CN106748829A - A kind of compound for promoting human cancer cell that apoptosis occurs and its application - Google Patents
A kind of compound for promoting human cancer cell that apoptosis occurs and its application Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
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Abstract
The invention discloses a kind of compound for promoting human cancer cell that apoptosis occurs and its application.The compound is that title is 2 (4 hydroxyanilines) phenol, the compound can with the p53 protein bindings of people after, it is the conformation of wild type to recover mutant p53 albumen, improves the transcriptional activity of p53 albumen, cause cancer cell that apoptosis occurs, so as to suppress the propagation of cell；Compound of the invention can induce cancer cell that apoptosis occurs, for the successive treatment of cancer provides a kind of new thinking with the p53 protein bindings of people by changing the p53 protein transcriptions activity being mutated in cancer cell.
Description
Technical field
The present invention relates to a kind of compound, a kind of compound for promoting cancer cell that apoptosis occurs and its application are relate to, should
Compound is can to induce cancer cell that apoptosis occurs by changing the transcriptional activity of the p53 albumen being mutated in cancer cell.
Background technology
P53 albumen, as transcription factor, is the guarder of genome, and p53 albumen can be activated when genome occurs to damage
Transcriptional activity, so as to cause the retardance of cell cycle and the apoptosis of cell.Found according to existing statistics, in 50% human cancer
P53 there occurs point mutation, so as to have impact on the function of p53 albumen.And thering is pertinent literature to report, the p53 albumen of mutation recovers
Activity can significantly prevent the occurrence and development of cancer.
The screening of traditional p53 protein activation factors is the screening from cell aspect mostly, by building p53 protein deficiencies
Cell line, then filters out the compound of the cell line that can influence p53 defects from existing compound library, and the compound
The normal cell lines of p53 are not influenceed.By this screening technique, some external research institutions have discovered that and several can swash
The compound of mutant p53 albumen living.In these compounds, have plenty of directly with the p53 protein bindings being mutated so as to improve p53
The stability of albumen and function, on the other hand, some compounds can indirectly by changing and p53 protein-interactings
Albumen and the p53 albumen of activated mutant.Because the probability that p53 albumen is undergone mutation in cancer is very big, finding can be special
The opposite sex and mutant p53 protein binding simultaneously recover the function of its wild type, and the treatment for cancer can provide a beneficial think of
Road.
The content of the invention
In order in solving the problems, such as background technology, the present invention propose a kind of compound for promoting cancer cell that apoptosis occurs and
Its application, the transcriptional activity of the p53 albumen that the compound passes through activated mutant in the present invention, and promote cancer cell and wither
Die, for the treatment of cancer provides a kind of thinking.
The technical solution adopted by the present invention is：
First, a kind of compound for promoting cancer cell that apoptosis occurs：
The compound is 2- (4- hydroxyanilines) phenol, and its molecular formula is as follows：
The compound specifically synthesizes in the following ways：
Compound dimethyl sulfoxide (DMSO) (DMSO) dissolves, and is positioned over after packing in -80 DEG C of refrigerators and is preserved.
The compound can with the p53 protein bindings of people after, it is the conformation of wild type to recover mutant p53 albumen, is drawn
Play cancer cell and apoptosis occurs.
2nd, the application of compound is in anticancer and prepares the application of cancer therapy drug.
The compound can with the p53 protein bindings of people after, it is the conformation of wild type to recover mutant p53 albumen, is drawn
Play cancer cell and apoptosis occurs, so as to realize antitumaous effect.
The compound can suppress the apoptosis that cell is bred and promotes cell, by increasing capacitance it is possible to increase the transcriptional activity of p53 albumen.
The compound can in vitro with the recombinant P 53 protein binding of people.
Described recombinant P 53 albumen is the fusion protein that glutathione transferase (GST) is label.
