CN106421790A - Application of CMPK (cytidine monophosphate kinase) inhibitor in preparing ovarian cancer treatment drugs - Google Patents

Application of CMPK (cytidine monophosphate kinase) inhibitor in preparing ovarian cancer treatment drugs Download PDF

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CN106421790A
CN106421790A CN201611055534.XA CN201611055534A CN106421790A CN 106421790 A CN106421790 A CN 106421790A CN 201611055534 A CN201611055534 A CN 201611055534A CN 106421790 A CN106421790 A CN 106421790A
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cmpk
ovarian cancer
seq
inhibitor
sirna
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CN106421790B (en
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许国雄
周代兵
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Jinshan Hospital of Fudan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.

Abstract

The invention relates to an application of CMPK (cytidine monophosphate kinase) inhibitor in preparing ovarian cancer treatment drugs. CMPK expression in ovarian cancer cell strains is knocked down through a siRNA and shRNA technology, ovarian cancer cells are changed in biological functions in that cell proliferation is lowered, apoptosis rate is increased, invasion and migration capability is lowered, and know-down effect is quite obvious, and the drugs targeting CMPK target genes can be designed and synthesized for ovarian cancer treatment. By the arrangement, a new concept is provided for clinical treatment of ovarian cancer, and a new direction is provided for research of gene treatment of the ovarian cancer.

