CN106929476A - A kind of application of demethylation reagent in human leukemia cell - Google Patents
A kind of application of demethylation reagent in human leukemia cell Download PDFInfo
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- CN106929476A CN106929476A CN201710198677.4A CN201710198677A CN106929476A CN 106929476 A CN106929476 A CN 106929476A CN 201710198677 A CN201710198677 A CN 201710198677A CN 106929476 A CN106929476 A CN 106929476A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0693—Tumour cells; Cancer cells
- C12N5/0694—Cells of blood, e.g. leukemia cells, myeloma cells
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2501/06—Anti-neoplasic drugs, anti-retroviral drugs, e.g. azacytidine, cyclophosphamide
Abstract
The invention provides a kind of application of demethylation reagent in human leukemia cell, specially basic element of cell division ortho Topolin Riboside, to the antitumor action of human leukemia cell line, belong to Biochemistry and Molecular Biology technical field as a kind of demethylation reagent.Data of the invention are set up in oTR to the in-vitro multiplication inhibitory activity that the 9 big knurls of people are that 60 kinds of tumor cell lines have highly significant, wherein on the basis most strong to the drug susceptibility of leukemia cell line.
Description
Technical field
The present invention relates to basic element of cell division ortho-Topolin Riboside (oTR) as a kind of demethylation reagent pair
The antitumor action of human leukemia cell line, belongs to Biochemistry and Molecular Biology technical field.
Background technology
Leukaemia is the malignant disease of hematopoietic tissue, also known as " leukemia ".Certain of hematopoietic cell is a series of, mainly a certain white
The precursor of cell series loses differentiation and maturation ability, in marrow neutralizes other hematopoietic tissues in malignant clone hyperplasia,
Accumulation, and liver, spleen, lymph node are invaded, final infiltration destruction body tissue, organ are suppressed normal hematopoiesis function.White blood
Disease is different from entity tumor, is not to be grown in local neoplasm, but whole body is disseminated, and may invade each system, organ and group
The malignant hematologic disease knitted.Clinical manifestation is anaemia, bleeding, infection and each organ infiltration's symptom.According to foreign statistic, leukaemia is about
3% or so of tumour total incidence is accounted for, is most common a kind of malignant tumour in children and youth.The incidence of disease of leukaemia is alive
In various countries of boundary, European and North America incidence of disease highest, its death rate is the populations of 3.2-7.4/10 ten thousand.Asia and South America incidence of disease compared with
Low, the death rate is the populations of 2.8-4.5/10 ten thousand.Traditional treatment is based on combined chemotherapy, and the complete remission rate of patient and long-term
DFS rate is relatively low, but conventional chemotherapeutics such as cytarabine (Ara-C) has the pairs such as bone marrow suppression, neurotoxicity
Effect.Therefore, find and effectively improve therapeutic efficiency, the small natural drug of toxic and side effect is come to treat leukaemia be very necessary.
The generation development of leukaemia is the complex process of multifactor participation, multi-step, is related to science of heredity and epigenetics
Change.Research in recent years finds that DNA methylation is the phenomenon of generally existing in human leukemia, is fallen ill with it closely related.
Promoter region CpG islands hyper-methylation (hypermethylation) are CDKN2, DNA-repair gene, promote apoptogene inactivation
One of major way.Miscellaneous nitrogen -2'- deoxycytidines (5-aza-2'-deoxycitydine, the 5- of methyltransferase inhibitors such as 5-
Aza-2dC the gene of silence of) making to methylate is expressed again, recovers its normal function, is had in leukemia treating good
Application prospect.Foreign countries have applied the methyltransferase inhibitors such as treatment such as azacitidine, Decitabine, procainamide acute
Marrow series leukemia (acute myelogenous leukemia, AML), myelodysplastic syndrome
(myelodysplasticsyn drome, MDS) and chronic myelocytic leukemia (chronic myelogenous
Leukemia, CML) clinical trial report.But the demethylation reagent of these clinical experimental stages has gastrointestinal reaction, bone
The larger toxic and side effect of implantation of marrow, hepatic lesion, neurotoxicity and lung failure etc., limits clinical practice.Therefore find
The demethylation reagent of the more effective and small natural origin of toxic and side effect is particularly important.
