37 ℃ in the dark, A450 was detected by a microplate reader.
EdU cell proliferation assay: cells were added to six-well plates and cultured overnight to allow the cells to adhere. Drug-treated cells were added, the culture medium was discarded, and a preheated EdU solution (10. mu.M) at 37 ℃ was added. Incubate at 37 ℃ for 2 h. The culture medium was discarded, and 1mL of the immunostaining fixative was added to each well and fixed at room temperature for 15 min. The fixative was removed and the cells were washed 3 times with 1mL wash for 5min each. 1mL of the permeation solution was added to each well and incubated at room temperature for 15 min. The permeate was removed and the cells were washed 3 times for 5min each with 1mL of wash solution. A Click reaction solution was prepared, and 0.5mL of the Click reaction solution was added to each well. Mix gently, incubate for 30min at room temperature in the dark. The Click reaction solution was removed and the cells were washed 3 times with 1mL of wash solution for 5min each. 1mL of Hoechst 33342 working solution is prepared, and the mixture is incubated for 10min at room temperature in a dark place. The Hoechst 33342 working solution was removed and the cells were washed 3 times with 1mL of wash solution for 5min each time. And (4) taking pictures and counting by a fluorescence microscope.
Clone formation experiments: cells in the logarithmic growth phase were trypsinized and diluted with complete medium. To six well plates, 1000 cells per well were added and cultured overnight to allow the cells to adhere. The cells were treated with the addition of the drug. Cells were continuously cultured in the incubator and every 3 days half of the medium was aspirated and the corresponding volume of fresh medium and drug was added for 14 days. The culture medium was removed and the cells were washed 3 times with PBS solution. Adding 4% paraformaldehyde solution, and fixing for 15 min. Removing the fixing solution, adding crystal violet staining solution, and staining for 15 min. Rinsing in clean water and drying. And (6) counting the photographed images.
Cell scratch test: cells were trypsinized and the complete medium resuspended. The six-well plate was seeded with a corresponding number of cells to allow 24h of cell confluency. And adding the medicament to treat the cells after the cells adhere to the wall. After 24h the complete medium was removed and vertically streaked with a 200. mu.L tip. Cells were gently washed 2 times with PBS solution. Adding serum-free medium, and culturing for 2 days. The photographic records were observed with a microscope at 0, 24, 48h, respectively.
Transwell experiment: cells were digested with trypsin, the medium was completed to stop digestion, and the supernatant was discarded by centrifugation. Resuspending in serum-free medium to 5X 10 6 Single cell suspension/mL. Add 500. mu.L of single cell suspension and drug to the upper well. 1.5mL of complete medium was added to the lower well. After 48h the chamber was removed, the medium was discarded and the PBS solution was washed 3 times. Fixing with 4% paraformaldehyde solution for 15 min. The fixative was removed and the cells inside the chamber were gently wiped off with a cotton swab. The chamber was stained in crystal violet staining solution for 15 min. Observed in a microscope and photographed.
The experimental results are as follows:
as shown in fig. 1, fig. 1 is a schematic diagram of the inhibitory ability of different drugs on different proliferative liver cancer primary cells (HCC703, HCC3434, HCC 4739); the figure shows that Elesclomol is the drug with the strongest inhibitory capacity in 3 strains of proliferative liver cancer primary cells (HCC703, HCC3434 and HCC 4739).
As shown in FIG. 2, FIG. 2 is a graph showing that Elesclomol inhibits the growth of proliferative liver cancer. Wherein Elesclomol inhibits IC50 of JHH-7 at 37.9nM in panel A; elesclomol inhibited SNU-423 in panel B with an IC50 of 17.5 nM; elesclomol (40nM) inhibits JHH-7 cell viability in panel C; elesclomol (20nM) inhibited SNU-423 cell viability in panel D.
As shown in FIG. 3, FIG. 3 is a graph of Elesclomol inhibiting the growth of proliferative liver cancer. Wherein, A is a statistical graph of the proportion of EdU positive cells to JHH-7 (P < 0.05); panel B is a statistical plot of the fraction of EdU-positive cells for SNU-423 (: P < 0.05); the results show that: elesclomol inhibits the growth of proliferative liver cancer.