Description

Application in the medicine of preparation treatment ovarian cancer for the inhibitor of CMPK
Technical field
The present invention relates to molecular biology and pharmaceutical technology field, specifically, the inhibitor being related to CMPK is controlled in preparation Treat the application in the medicine of ovarian cancer.
Background technology
Ovarian cancer is mortality rate highest tumor in feminine proses, and early symptom is hidden, in clinic once examining Disconnected, the overwhelming majority is in late period, poor prognosis.Existing Therapeutic Method is mainly chemotherapy and adds operation.Chemotherapy side effect is more, Post operation Lose disease risk larger.Therefore, find can early diagnosiss ovarian cancer biomarker, and the research and development few novel drugs of side reaction for Significant for the treatment of ovarian cancer.
Cytidylate kinase (Cytidine monophosphate kinase, CMPK) be nucleoside monophosphate kinase family member it One, play an important role in the biosynthesiss of nucleoside metabolism, DNA damage reparation, tumor occur.It has now been found that, The height of CMPK expression is to the tumor pharmacother sensitivity such as breast carcinoma, cancer of pancreas, pulmonary carcinoma, glioma and life cycle aspect Play an important role (Liu, N.-2016；Ohmine,K.-2015；Ryu,J.-2011).But with regard to CMPK ovarian cancer breed, There is not been reported for the biological study of the aspects such as transfer, invasion and attack, apoptosis.
Content of the invention
The purpose of the present invention is a kind of new application of the inhibitor providing CMPK for deficiency of the prior art.
First aspect, there is provided application in the medicine of preparation treatment ovarian cancer for the inhibitor of CMPK.
Second aspect, there is provided application in reagent preparation for the inhibitor of CMPK, described reagent is used for：
A) suppression human epithelial ovarian carcinoma cells proliferation, migration or invasion and attack；
B) ovarian cellular apoptosis are promoted；Or
C) block the cell cycle of ovarian cancer cell.
As a kind of specific embodiment, described inhibitor is selected from CMPK albumen or their transcript for target sequence The row and siRNA of its protein expression or genetic transcription, dsRNA, shRNA, Microrna, antisensenucleic acidses can be suppressed；Or can table Reach or formed the construction of described siRNA, dsRNA, Microrna, antisensenucleic acidses.
As a kind of specific embodiment, described shRNA coded sequence such as SEQ ID NO.1 and SEQ ID NO.2 institute Show.
As a kind of specific embodiment, described siRNA sequence is as shown in SEQ ID NO.3 and SEQ ID NO.4.
A kind of third aspect, there is provided shRNA molecule treating ovarian cancer, described siRNA molecule coded sequence such as SEQ Shown in ID NO.1 and SEQ ID NO.2.
A kind of fourth aspect, there is provided siRNA molecule treating ovarian cancer, described siRNA molecule sequence such as SEQ ID Shown in NO.3 and SEQ ID NO.4.
The invention has the advantages that：
The present invention is struck after CMPK expression in low Ovarian Cancer Cells with shRNA technology with siRNA, and ovarian cancer cell occurs Biological function changes：Cell proliferation declines, and apoptosis rate increases；Invasion and attack are declined with transfer ability, and it is very notable to strike fall effect. The medicine that synthesis therefore can be designed for CMPK target gene is used for treating ovarian cancer, and the present invention provides for clinical treatment ovarian cancer New thinking, the gene therapy for studying ovarian cancer provides new direction.
Brief description
Fig. 1：A、B：After striking low CMPK, compare NC-siR (Negative Control-siRNA) group, OVCAR-3 and SK- OV-3 ability of cell proliferation is substantially suppressed；C、E：With siRNA transfect Ovarian Cancer Cells OVCAR-3 after CMPK strike poorly efficient fruit Judge (CMPK-siR)；D、F：With siRNA transfect Ovarian Cancer Cells SK-OV-3 after CMPK strike poorly efficient fruit (CMPK-siR). Experiment is all in triplicate.*P<0.05, * * P<0.01.
Fig. 2：A：Strike after low CMPK with CMPK-shRNA, the growth of cell 3D micro-assembly robot is slack-off, and volume diminishes；B：3D micro-assembly robot After culture 15 days, growth curve analysis display, compare NC (Negative Control) group, CMPK-shRNA 3D micro-assembly robot is straight Footpath is less than NC group.Experiment is all in triplicate.*P<0.05.
Fig. 3：A、B：Migration experiment finds, strikes after low ovarian cancer cell CMPK with siRNA, and transfer ability declines；C、D：Invade Attack experiment to find, compare NC group, CMPK-shRNA group invasive ability declines；E、F、G：Struck after low CMPK with shRNA, transfer invasion and attack Associated protein MMP-9 is declined with MMP-2 expression.Experiment is all in triplicate.*P<0.05, * * P<0.01.
Fig. 4：A、B：Compare NC group, ovarian cancer cell the G2/M phase and blocks；C-F：ShRNA strikes low CMPK effect analyses (CMPK-shRNA)；G-J：After striking low ovarian cancer cell CMPK, breed nuclear antigen PCNA down-regulated expression.Experiment is all in triplicate.* P<0.05, * * P<0.01.
Fig. 5：A、B：Compare NC group, striking low CMPK group ovarian cellular apoptosis rate increases；C、D：After shRNA strikes low CMPK Active-caspase-3 up-regulated.Experiment is all in triplicate.*P<0.05, * * P<0.01.
Specific embodiment
The specific embodiment below in conjunction with the accompanying drawings present invention being provided elaborates.
As used herein, described " CMPK inhibitor " includes antagonist, lower adjustment, blocker, blocker etc., as long as They can lower the expression of CMPK.They can be compound, chemical small molecule, biomolecule.Described biology divides Son can be nucleic acid level (including DNA, RNA) or suppression CMPK expression viral product.
Described CMPK inhibitor refers to any activity reducing CMPK, the stability of reduction CMPK, lowers CMPK's Expression, the material reducing CMPK effective acting time, these materials are used equally to the present invention, as useful for lowering CMPK Material.For example, described inhibitor is：Nucleic acid inhibitor, protein inhibitor, nuclease, nucleic acid binding molecule, as long as it can Lower the expression of CMPK.
Embodiment 1
First, experimental technique
The impact to human epithelial ovarian carcinoma cells proliferation for the 1CMPK
A) select Ovarian Cancer Cells OVCAR-3 and SK-OV-3, struck with the shRNA+GFP carrying anti-puromycin gene Low CMPK, is screened using puromycin, builds stable cell strain CMPK-shRNA-OVCAR-3 and CMPK-shRNA-SK- OV-3.CMPK-shRNA coded sequence：CMPK-homo-422Sense：5’- GatccGAAAGATTGTACCAGTTGATTCAAGAGATCAACTGGTACAATCTTTCTTTT TTg-3 ' (SEQ ID NO.1), Antisense：5’-aattcAAAAAAGAAAGATTGTACCAGTTGATCTCTTGAATCAACTGGTACAATCTTTCg-3’ (SEQ ID NO.2).CMPK-shRNA virion is added to set up stable cell strain by MOI=20 (OVCAR-3/SK-OV-3)； Matched group idle running equivalent lentiviral particle (NC).Verify through Western blotting and knock out efficiency.