N6-2- benzylamine hydroxyl -9- ribofuranosylpurines (ortho-Topolin Riboside, oTR) are a kind of presence
The natural nucleus glycoside aromatic series basic element of cell division synthesized in willow leaf when dawn.2010 according to US National cancer research
Center (NIC) test result finds that oTR is 60 kinds of tumor cell line (NIC to the 9 big knurls of people60) there is the external of highly significant
Proliferation inhibition activity, wherein to the most strong (IC of drug susceptibility of leukemia cell line50≦1.7μM).And by medicine body
Screening model-doughnut method finds oTR in vivo to some tumor model mouse without obvious acute toxic reaction.Above-mentioned knot
Fruit fully shows that oTR has very strong antitumor clinical practice potentiality and clinical medicinal grinds as a kind of ucleosides basic element of cell division
Make an offer value.
The modification of human DNA methylization mainly passes through dnmt rna 1 (DNMT1) and dnmt rna 3
(DNMT3) complete.Wherein, DNMT1 contents are also the regulation CpG most important enzymes of island dna methylation state at most.But at present
Whether there is not been reported to act on and play the research of antitumor action by adjusting demethylation to DNMT1 on oTR.
The content of the invention
The present invention is directed to above-mentioned prior art, antineoplastic application in human leukemia cell line the invention provides oTR.
Technical scheme：
A kind of application of demethylation reagent in human leukemia cell, step is as follows：
(1) cell culture：Human leukemia cell line THP-1 is suspended in the aseptic RPMI containing inactivated fetal bovine serum
In RPMI-1640, concentration is placed in for 5%CO2, relative humidity be to cultivate in the incubator that 90%, temperature is 37 DEG C, cell is long
To blake bottle floor space 70%~80% passes on 1 time；
(2) medicine is prepared：The Ara-C culture mediums of aseptic RPMI 1640 dissolve, and oTR 0.1%DMSO dissolve, and continue to use
It is 0.1 μM -30 μM that the Ara-C and oTR that the culture mediums of aseptic RPMI 1640 will dissolve are diluted to concentration, and filtration sterilization, room temperature is protected
Deposit；
(3) cell is processed：By in exponential phase 5 × 103~1 × 104Individual cell is inoculated in every hole and contains 100 μ
In 96 orifice plates of lRPMI RPMI-1640s, 10 groups of experiments, every group of 4 multiple holes, the 1st group are set：Blank control group；2nd group：
0.1%DMSO groups；3rd group：0.3 μ Μ oTR groups；4th group：1.5 μ Μ oTR groups；5th group：15 μ Μ oTR groups；6th group：30μΜ
OTR groups；7th group：0.3 μ Μ Ara-C groups；8th group：1.5 μ Μ Ara-C groups；9th group：15 μ Μ Ara-C groups；10th group：0.3μ
Μ Ara-C groups, respectively to corresponding medicine is added in each group, are placed in concentration for 5%CO2, relative humidity be 90%, temperature be 37
DEG C incubator in be incubated 3-5 days, cell count；
(4) cell proliferation inhibition rate is detected：By in exponential phase 5 × 103~1 × 104Individual cell is inoculated in every hole
In 96 orifice plates containing 100 μ lRPMI RPMI-1640s, cell is processed again according to the method for step (3) treatment cell, put