Described recombinant P 53 albumen is built in the following ways：
A) in by building the cDNA library of people, expanded by PCR and obtain Human p53 gene and be wild type by sequencing
P53 genes, then using Fast Mutagenesis System kits, obtain 175 arginine sport histidine and
The mutant p53 genes of cysteine are sported in 220 tyrosine；
B) p53 genes and mutant p53 genes that wild type is obtained in step a) are passed through into restriction endonuclease BamH1 and Xho1
It is connected to after double digestion on the vector pGEX 6p-2 plasmids of prokaryotic expression, is then transformed into prokaryotic expression bacterial strain BL21DE3；
C) the prokaryotic expression bacterial strain BL21DE3 in step b) is added different when 37 DEG C of cultures to OD600 are 0.6 or so
Propyl dithiocarbamate galactoside makes its concentration in nutrient solution for 0.5mM, then shakes bacterium culture collects thalline, uses phosphate-buffered
Liquid re-suspended cell, ultrasonication takes supernatant and Glutathione sepharose 4FastFlow agarose mediums after centrifugation
With reference to after 4 degrees Celsius are incubated 3 hours, with 30ml phosphate buffer cleansing mediums, then being washed with 10mM reduced glutathiones
It is de-, obtain recombinant P 53 albumen.
The present invention be by compound recombinate GST-p53 albumen be incubated after, by sephadex chromatography post
After sephadex G50 fillers, the protein peak under outflow G50 sephadex column 280nm wavelength, albumen meeting and compound are collected
With reference to, and flow out G50 fillers together with albumen, prove that the compound can in vitro occur phase interaction with compound with this
With.
Specifically prove that the compound can be with the p53 protein bindings of restructuring in the following ways：
It is incubated 1 hour at a temperature of 25 DEG C with the recombinant P 53 albumen and the compound that are obtained from prokaryotic expression system, so that
Albumen can be combined sufficiently with compound, then (gather Portugal protein micromolecular compound by molecular sieve sephadex G50
Sugared gel G50, GE Healthcare, the U.S.), protein peak is collected after outflow G50 sephadex columns, again with methanol after freezing
Dissolving, after the albumen of centrifugation removal denaturation, takes the compound of supernatant, as with the protein bound compound of recombinant P 53.
It is assumed that after the compound and p53 protein bindings, protein micromolecular compound is formd, during by G50 gel columns,
P53 albumen is much larger than compound due to molecular weight, so can be flowed out from G50 pillars earlier than compound, and if p53 albumen with
After the compound combines to form compound, can first be flowed out from pillar with micromolecular compound, it is therefore desirable to collect 280nm ripples
Lower protein peak long, is then lyophilized, again with methanol dissolving, and after the albumen of centrifugation removal denaturation, the compound in supernatant is used
GC-MS (GC-MS) is identified, obtained and the protein bound compound of recombinant P 53.
The present invention implements to obtain the pure compounds by organic synthesis, and the work(of the compound is verified by cell experiment
Can, by MTS, Caspase3/7 enzyme activity determinations find that the compound can suppress the apoptosis that cell is bred and promotes cell, lead to
Annexi V/PI dyeing is crossed, flow cytometer is determined, it is found that the compound suppresses the propagation of cancer cell by apoptosis really,
Then by building the luciferase reporting plasmid containing the promoter combined with p53, the luciferase after compound treatment is determined
Activity, so as to learn that the compound can increase the transcriptional activity of p53.
The beneficial effects of the invention are as follows there is provided a kind of energy specifically with p53 protein bindings and then recover its wild type function
Compound, by the transcriptional activity of the p53 albumen of activated mutant, and promotes cancer cell generation apoptosis, and experiments verify that
The compound can suppress the apoptosis that cell is bred and promotes cell, by increasing capacitance it is possible to increase the transcriptional activity of p53.
Brief description of the drawings
Fig. 1 is the mass spectrogram that the compounds of this invention is identified with GC-MS (GC-MS).
Fig. 2 is NMR (nuclear magnetic resonance) figure that the compounds of this invention is identified with the NMR (nuclear magnetic resonance) of 1H.
Fig. 3 is cell propagation feelings of the embodiment by MTS measuring A375 cells after various concentrations compound treatment
Condition schematic diagram.
Fig. 4 is that embodiment is obtained under different compound concentration treatment, detects the caspase3/7 enzyme activity numbers of A375 cells
Amount situation map, under 50uM and 10uM, cell caspase3/7 enzyme activity increases, apoptosis.
