CN109350749A - NOD1/2 is improving application of the tumour cell to the sensitive drug of chemotherapeutics as preparation - Google Patents
NOD1/2 is improving application of the tumour cell to the sensitive drug of chemotherapeutics as preparation Download PDFInfo
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- CN109350749A CN109350749A CN201811377142.4A CN201811377142A CN109350749A CN 109350749 A CN109350749 A CN 109350749A CN 201811377142 A CN201811377142 A CN 201811377142A CN 109350749 A CN109350749 A CN 109350749A
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Abstract
The invention belongs to biomedicine fields, and in particular to NOD1/2 is improving application of the tumour cell to the sensitive drug of chemotherapeutics as preparation.Present invention firstly discovers that the chemosensitivity of liver cancer cells can be improved in NOD1 and NOD2.NOD1 is by inhibiting p-SRC-MAPK signal shaft to improve the chemosensitivity of liver cancer cells, and there are certain synergistic effects with 5-F Μ for depression effect of the NOD1 to liver cancer cells.NOD2 improves the chemosensitivity of liver cancer cells by activation AMPK signal path, and there are certain synergistic effects with 5-F Μ for depression effect of the NOD2 to liver cancer cells.NOD1/2 gene significantly improves Results of Chemotherapy in the application for improving liver cancer cells chemosensitivity, and can reduce the side effect of chemotherapy generation.
Description
Technical field
The invention belongs to biomedicine fields, and in particular to NOD1/2 is improving tumour cell to chemotherapeutics as preparation
Sensitive drug application.
Background technique
Hepatocellular carcinoma (hepatocell μ larcarcinoma, HCC, hereinafter referred to as liver cancer) is that one kind seriously threatens China
The malignant neoplastic disease of people's life and health.Worldwide, it is former to have become the third-largest cancer related mortality for liver cancer
Cause.In recent years since, imaging diagnosis technology relevant to liver cancer and surgery operating technology are continuously improved.Using sorafenib as generation
The hepatoma-targeting therapeutic agent of table also obtains the approval of U.S. Food and Drug Administration.These achievements be liver cancer diagnosis with
Treatment provides more more effectively selections.But regrettably, take a broad view of the status of current liver cancer clinical treatment, the art of hepatocarcinoma patient
Five year survival rate is not significantly increased afterwards.
Currently, surgical operation is still the preferred therapy of liver cancer.But since the onset of liver cancer course of disease is long, onset concealment, one
The best opportunity for the method radical cure liver cancer for dividing patient just to be had already passed by when making a definite diagnosis with operation.Mid and late liver cancer patient is mostly not
The treatments such as operation excision, ablation are appropriate for, systemic therapy is still its important treatment means.And unfortunately, liver cancer cells
It is easy to generate chemotherapeutics drug resistance, anti-tumor drug chemotherapeutics itself may also cause biggish poison is secondary to make body
With, therefore the effect of chemotherapy liver cancer is still unsatisfactory so far.
Summary of the invention
In order to solve the above technical problems, the present invention provides NOD1/2 and is improving tumour cell to chemotherapeutics as preparation
The application of sensitive drug.
First aspect of the present invention provides NOD1/2 and is improving tumour cell to the sensibility medicine of chemotherapeutics as preparation
The application of object, NOD1/2 high expression or overexpression, improve tumour cell to the sensibility of chemotherapeutics.
The second aspect of the present invention provides a kind of pharmaceutical composition for improving liver cancer cells to chemotherapy drug susceptibility, institute
State recombinant plasmid or recombinant virus that pharmaceutical composition includes at least the gene containing NOD1/2.
Further, described pharmaceutical composition further include water-soluble filler, pH adjusting agent, stabilizer, water for injection and
Osmotic pressure regulator.
Further, water-soluble filler includes mannitol, low molecular dextran, sorbierite, polyethylene glycol, grape
One of sugar, lactose and galactolipin are a variety of.
Further, the pH adjusting agent is physiologically acceptable acid, alkali and/or salt；The acid is selected from citric acid, phosphorus
One of acid, lactic acid, tartaric acid and/or hydrochloric acid are a variety of；The alkali is selected from potassium hydroxide, sodium hydroxide and/or hydroxide
One of ammonium is a variety of；The salt is selected from sodium carbonate, potassium carbonate, ammonium carbonate salts, sodium bicarbonate, saleratus, ammonium hydrogen carbonate
One of salt is a variety of.