In concentration be 5%CO2, relative humidity be to be incubated 3-5 days in the incubator that 90%, temperature is 37 DEG C, each 4 multiple holes；Using
CCK-8 kits are detected, per in the cell suspension of hole plus 10 μ l CCK-8 solution, are placed in 37 DEG C, CO2It is incubated in incubator
2h, determines the absorbance of each group cell at 450nm, record data；
(5) detection cell hypoploid peak：After the active THP-1 cells of growth conditions are processed into 48h with oTR, streaming pipe is used
Three samples are distributed into, dye solution, each sample are prepared according to Annexin V-FITC apoptosis detection kits specification
Add 500 μ l dye solutions, 37 DEG C of lucifuges to be incubated 30min, finally washed once with PBS；BD is used after 300 mesh sieve net filtrations
Machine testing on FACSCalibur flow cytometers, calculates apoptosis rate；
(6) influences of the detection oTR to DNMT1 enzymatic activitys：Nuclear extract after the treatment of extraction step (3) each group, according to
EpiquickDNA methyl transferase activities/inhibition analysis kit ELIASA reads light absorption value and calculates DNMT and lives in 450nm
Property；DNMT1 carries out vivoexpression clone and purifying, and inhibitory activity of the light absorption value detection oTR to DNMT1 is read at 450 nm；
(7) bioinformatics molecular docking experiment：Using bioinformatics molecular docking analogy method, by transmethylase
(DNMT) natural substrate adenosylhomocysteine (SAH) docks steric forces and oTR and DNMT1 with DNMT1 simulations
Simulation docking steric forces.
Beneficial effects of the present invention：Data foundation of the invention is that 60 kinds of tumor cell lines have to the 9 big knurls of people in oTR
The in-vitro multiplication inhibitory activity of highly significant, wherein on the basis most strong to the drug susceptibility of leukemia cell line.
Brief description of the drawings
Fig. 1 is the inhibitory action that basic element of cell division oTR breeds to human leukemia cell.
Fig. 2 is the cell number change of various concentrations oTR treatment THP-1 cells.
Fig. 3 is effects of the oTR to human leukemia cell's apoptosis.3 (a) control group.After 3 (b) 1.5 μ Μ oTR treatment 48h
The cell cycle of THP-1 cells.
Fig. 4 is that oTR is acted on DNMT1 inhibition of enzyme activity.It is total after 4 (a) various concentrations oTR effect leukemia cell lines 48h
The activity change of DNMT.The external influences that enzymatic activity is cloned to DNMT1 of 4 (b) various concentrations oTR, 1：DNMT1；2：0.1μΜ
oTR；3：0.1μΜoTR+DNMT1；4：0.5μΜoTR+DNMT1；5：1μΜoTR+DNMT1；6：5μΜoTR+DNMT1；7：10μ
ΜoTR+DNMT1。
Fig. 5 is ten before native ligand SAH docks steric forces schematic diagram and ranking with DNMT1 simulations
Libdockscore values.
Fig. 6 is the Libdockscore values that oTR docks before steric forces schematic diagram and ranking ten with DNMT1 simulations.
Specific embodiment
Below in conjunction with accompanying drawing and technical scheme, specific embodiment of the invention is further illustrated.
Cell, kit and reagent that the present invention is used：Human leukemia THP-1 cell lines, hyclone, dual anti-(green grass or young crops
Mycin/streptomysin), the culture mediums of RPMI 1640, CCK-8 kits, Apoptosis staining kit, Ara-C and oTR.