Fig. 5 is that embodiment A375 cells are processed with after the compounds of this invention treatment in DMSO respectively, uses Annexin V/PI
Method detects the schematic diagram of Apoptosis situation.
Fig. 6 be embodiment after the compound treatment of various concentrations, A375 cells by western blot detect cell
The expression figure of interior p53 albumen.
Fig. 7 be embodiment after the compound treatment of various concentrations, MDA-MB-435 cells are examined by western blot
Survey the expression figure of intracellular p53 albumen.
Fig. 8 is that embodiment A375 cells use monoclonal antibody again after being processed with DMSO and the compounds of this invention respectively
The result figure of two-photon laser Laser Scanning Confocal Microscope after simultaneously fluorescence secondary antibody is marked after Pab1620 treatment.
Specific embodiment
The invention will be further described with reference to the accompanying drawings and examples.
Embodiments of the invention are as follows：
1) restructuring GST-p53 albumen is built, is marked using GST labels：
A) by extracting the RNA of MCF-7 cells (a kind of breast cancer cell, p53 albumen is wild type) with Trizol methods, so
It is with PrimeScriptTMII 1st Strand cDNA Synthesis Kit (TAKRA, Dalian is precious raw biological) that RNA is anti-afterwards
Switch to single-stranded DNA, and with this single stranded DNA as template, the p53 genes of the wild type for obtaining people are expanded by PCR, then use
Fast Mutagenesis System (Transgen, Beijing Quanshijin Biotechnology Co., Ltd) kit, obtains 175
Arginine (R) sports histidine (H), and 220 tyrosine sport the mutant p53 genes of cysteine (C), wild type and
The p53 gene orders of saltant type pass through sequence verification；
B) p53 genes and mutant p53 genes that wild type is obtained in step a) are passed through into restriction endonuclease BamH1 and Xho1
(Thermo) it is connected to after double digestion on the vector pGEX 6p-2 of prokaryotic expression (GE Healthcare) plasmid, is then transformed into
In prokaryotic expression bacterial strain BL21DE3；
C) it is 0.6 the prokaryotic expression bacterial strain BL21DE3 in step b) to be cultivated to OD600 (600nm optical density) at 37 DEG C
During left and right, isopropylthiogalactoside (IPTG, gala sugar analogue) is added to make its concentration in nutrient solution be 0.5mM；
Then bacterium culture 20h is shaken under 16 DEG C and rotating speed 120rpm, then collects thalline, with phosphate buffer (PBS) re-suspended cell,
Ultrasonication, is purified by Glutathione sepharose 4FastFlow (GE Healthcare) agarose column and obtained
Restructuring GST-p53 albumen.
2) the above-mentioned product that obtains is using the restructuring further in-vitro screening of GST-p53 albumen：
With the restructuring GST-p53 albumen that is obtained from prokaryotic expression system and said extracted to compound at a temperature of 25 DEG C
It is incubated 1 hour, then by this mixture over-molecular sieve sephadex G50, (sephadex G 50, GE Healthcare are beautiful
State), the protein peak under 280nm wavelength is collected after outflow G50 sephadex columns, again with methanol dissolving after freezing, centrifugation removal
After the albumen of denaturation, the compound of supernatant is taken, as with the restructuring protein bound compounds of GST-p53, then extracted this
The compound for arriving carries out the identification of compound with gas chromatography-mass spectrum (GC-MS, Thermo Fisher).
After having micromolecular compound and protein binding, as at first albumen one flow out from pillar, without with albumen knot
The micromolecular compound of conjunction then flows out after albumen, therefore collects albumen, then with methanol extraction compound therein.
Embodiment identifies chromatographic mass spectrometry figure such as Fig. 1 institutes of the compounds of this invention with GC-MS (GC-MS)
Show, gas chromatography-mass spectrum (GC-MS) identification embodiment obtain with recombinant P 53 albumen specific bond after compound, electronics Hong
Hit ionize to obtain fragment ion peak mass spectrum as scheme (energy of 70 electron volts), then by with NIST (American National Standard and Technical Board)
The data of 2005 editions can carry out the comparing of forward and reverse, and the possibility molecular formula and structural formula for obtaining the compound are as follows：
And the 1H NMR (nuclear magnetic resonance) of the compound are as shown in Figure 2.