Further, the stabilizer is EDTA-2Na, sodium thiosulfate, sodium pyrosulfite, sodium sulfite, phosphoric acid hydrogen two
Potassium, sodium bicarbonate, sodium carbonate, arginine, glutamic acid, Macrogol 6000, Macrogol 4000 and lauryl sodium sulfate or
One of trishydroxymethylaminomethane is a variety of；The osmotic pressure regulator is sodium chloride and/or potassium chloride.
Further, described pharmaceutical composition is tablet, dispersible tablet, enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, sugar-coat
Agent, granule, dry powder doses, oral solution, the small liquid drugs injection of injection, injection freeze-dried powder, big infusion or primary infusion.
The beneficial effect that the present invention obtains
Present invention firstly discovers that the chemosensitivity of liver cancer cells can be improved in NOD1 and NOD2.NOD1 is by inhibiting p-
SRC-MAPK signal shaft improves the chemosensitivity of liver cancer cells, and NOD1 deposits the depression effect of liver cancer cells with 5-F Μ
In certain synergistic effect.NOD2 improves the chemosensitivity of liver cancer cells, and NOD2 pairs by activation AMPK signal path
There are certain synergistic effects with 5-F Μ for the depression effect of liver cancer cells.NOD1/2 gene is improving liver cancer cells chemosensitivity
Property application, significantly improve Results of Chemotherapy, and can reduce chemotherapy generation side effect.
Biological raw material used in the present invention is easy to get, safe and reliable, manufactured pharmaceutical composition reasonable composition, and curative effect is bright
It is aobvious, have a wide range of application, use environment is friendly.
Detailed description of the invention
The Figure of description for constituting a part of the invention is used to provide further understanding of the present invention, and of the invention shows
Examples and descriptions thereof are used to explain the present invention for meaning property, does not constitute improper limitations of the present invention.
Fig. 1 NOD1 significantly improves the chemosensitivity of liver cancer cell lines；Figure 1A is by liver cancer cell lines HepG2 kind in 96 orifice plates
In, it is adherent overnight after, exogenous to be transferred to myc-NOD1, transfection is added the 5-F Μ of various concentration gradient when changing liquid, after dosing 72h,
CCK-8 method detects cell viability；Figure 1B by liver cancer cell lines HepG2 kind in 96 orifice plates, it is adherent overnight after, it is exogenous to be transferred to
Myc-NOD1,5-F Μ (10 μ g/ml) is added when changing liquid in transfection, and after dosing 48h, CCK-8 method detects cell viability；Fig. 1 C is by liver
Cancerous cell line HepG2 kind in 6 orifice plates, it is adherent overnight after, exogenous to be transferred to myc-NOD1,5-F Μ (10 is added when changing liquid in transfection
μ g/ml), isometric DMSO is added as compareing, after dosing 48h, collects supernatant and attached cell and crack protein, western
Blot detects the protein expression level variation of p-SRC, p-ERK, P21.Using 4 weeks or so male nude mouse 20, by liver cancer cells
It is that HepG2 (1*10^7) is subcutaneously injected on the inside of nude mice or so armpit；After naked eyes visual tumors occur, start to give note in the tumor of left side
It penetrates myc-NOD1 plasmid (20 μ g), meanwhile, right side gives equivalent myc-vector (20 μ g), and injection is primary every other day；Respectively will
It is two groups that myc-NOD1 and myc-vector, which is divided to, wherein one group gives 5-F Μ (10mg/kg) and injected, another group is given together
Volume PBS injection, is administered once every other day.After injecting plasmid 26 days for the first time, puts to death nude mice and remove tumor tissues, weigh and measure
The tumour line of apsides；The growth curve of Fig. 1 D nude mouse tumor；The nude mouse tumor photo that Fig. 1 E is separated；It is naked that Fig. 1 F-G separates each group
The volume (Fig. 1 F) and weight (Fig. 1 H) of mouse tumour.Fig. 1 I extracts the albumen of each group nude mouse tumor, Western blot detection
The expression of the GAP-associated protein GAPs such as myc, p-SRC, p-ERK, P21 changes.