Embodiment 1
In-vitro multiplication inhibitory activity of the oTR to human leukemia cell：The human leukemia cell THP-1 of recovery is incubated at and is contained
Have in 10%FBS inactivated fetal bovine serums, the aseptic RPMI1640 nutrient solutions of 1% penicillin/1% streptomysin (dual anti-), be placed in outstanding
In floating cell bottle, in 37 DEG C, 5%CO2And cultivated in the incubator under saturated humidity, cell is long to 70%-80% or so passage 1
It is secondary.Continue to cultivate and obtain the active human leukemia cell of growth conditions, collect cell.By in exponential phase 5 × 103It is individual
Cell is inoculated in 96 orifice plates that 100 μ lRPMI RPMI-1640s are contained in every hole, and according to experiment demand, treatment group is separately added into
The Ara-C or oTR of 0.1%DMSO, 0.3 μM, 1.5 μM, 15 μM, 30 μM concentration, are put into incubator and are incubated 3~5 days, each 4
Multiple holes.Detected using CCK-8 kits, 10 μ l CCK-8 solution are added in the cell suspension of every hole, be placed in 37 DEG C, CO2Culture
2h is incubated in case.Determine the absorbance of each group cell at 450nm, record data, using the variance analysis side of Repeated Measurement Data
Method analyzes each group of data, as a result as shown in Figure 2.Fig. 2 is visible, using the oTR of various concentrations to human leukemia cell THP-1's
Multiplication rate is substantially less than Ara-C and DMSO, shows that oTR can suppress the multiplication rate of human leukemia cell THP-1.
Embodiment 2
OTR induces THP-1 Apoptosis：After the active THP-1 cells of growth conditions are processed into 48h with 0.3 μM of oTR,
Dye solution is prepared according to Annexin V-FITC apoptosis detection kits specification, each sample adds 500 μ l dyeing slow
37 DEG C of lucifuges of fliud flushing are incubated 30min, are finally washed once with PBS.BD FACSCalibur fluidic cells are used after 300 mesh sieve net filtrations
Machine testing on instrument, calculates apoptosis rate.As shown in figure 3, Fig. 3 is visible, DNA is broken result during Apoptosis, causes thin
Intracellular DNA content is reduced there is hypoploid peak.Compared with control group (1.21%), oTR treatment groups (19.23%) THP-1 cells
There is obvious hypoploid peak (Fig. 3), illustrate under same experimental conditions, oTR can induce THP-1 apoptosis.
Embodiment 3
It is a kind of demethylation reagent to further illustrate oTR, we have found further experiment, it is various after oTR effects
The expression quantity of dnmt rna 1 (DNMT1) is substantially reduced in tumour cell.Simulated by bioinformatics molecular docking and sent out
Existing, oTR can be equally entrenched in the activation site of DNMT1 crystal models compared with the natural substrate SAM of DNMT1；Small molecule
Compatibility scoring functions Libdockscore value analysis shows, the score value of oTR and SAH is (Fig. 5 and Fig. 6) of slight difference, above-mentioned knot
Fruit tentatively show that oTR is bigger to the activity influence of DNMT1, therefore we further it is carried out vivoexpression clone and after purification
It was found that oTR substantially suppresses the activity of DNMT1, the result points out oTR by suppressing the antitumor of the activation plays of DNMT1 oTR
Effect.Whether result of the test is visible, and oTR is a kind of demethylation reagent, but can be existing as a kind of clinical demethylation medicine
And do not know.