B) WST-1 method：OVCAR-3 (4000cells/ hole) and SK-OV-3 (3000cells/ hole) is incubated in 96 orifice plates 24h, is divided into Blank group, Reagent group, NC-siRNA group, CMPK-siRNA group.Transfection reagent X-Gene：SiRNA=6:1 (V/M), X-Gene and siRNA (CMPK-homo-422Sense：5’-GAAAGAUUGUACCAGUUGA-3’(SEQ ID NO.3), 3 ' ends plus TT, Antisense：5 '-UCAACUGGUACAAUCUUUC-3 ' (SEQ ID NO.4), 3 ' ends plus TT) respectively With Opti-MEM 15 μ l dilution, mixing in 5min, after standing 15min, it is added to and uses serum-free medium Opti-MEM (GIBCO) change fresh complete medium into after culture 5h and put CO2Cultivate in incubator.Negative Control group add with NC (the Sense of siRNA equivalent：5 '-GCGACGAUCUGCCUAAGAU-3 ' (SEQ ID NO.5), 3 ' ends plus TT； Antisense：5 '-AUCUUAGGCAGAUCGUCGC-3 ' (SEQ ID NO.6), 3 ' ends plus TT).Blank group, Reagent group Respectively plus equivalent Opti-MEM, transfection reagent, in OD after 24h, 48h, 72h450Nm surveys absorbance.Before each time point detection, inhale Fall culture medium, every hole adds 10 μ l WST-1 liquid and 90 μ l complete mediums, put back to incubator and continue culture 2 hours.
C) 3D Hanging drop culture：3D Hanging drop culture plate is bought in Insphero company, according to 3D Hanging drop culture workbook, will CMPK-shRNA-OVCAR-3 and NC-OVCAR-3 (equal 400/40 μ l) hanging drop are added in GravityPlus plate, will after 3 days 3D micro-assembly robot is transferred to GravityTRAP plate, and take pictures under every clear water surface measurement micro-assembly robot two orthogonal diameter d1, d2, puts down All radiuses(Khaitan, D., et al-2006), changes liquid once every two days.Micro-assembly robot is in GravityTRAP plate Interior observation 15 days.
The impact to Ovarian Cancer Cells migration and invasion and attack for the 2CMPK
A) cell cut migration experiment：SK-OV-3 cell is laid in six orifice plates, reaches 85% left side to second day cell confluency degree Right.After exhaustion culture medium, entreat standardized straight line, PBS in the orifice plate with the aseptic pipette tips of 200 μ l, exhaust floating cells.Point Blank group, Reagent group, NC-siR group, CMPK-siR group.Transfection reagent X-Gene：SiRNA=6:1 (V/M), X-Gene with SiRNA (CMPK-homo-422, sequence is ibid) uses Opti-MEM 100 μ l to dilute respectively, mixing in 5min, after standing 15min, Change into without serum fresh culture DMEM after adding serum-free medium Opti-MEM culture 5h, put CO2Cultivate in incubator. NC-siR group adds the NC (sequence is ibid) with siRNA equivalent.Blank group, Reagent group add equivalent Opti-MEM respectively, turn Transfection reagent, claps 24h point cut spacing under mirror after 24h.The same 24h of 48h, 72h processing method.Before each time point detection, change fresh Serum-free medium DMEM.
B) Transwell Matrigel：CMPK-shRNA-SK-OV-3 cell is suspended with serum-free DMEM, counts 60000 Individual/100 μ l, upper room adds 100 μ l cell suspension, and lower room adds the DMEM that 700 μ l contain 15%FBS, takes out upper room after 48 hours, Cotton swab dabs off the cell of little interior, and PBS washes 3 times, and 4% paraformaldehyde fixes 15 minutes, and crystal violet is soaked 30 minutes, PBS Wash 3 times, the little outdoor cell of counted under microscope, experiment is in triplicate.
C) protein blot experiment：Extract through shRNA steady turn strike low cell strain OVCAR-3 and SK-OV-3 cell protein with Negative control histone, detects metastasis related protein MMP-9, MMP-2.
The impact to the ovarian cancer cell cycle for the 3CMPK
a)Flow Cytometry：ShRNA is steady, and the low cell strain OVCAR-3 that strikes turning is laid on 6 respectively with matched group NC cell In orifice plate (cell 250,000/hole), to cell confluency degree reach 85%～90% when, pancreatin digest, complete medium terminate digestion, 800rpm, 6min；PBS 2ml washes 1 time；800rpm, 6min；With 300 μ l deionized water re-suspended cells, add the anhydrous second of 700 μ l Alcohol, 4 DEG C of fixing 3h；800rpm, 7min；Abandon supernatant, PBS, 800rpm, 7min；Abandon supernatant, often pipe plus 500 μ l PI dyestuffs (BD, cat550825), room temperature lucifuge 15min, flow cytometer cell cycle analysis, experiment is repeated 3 times.
B) protein blot experiment：Detection proliferation-associated protein PCNA.
The impact to ovarian cellular apoptosis for the 4CMPK
a)Flow Cytometry：ShRNA is steady, and the low cell strain OVCAR-3 that strikes turning is laid on 6 respectively with matched group NC cell In orifice plate (cell 250,000/hole), to cell confluency degree reach 85%～90% when, collect cell culture medium, with without EDTA pancreatin Digestion, complete medium terminates digestion, 800rpm, 6min；PBS 2ml washes 2 times；800rpm, 7min；Abandon supernatant, add 100 μ l After 1 × Binding Buffer, every hole is separately added into 3 μ l PI and 3 μ l APC (this process lucifuge)；After 15min, every hole adds 200 μ l1 × Binding Buffer, lucifuge, gently mix；Flow cytometer Apoptosis assay, experiment is repeated 3 times.
B) protein blot experiment：Detection apoptotic signal proteins Caspase-3 and active caspase-3.
2nd, result and analysis
1st, after striking low CMPK, Ovarian Cancer Cells breed suppressed (Fig. 1, Fig. 2).
2nd, after striking low CMPK, Ovarian Cancer Cells migration and invasive ability decline (Fig. 3).
3rd, strike after low CMPK with shRNA, Ovarian Cancer Cells cell cycle the G2/M phase and blocks (Fig. 4).
4th, strike after low CMPK with shRNA, Ovarian Cancer Cells apoptosis rate increases (Fig. 5).
In sum, strike after CMPK expression in low Ovarian Cancer Cells with siRNA with shRNA technology, ovarian cancer cell Biological function occurs change：Cell proliferation declines, and apoptosis rate increases；Invasion and attack are declined with transfer ability.And constructed by the present invention SiRNA and shRNA notable for the inhibitory action of ovarian cancer cell.Based on result above, synthesis can be designed and be directed to CMPK target The medicine of gene is used for treating ovarian cancer.
The above is only the preferred embodiment of the present invention it is noted that ordinary skill people for the art Member, on the premise of without departing from the inventive method, can also make some improvement and supplement, these improve and supplement also should be regarded as Protection scope of the present invention.
SEQUENCE LISTING
<110>Jinshan Hospital Fudan University
<120>Application in the medicine of preparation treatment ovarian cancer for the inhibitor of CMPK
<130> /
<160> 6
<170> PatentIn version 3.3
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Claims (7)