Fig. 2 NOD2 significantly improves the chemosensitivity of liver cancer cell lines；The present invention by liver cancer cell lines BEL7402 and
HepG2 is inoculated in 96 orifice plates respectively with the density in the hole 1*10^4/, exogenous overexpression NOD2, is added not when liquid is changed in transfection
With the 5-F Μ of concentration gradient, cell viability is detected after 72 hours, analysis finds that NOD2 can effectively improve liver cancer cells to 5-F
The sensibility (Fig. 2A-B) of Μ.Further investigation revealed that there is centainly the depression effect and 5-F Μ of liver cancer cells in NOD2
Synergistic effect (Fig. 2 C-D).It is research after 5-F Μ is added in liver cancer cell lines, whether NOD2 can increase Apoptosis.At
5-F Μ (10 μ g/ml) is added in the NOD2 overexpressing cell Model B EL7402 of function building, DMSO is added in control group.Agent-feeding treatment
Collect supernatant and attached cell after 48h, the bis- dyes of AnnexinV/PI, machine testing is found in streaming, after NOD2 adds 5-F Μ processing, carefully
The apoptosis quantity of born of the same parents increased significantly (Fig. 2 E).Further investigation revealed that NOD2 is thin by activation AMPK signal shaft raising liver cancer
The chemosensitivity (Fig. 2 F) of born of the same parents.
Specific embodiment
It is noted that described further below be all exemplary, it is intended to provide further instruction to the present invention.Unless another
It indicates, all technical and scientific terms used herein has usual with general technical staff of the technical field of the invention
The identical meanings of understanding.
It should be noted that term used herein above is merely to describe specific embodiment, and be not intended to restricted root
According to exemplary embodiments of the present invention.As used herein, unless the context clearly indicates otherwise, otherwise singular
Also it is intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet
Include " when, indicate existing characteristics, step, operation and/or their combination.
In order to enable those skilled in the art can clearly understand technical solution of the present invention, below with reference to tool
The embodiment of the body technical solution that the present invention will be described in detail.
Myc-NOD1 expression plasmid used in the present invention is given in Dr.S μ ng O μ k Kim (Μ niversity of
Western Ontario)；Myc-NOD2 expression plasmid is given in Dr.Ralph R.Isberg (T μ fts Μ niversity
School of Medicine)。
The construction method of Myc-NOD1 expression plasmid is as described in document: Li μM, Haenssler E, Μ ehara T, et
al.The Legionella pneμmophila EnhC protein interferes with immμnostimμlatory
mμramyl peptide prodμction to evade innate immμnity[J].Cell Host&Microbe,
2012,12(2):166-176.
The construction method of Myc-NOD2 expression plasmid is as described in document: Park S, Ha S D, Coleman M, et
al.p62/SQSTM1Enhances NOD2-Mediated Signaling and Cytokine Prodμction throμgh
Stabilizing NOD2Oligomerization[J].Plos One,2013,8(2):e57138.
NOD1 gene nucleotide series are as shown in SEQ ID NO.1；NOD2 gene nucleotide series such as SEQ ID NO.2 institute
Show.
The chemosensitivity of 1 NOD1/2 of embodiment raising liver cancer cells
NOD1 significantly improves the chemosensitivity of liver cancer cell lines: adherent by liver cancer cell lines HepG2 kind in 96 orifice plates
It is exogenous to be transferred to myc-NOD1 after overnight, after the 5-F Μ of addition various concentration gradient when liquid is changed in transfection, dosing 72h, CCK-8 method
Detect cell viability；By liver cancer cell lines HepG2 kind in 96 orifice plates, it is adherent overnight after, exogenous to be transferred to myc-NOD1, transfection
5-F Μ (10 μ g/ml) is added when changing liquid, after dosing 48h, CCK-8 method detects cell viability；Analysis finds that NOD1 can be mentioned effectively
High liver cancer cells illustrate that NOD1 can significantly improve liver cancer cells to the chemosensitivity of 5-F Μ to the sensibility (Figure 1A-B) of 5-F Μ
Property.By liver cancer cell lines HepG2 kind in 6 orifice plates, it is adherent overnight after, exogenous to be transferred to myc-NOD1, addition when liquid is changed in transfection
5-F Μ (10 μ g/ml) is added isometric DMSO as compareing, after dosing 48h, collects supernatant and attached cell and crack protein,
Western blot detects the protein expression level variation of p-SRC, p-ERK, P21, and experimental result is as shown in Figure 1 C.