Claims (1)
1. application of a kind of demethylation reagent in human leukemia cell, it is characterised in that step is as follows：
(1) cell culture：Human leukemia cell line THP-1 is suspended in into the aseptic RPMI 1640 containing inactivated fetal bovine serum to train
In nutrient solution, concentration is placed in for 5%CO2, relative humidity be to cultivate in the incubator that 90%, temperature is 37 DEG C, cell is long to cultivating
70%~80% passage of bottom of bottle area 1 time；
(2) medicine is prepared：The Ara-C culture mediums of aseptic RPMI 1640 dissolve, and oTR 0.1%DMSO dissolve, and continue with aseptic
It is 0.1 μM -30 μM, filtration sterilization, room temperature preservation that the Ara-C and oTR that the culture mediums of RPMI 1640 will dissolve are diluted to concentration；
(3) cell is processed：By in exponential phase 5 × 103~1 × 104Individual cell is inoculated in every hole and contains 100 μ lRPMI
In 96 orifice plates of RPMI-1640,10 groups of experiments, every group of 4 multiple holes, the 1st group are set：Blank control group；2nd group：0.1%
DMSO groups；3rd group：0.3 μ Μ oTR groups；4th group：1.5 μ Μ oTR groups；5th group：15 μ Μ oTR groups；6th group：30 μ Μ oTR groups；
7th group：0.3 μ Μ Ara-C groups；8th group：1.5 μ Μ Ara-C groups；9th group：15 μ Μ Ara-C groups；10th group：0.3μΜAra-C
Group, respectively to corresponding medicine is added in each group, is placed in concentration for 5%CO2, relative humidity be training that 90%, temperature is 37 DEG C
It is incubated 3-5 days in foster case, cell count；
(4) cell proliferation inhibition rate is detected：By in exponential phase 5 × 103~1 × 104Individual cell is inoculated in every hole and contains
In 96 orifice plates of 100 μ lRPMI RPMI-1640s, cell is processed again according to the method for step (3) treatment cell, be placed in dense
It is 5%CO to spend2, relative humidity be to be incubated 3-5 days in the incubator that 90%, temperature is 37 DEG C, each 4 multiple holes；Tried using CCK-8
Agent box detected, per in the cell suspension of hole plus 10 μ l CCK-8 solution, is placed in 37 DEG C, CO22h is incubated in incubator, is determined
The absorbance of each group cell, record data at 450nm；
(5) detection cell hypoploid peak：After the active THP-1 cells of growth conditions are processed into 48h with oTR, dispensed with streaming pipe
Into three samples, dye solution is prepared according to Annexin V-FITC apoptosis detection kits specification, each sample is added
500 37 DEG C of μ l dye solutions lucifuges are incubated 30min, are finally washed once with PBS；BD is used after 300 mesh sieve net filtrations
Machine testing on FACSCalibur flow cytometers, calculates apoptosis rate；
(6) influences of the detection oTR to DNMT1 enzymatic activitys：Nuclear extract after the treatment of extraction step (3) each group, according to
EpiquickDNA methyl transferase activities/inhibition analysis kit ELIASA reads light absorption value and calculates DNMT and lives in 450nm
Property；DNMT1 carries out vivoexpression clone and purifying, and inhibitory activity of the light absorption value detection oTR to DNMT1 is read at 450 nm；
(7) bioinformatics molecular docking experiment：Using bioinformatics molecular docking analogy method, by the day of transmethylase
Right substrate adenosylhomocysteine docks steric forces and oTR and docks space behavior with DNMT1 simulations with DNMT1 simulations
Power.
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| CN107643238A (en) * | 2017-09-19 | 2018-01-30 | 中山大学附属第医院 | A kind of method for quantitatively detecting blood circulation particle concentration |
| CN107648253A (en) * | 2017-09-20 | 2018-02-02 | 大连理工大学 | A kind of basic element of cell division causes the application of human leukemia cell's apoptosis by nucleoside transporting body |
| CN107898804A (en) * | 2017-12-21 | 2018-04-13 | 大连理工大学 | A kind of application of anti-tumor agent comprising salmosin in human leukemia cell |
| CN108553477A (en) * | 2018-07-13 | 2018-09-21 | 大连理工大学 | Application of the ucleosides basic element of cell division in human muscle creatine kinase M4 type cells |
| CN108865999A (en) * | 2018-07-13 | 2018-11-23 | 大连理工大学 | Application of one kind induction differentiation agents in human muscle creatine kinase M2 type cell |
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| CN107898804A (en) * | 2017-12-21 | 2018-04-13 | 大连理工大学 | A kind of application of anti-tumor agent comprising salmosin in human leukemia cell |
| CN108553477A (en) * | 2018-07-13 | 2018-09-21 | 大连理工大学 | Application of the ucleosides basic element of cell division in human muscle creatine kinase M4 type cells |
| CN108865999A (en) * | 2018-07-13 | 2018-11-23 | 大连理工大学 | Application of one kind induction differentiation agents in human muscle creatine kinase M2 type cell |
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Application publication date: 20170707 |