As shown in FIG. 4, FIG. 4 is a graph of the ability of Elesclomol to inhibit clonogenic and migratory activities of JHH-7 cells. Wherein, A graph and D graph are used for detecting the influence of Elesclomol on JHH-7 cell migration capacity through a scratch test; b and E are graphs obtained by detecting the influence of Elesclomol on the migration capacity of JHH-7 cells through a Transwell experiment; panel C and F are plate cloning experiments to examine the effect of Elesclomol on the clonogenic capacity of JHH-7 cells. (P <0.05, P < 0.01); the results show that: elesclomol inhibits the clonal formation and migration ability of JHH-7 cells.
As shown in fig. 5, fig. 5 is a graph of the ability of Elesclomol to inhibit clonal formation and migration of SNU-423 cells. Wherein, A graph and D graph are scratch experiments for detecting the influence of Elesclomol on the cell migration capacity of SNU-423; b and E are graphs obtained by detecting the influence of Elesclomol on the cell migration capacity of SNU-423 through a Transwell experiment; panels C and F are plate cloning experiments to examine the effect of Elesclomol on the clonogenic capacity of SNU-423 cells. (P <0.05, P < 0.01); the results show that: elesclomol inhibits the clonogenic and migratory capacity of SNU-423 cells.
Any compound containing an Elesclomol structure or a combination or pharmaceutically acceptable salt thereof or a composition thereof is expected to become a novel drug for treating proliferative hepatocellular carcinoma.
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention. Those skilled in the art can make various changes, modifications and equivalents to the disclosed technology without departing from the spirit and scope of the present invention, and all such changes, modifications and equivalents are intended to be included therein as equivalents of the present invention; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (6)
- Use of Elesclomol (CAS No.: 488832-69-5) for the preparation of a medicament for the treatment of hepatocellular carcinoma.
- 2. The use of claim 1, wherein the hepatocellular carcinoma is a proliferative hepatocellular carcinoma with high malignancy and poor prognosis.
- 3. The use according to claim 2, wherein said proliferative hepatocellular carcinoma is characterized by an increased level of proliferation-associated proteins.
- 4. Use according to claim 3, wherein the proliferation-related proteins comprise CBX4, DDX21, JMJD6, LIG1, MCM2, MCM6, MKI67, MSH2, NDRG1, PARP1, PCNA, POLE3, POLR1E, PRMT3, PYCR2, RAD1, RHEB, SQSTM1, TOP2A or XRCC 1.
- 5. The use according to any one of claims 1 to 4, wherein the medicament is in a dosage form selected from the group consisting of tablets, powders, granules, capsules, oral liquids, injections and sustained release formulations.
- Use of Elesclomol (CAS No.: 488832-69-5) in the preparation of a medicament for treating diseases related to hepatocellular carcinoma metastasis.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20080119440A1 (en) * | 2006-08-31 | 2008-05-22 | Keizo Koya | Combination with Bis(thiohydrazide amides) for treating cancer |
| US20140329892A1 (en) * | 2011-11-10 | 2014-11-06 | Synta Pharmaceuticals Corp. | Administration of a bis(thiohydrazide amide) compound for treating cancers |
| CN104703623A (en) * | 2012-03-19 | 2015-06-10 | 普莱希科公司 | Compounds and methods for kinase modulation, and indications therefor |
| CN113365610A (en) * | 2018-10-04 | 2021-09-07 | 现代化制药公司 | Methods of making and delivering bisantrene formulations |
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2022
- 2022-07-06 CN CN202210787815.3A patent/CN115054592A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080119440A1 (en) * | 2006-08-31 | 2008-05-22 | Keizo Koya | Combination with Bis(thiohydrazide amides) for treating cancer |
| US20140329892A1 (en) * | 2011-11-10 | 2014-11-06 | Synta Pharmaceuticals Corp. | Administration of a bis(thiohydrazide amide) compound for treating cancers |
| CN104703623A (en) * | 2012-03-19 | 2015-06-10 | 普莱希科公司 | Compounds and methods for kinase modulation, and indications therefor |
| CN113365610A (en) * | 2018-10-04 | 2021-09-07 | 现代化制药公司 | Methods of making and delivering bisantrene formulations |
Non-Patent Citations (1)
| Title |
|---|
| XINGXING HUO ET AL.: "Identification of an autophagy-related gene signature that can improve prognosis of hepatocellular carcinoma patients", BMC CANCER, pages 1 - 13 * |
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