3) embodiment verifies the function of the compound by cell experiment further below, if can have influence on cancer cell
Propagation, apoptosis.Find that the compound can be different degrees of by the treatment to several plants of gastric carcinoma cell lines and breast cancer cell line
Promotion these cancer cells apoptosis, and verified by the method that caspase3/7 enzyme activity and Annexin V/PI are dyeed.
The compound that further embodiments of the invention are obtained is verified in the following ways, it was demonstrated that the compounds of this invention
After treatment cancer cell, the increment of cancer cell can be suppressed under the concentration of 50uM/L, promote cancer cell that apoptosis occurs.
MDA-MB-435 cells (breast cancer cell, purchased from American Type culture center ATCC) L15 culture mediums 10%
The culture of 37 DEG C of hyclone (FBS), A375 cells (MC, purchased from ATCC) DMEM culture mediums, 10% tire ox
Serum (FBS) is in 5% carbon dioxide, 37 DEG C of cultures.Growth conditions good A375 cells and MDA-MB-435 cells are taken, is taped against
96 orifice plates, 10000 each holes of cell after making cell pellet overnight adherent, add control dimethyl sulfoxide (DMSO) (DMSO), make its final concentration
It is tri- concentration gradients of 1% (V/V, volume ratio) and treatment group 100uM, 50uM, 10uM, after making compound effects 24h, uses
Caspase-GloTM37 cell apoptosis detection kits (Promega, the U.S.) chemiluminescence sends out thin after detection compound is processed
The enzyme activity (caspase3/7) of intracellular aspartic acid specificity cysteine protease 3 and 7.If after compound treatment, cell
Generation apoptosis, then the enzymatic activity of intracellular caspase3/7 can increase.
Meanwhile, in order to further confirm that the compound can promote cancer cell that apoptosis occurs, also with Annexin V/PI methods
Detect the early apoptosis of cell.Its specific method is as follows：6 orifice plates spread A375 cells and MDA-MB-435 cells, and 200000 thin
Each hole of born of the same parents, after making cell attachment 12h, adds final concentration of 1% dimethyl sulfoxide (DMSO) (DMSO) conduct control, is subsequently adding
The compound treatment cell of 100uM, 50uM, 10uM, after processing 4 hours, with FITC Annexin V Apoptosis
Detection Kit I (the BD U.S.) this kit marks cell, is then detected with flow cytometer (the Beckman U.S.) and withered
Die.If after compound treatment, cell there occurs apoptosis, then early stage apoptosis, the phosphatidylserine meeting on cell membrane
Translated into from inside and outside cell membrane extracellular, just can be combined with this phosphatide Specific binding proteins of Annexin V, but Annexin V
By FITC (fluorescein isothiocynate) couplings, and then nucleus is divided by PI (propidium iodide) specific staining with drain cell instrument
Analysis fluorescing matter, so as to obtain the situation of the Apoptosis after compound treatment.
4) compound can change the conformation of mutant p53 albumen, the conformation for making it return to wild-type p 53 protein.
Two kinds of special the monoclonal antibody Pab1620 and Pab240 (the Abcam U.S.) for wherein using, wherein Pab1620 is capable of identify that
The p53 albumen of wild type conformation, and Pab240 can recognize that the p53 albumen of saltant type conformation, by MDA-MB-435 cells and
A375 cells are taped against in culture dish respectively, with DMSO and the compound treatment cell for being dissolved in DMSO, after processing 24 hours, use PBST
(phosphate buffer and Tween20) by cell rupture of membranes, after being blockaded 1 hour with BSA (bovine serum albumin(BSA)), with Pab1620 and
Pab240 and cell incubation 12 hours, then with a kind of secondary antibody Alexa Fluor488Dye with the anti-mouse of green fluorescence
After (Molecular probe, the U.S.) is processed 1 hour, then 5 points are processed with DAPI (a kind of blue-fluorescence fuel of dye nucleus)
Clock, it is then strong and weak with two-photon laser Laser Scanning Confocal Microscope (Zesiss, Germany) observation blue-fluorescence before and after compound treatment
Change, so as to obtain the change of p53 protein conformations after compound treatment.