  1. Application in the medicine of preparation treatment ovarian cancer for the inhibitor of 1.CMPK.
  2. Application in reagent preparation for the inhibitor of 2.CMPK is it is characterised in that described reagent is used for：
    A) suppression human epithelial ovarian carcinoma cells proliferation, migration or invasion and attack；
    B) ovarian cellular apoptosis are promoted；Or
    C) block the cell cycle of ovarian cancer cell.
  3. 3. application according to claim 1 and 2, described inhibitor is selected from CMPK albumen or their transcript as target The sequence and siRNA of its protein expression or genetic transcription, dsRNA, shRNA, Microrna, antisensenucleic acidses can be suppressed；Or energy Expression or the described siRNA of formation, dsRNA, Microrna, the construction of antisensenucleic acidses.
  4. 4. application according to claim 3 it is characterised in that described shRNA coded sequence such as SEQ ID NO.1 with Shown in SEQ ID NO.2.
  5. 5. application according to claim 3 is it is characterised in that described siRNA sequence such as SEQ ID NO.3 and SEQ ID Shown in NO.4.
  6. 6. a kind of shRNA molecule treating ovarian cancer is it is characterised in that described siRNA molecule coded sequence such as SEQ ID Shown in NO.1 and SEQ ID NO.2.
  7. 7. a kind of siRNA molecule treating ovarian cancer it is characterised in that described siRNA molecule sequence such as SEQ ID NO.3 and Shown in SEQ ID NO.4.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004045543A2 (en) * 2002-11-14 2004-06-03 Dharmacon, Inc. Functional and hyperfunctional sirna
US20100151004A1 (en) * 2007-03-07 2010-06-17 University Of Medicine And Dentistry Of New Jersey Modulation of drug sensitivity
CN105658648A (en) * 2013-08-13 2016-06-08 加利福尼亚大学董事会 Deoxycytidine kinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004045543A2 (en) * 2002-11-14 2004-06-03 Dharmacon, Inc. Functional and hyperfunctional sirna
US20100151004A1 (en) * 2007-03-07 2010-06-17 University Of Medicine And Dentistry Of New Jersey Modulation of drug sensitivity
CN105658648A (en) * 2013-08-13 2016-06-08 加利福尼亚大学董事会 Deoxycytidine kinase inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIU ET AL.: "Prognostic significance of nuclear expression of UMP-CMP kinase in triple negative breast cancer patients", 《SCIENTIFIC REPORTS》 *
RYU ET AL.: "Differential Effect of Polymorphisms of CMPK1 and RRM1 on Survival in Advanced Non-small Cell Lung Cancer Patients Treated with Gemcitabine or Taxane/Cisplatinum", 《JOURNAL OF THORACIC ONCOLOGY》 *

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