NOD2 significantly improves the chemosensitivity of liver cancer cell lines: the present invention by liver cancer cell lines BEL7402 and HepG2 with
The density in the hole 1*10^4/ is inoculated in respectively in 96 orifice plates, exogenous overexpression NOD2, and various concentration ladder is added when liquid is changed in transfection
The 5-F Μ of degree, detects cell viability after 72 hours, analysis finds that NOD2 can effectively improve liver cancer cells to the sensitivity of 5-F Μ
Property (Fig. 2A-B).Illustrate that NOD2 can significantly improve liver cancer cells to the chemosensitivity of 5-F Μ.
Further investigation revealed that there are certain synergistic effect (figures for depression effect and 5-F Μ of the NOD2 to liver cancer cells
2C-D).It is research after 5-F Μ is added in liver cancer cell lines, whether NOD2 can increase Apoptosis.In the NOD2 that success constructs
5-F Μ (10 μ g/ml) is added in overexpressing cell Model B EL7402, DMSO is added in control group.On being collected after agent-feeding treatment 48h
Clear and attached cell, the bis- dyes of AnnexinV/PI, machine testing is found in streaming, after NOD2 adds 5-F Μ processing, the apoptosis number of cell
Amount increased significantly (Fig. 2 E).Further investigation revealed that NOD2 is quick by the chemotherapy that activation AMPK signal shaft improves liver cancer cells
Perceptual (Fig. 2 F).
The chemosensitivity of 2 NOD1 of embodiment raising nude mice model liver cancer cells
NOD1 significantly improves the chemosensitivity of liver cancer cell lines: using 4 weeks or so male nude mouse 20, by liver cancer cells
It is that HepG2 (1*10^7) is subcutaneously injected on the inside of nude mice or so armpit.After naked eyes visual tumors occur, start to give note in the tumor of left side
It penetrates myc-NOD1 plasmid (20 μ g), meanwhile, right side gives equivalent myc-vector (20 μ g), and injection is primary every other day；Respectively will
It is two groups that myc-NOD1 and myc-vector, which is divided to, wherein one group gives 5-F Μ (10mg/kg) and injected, another group is given together
Volume PBS injection, is administered once every other day.After injecting plasmid 26 days for the first time, puts to death nude mice and remove tumor tissues, weigh and measure
The tumour line of apsides.Nude mouse tumor growth curve can significantly inhibit its life after showing NOD1 group nude mouse tumor application 5-F Μ processing
Long rate (Fig. 1 E), while injecting the volume and weight of NOD1 and 5-F Μ group its tumour and more only NOD1 injection group and while injecting
Empty carrier and 5-F Μ group are remarkably decreased (Fig. 1 F-G).By extracting tumor tissues albumen and application Western blot detection
The expression of GAP-associated protein GAP further demonstrates NOD1 by inhibiting p-SRC-MAPK signal shaft to improve change of the liver cancer cells to 5-F Μ
It treats sensibility (Fig. 1 H).