The compound that embodiment is obtained is added separately to A375 cells and MDA-MB-435 cells and carries out cell propagation detection,
96 orifice plates paving cell, 10000/hole, treats that cell pellet overnight is adherent, is then respectively adding the compound treatment of various concentrations, DMSO groups
As control (three are repeated as a group), then with MTS (tetrazole compound, Promega companies), the every holes of 20ul/, then 37
After DEG C being incubated 2h, the light absorption value in often hole is detected 490nm at ELIASA, as a result as shown in Figure 3.
Determine cell after compound treatment, the enzyme activity of intracellular caspase3/7.Because during apoptosis, mainly
It is that Apoptosis occurs by activation caspase3/7, the coupling trip luciferase provided with Promega companies
Caspase substrates, when caspase3/7 plays a role, can cut substrate and send fluorescence, and fluorescent value size is reflected
The size of caspase3/7 enzyme activity, and then reflect the situation that apoptosis occurs, as a result as shown in Figure 4.It is visible in figure, MDA-MB-
In 435 cells, under 50uM and 10uM, it is found that cell caspase3/7 enzyme activity increases, apoptosis.
Flow cytomery after compound treatment, the situation of apoptosis.50000 cells are taped against 6 holes
Plate, makes its adherent 12 hour by 50000/hole, then processes cell after 24 hours with DMSO and 50uM compound treatments, uses
The lower attached cell of pancreatin digestion, then washed with cold PBS, then with Annexin V/PI mark 15 minutes at room temperature, then with stream
Formula cell instrument detects apoptosis situation, as a result as shown in Figure 5.
Two figures represent embodiment by A375 cells after DMSO (left side) and 50uM compound treatments respectively above Fig. 5
(right side), after marking dyeing with Annexin V/PI, by flow cytomery early apoptosis of cells ratio, visible 50uM in figure
Apoptosis degree is obvious after compound treatment.
The figure of Fig. 5 figure below two represent respectively by MDA-MB-435 cells (one plant of breast cancer cell) in DMSO (left side) and
After 50uM compound treatments (right side), after marking dyeing with Annexin V/PI, by flow cytomery early apoptosis of cells
Ratio, flow cytomery Apoptosis degree is obvious after visible 50uM compound treatments in figure.
In order to verify that the compound promotes the mechanism of Apoptosis, detect first in compound treatment, intracellular p53 eggs
The change of Bai Hanliang, therefore in 6 orifice plates, per 50000, hole cell, it is overnight adherent after, with compound treatment 24 hours, then will
Cell dissociation gets off, then ultrasonication, is detected in the case of different disposal by the method for western blot, intracellular
The change of p53 protein contents.Result difference is as shown in Figure 6 and Figure 7.Visible in Fig. 6, A375 cells are examined by western blot
Survey intracellular p53 albumen and express not variant in compound treatment.Visible MDA-MB-435 cells pass through in Fig. 7
Western blot detect that intracellular p53 albumen expresses not variant in compound treatment.
MDA-MB-435 cells after above-mentioned treatment are respectively with used after DMSO and 50uM compound treatments of the present invention can be with spy
Monoclonal antibody Pab1620 (abcam) treatment of the identification p53 wild type conformations of the opposite sex, and with pair light after fluorescence secondary antibody mark
Sub- confocal laser scanning microscope, its result is respectively such as Fig. 5 left sides and .MDA-MB-435 cells 50uM concentration shown in right side
Compound treatment cell after, the change of intracellular p53 wild type proteins conformation is detected with Pab1620, wherein A is control group
Blue-fluorescence intensity after DMSO treatment, B is the intensity of blue-fluorescence after 50uM compound treatments, it can be seen that at compound
The wild type conformation of albumen increases after reason, as a result as shown in figure 8, and found by the method for fluorescent co-location, change when with this
After compound treatment, the dyeing of pab1620 monoclonal antibodies is deepened, and by contrast, the dyeing of pab240 monoclonal antibodies weakens, thus
The transcriptional activity of p53 albumen can actually be significantly improved after the compound treatment.
Thus provable compound of the invention can promote the apoptosis of cell by strengthening the transcriptional activity of p53,
The change of intracellular p53 protein contents can not be changed after compound treatment cell, but the conformation of p53 albumen can be changed,
And promote the transcriptional activity of p53 albumen.
Above-mentioned visible, the compound of the invention is strictly that, by influenceing the activation plays function of p53 albumen, and can enter one
Step builds reporter plasmid of the transcription land containing p53 downstream genes as promoter.
Claims (9)
1. there is the compound of apoptosis in a kind of promotion cancer cell, it is characterised in that：The compound is 2- (4- hydroxyanilines) phenol,
Its molecular formula is as follows：
2. there is the compound of apoptosis in a kind of promotion cancer cell according to claim 1, it is characterised in that：The compound
Dissolved with dimethyl sulfoxide (DMSO) (DMSO), be positioned over after packing in -80 DEG C of refrigerators and preserved.
3. there is the compound of apoptosis in a kind of promotion cancer cell according to claim 1, it is characterised in that：The compound
Can with the p53 protein bindings of people after, it is the conformation of wild type to recover mutant p53 albumen, causes cancer cell that apoptosis occurs.
4. the application of compound according to claim 1, it is characterised in that：It is anticancer and the application for preparing cancer therapy drug.
5. the application of compound according to claim 4, it is characterised in that：The compound can be with the p53 albumen of people
With reference to rear, recover the conformation that mutant p53 albumen is wild type, cause cancer cell that apoptosis occurs, so as to realize antitumaous effect.
6. the application of compound according to claim 4, it is characterised in that：The compound can suppress cell and breed and promote
Enter the apoptosis of cell, by increasing capacitance it is possible to increase the transcriptional activity of p53 albumen.
7. according to the application of any described compound of Claims 1 to 4 or any described compound of claim 5~6,
It is characterized in that：The compound can in vitro with the recombinant P 53 protein binding of people.
8. the application of compound according to claim 7 or compound, it is characterised in that：Described recombinant P 53 albumen
It is that glutathione transferase (GST) is the fusion protein of label.
9. the application of compound according to claim 7 or compound, it is characterised in that：Described recombinant P 53 albumen
Built in the following ways：
A) in by building the cDNA library of people, expanded by PCR and obtain Human p53 gene and by p53 that sequencing is wild type
Gene, then using Fast Mutagenesis System kits, obtain 175 arginine sport histidine and
220 tyrosine sport the mutant p53 genes of cysteine；
B) the p53 genes and mutant p53 genes of wild type will be obtained in step a) by the double enzymes of restriction endonuclease BamH1 and Xho1
It is connected to after cutting on the vector pGEX 6p-2 plasmids of prokaryotic expression, is then transformed into prokaryotic expression bacterial strain BL21DE3；
C) the prokaryotic expression bacterial strain BL21DE3 in step b) is added into isopropyl when 37 DEG C of cultures to OD600 are 0.6 or so
Thiogalactoside makes its concentration in nutrient solution for 0.5mM, then shakes bacterium culture collects thalline, uses phosphate buffer weight
Outstanding cell, ultrasonication takes supernatant and the FastFlow agarose medium knots of Glutathione sepharose 4 after centrifugation
Close, after 4 degrees Celsius are incubated 3 hours, with 30ml phosphate buffer cleansing mediums, then washed with 10mM reduced glutathiones
It is de-, obtain recombinant P 53 albumen.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111073947A (en) * | 2018-10-19 | 2020-04-28 | 三峡大学 | Apoptosis detection kit and detection method and application thereof |
| CN112159327A (en) * | 2020-10-28 | 2021-01-01 | 浙江大学 | Compound for inhibiting proliferation of human cancer cells in nude mice |
-
2016
- 2016-11-23 CN CN201611047565.0A patent/CN106748829A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| NICOLAS BASSE ET AL.: "Toward the Rational Design of p53-Stabilizing Drugs：Probing the Surface of the Oncogenic Y220C Mutant", 《CHEMISTRY & BIOLOGY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111073947A (en) * | 2018-10-19 | 2020-04-28 | 三峡大学 | Apoptosis detection kit and detection method and application thereof |
| CN112159327A (en) * | 2020-10-28 | 2021-01-01 | 浙江大学 | Compound for inhibiting proliferation of human cancer cells in nude mice |
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