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
SEQUENCE LISTING
<110>Shandong University
<120>NOD1/2 is improving application of the tumour cell to the sensitive drug of chemotherapeutics as preparation
<130>
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tggctcatcc ggagcctgta cgagatgcag gaggagcggc tggctcggaa ggctgcacgt 2280
ggcctgaatg ttgggcacct caagttgaca ttttgcagtg tgggccccac tgagtgtgct 2340
gccctggcct ttgtgctgca gcacctccgg cggcccgtgg ccctgcagct ggactacaac 2400
tctgtgggtg acattggcgt ggagcagctg ctgccttgcc ttggtgtctg caaggctctg 2460
tatttgcgcg ataacaatat ctcagaccga ggcatctgca agctcattga atgtgctctt 2520
cactgcgagc aattgcagaa gttagctcta ttcaacaaca aattgactga cggctgtgca 2580
cactccatgg ctaagctcct tgcatgcagg cagaacttct tggcattgag gctggggaat 2640
aactacatca ctgccgcggg agcccaagtg ctggccgagg ggctccgagg caacacctcc 2700
ttgcagttcc tgggattctg gggcaacaga gtgggtgacg agggggccca ggccctggct 2760
gaagccttgg gtgatcacca gagcttgagg tggctcagcc tggtggggaa caacattggc 2820
agtgtgggtg cccaagcctt ggcactgatg ctggcaaaga acgtcatgct agaagaactc 2880
tgcctggagg agaaccatct ccaggatgaa ggtgtatgtt ctctcgcaga aggactgaag 2940
aaaaattcaa gtttgaaaat cctgaagttg tccaataact gcatcaccta cctaggggca 3000
gaagccctcc tgcaggccct tgaaaggaat gacaccatcc tggaagtctg gctccgaggg 3060
aacactttct ctctagagga ggttgacaag ctcggctgca gggacaccag actcttgctt 3120
tga 3123
Claims (10)
1.NOD1/2 is improving application of the tumour cell to the sensitive drug of chemotherapeutics as preparation, which is characterized in that
NOD1/2 high expression is overexpressed, and improves tumour cell to the sensibility of chemotherapeutics.
2. application according to claim 1, which is characterized in that the tumour cell is liver cancer cells.
3. application according to claim 1, which is characterized in that NOD1/2 is NOD1 or NOD2.
4. any application according to claim 1~3, which is characterized in that the chemotherapeutics is fluorouracil.
5. a kind of liver cancer cells that improve are to the pharmaceutical composition of chemotherapy drug susceptibility, which is characterized in that described pharmaceutical composition
Including at least the recombinant plasmid or recombinant virus of the gene containing NOD1/2.
6. pharmaceutical composition according to claim 5, which is characterized in that described pharmaceutical composition further includes water soluble bulk
Agent, pH adjusting agent, stabilizer, water for injection and osmotic pressure regulator.
7. pharmaceutical composition according to claim 6, which is characterized in that water-soluble filler includes mannitol, low molecule
One of dextran, sorbierite, polyethylene glycol, glucose, lactose and galactolipin are a variety of.
8. pharmaceutical composition according to claim 6, which is characterized in that the pH adjusting agent be it is physiologically acceptable acid,
Alkali and/or salt；The acid is selected from one of citric acid, phosphoric acid, lactic acid, tartaric acid and/or hydrochloric acid or a variety of；The alkali is selected from
One of potassium hydroxide, sodium hydroxide and/or ammonium hydroxide are a variety of；The salt is selected from sodium carbonate, potassium carbonate, ammonium carbonate
One of salt, sodium bicarbonate, saleratus, bicarbonate ammonium salt are a variety of.
9. pharmaceutical composition according to claim 6, which is characterized in that the stabilizer is EDTA-2Na, thiosulfuric acid
Sodium, sodium pyrosulfite, sodium sulfite, dipotassium hydrogen phosphate, sodium bicarbonate, sodium carbonate, arginine, glutamic acid, Macrogol 6000,
Macrogol 4000 and one of lauryl sodium sulfate or trishydroxymethylaminomethane are a variety of；The osmotic pressure regulator
For sodium chloride and/or potassium chloride.
10. pharmaceutical composition according to claim 5, which is characterized in that described pharmaceutical composition be tablet, dispersible tablet,
Enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, sugar-coat agent, granule, dry powder doses, oral solution, the small liquid drugs injection of injection, injection
With freeze-dried powder, big infusion or primary infusion.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811377142.4A CN109350749B (en) | 2018-11-19 | 2018-11-19 | Application of NOD1/2 in preparation of medicine for improving sensitivity of tumor cells to chemotherapeutic drugs |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811377142.4A CN109350749B (en) | 2018-11-19 | 2018-11-19 | Application of NOD1/2 in preparation of medicine for improving sensitivity of tumor cells to chemotherapeutic drugs |
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| CN109350749A true CN109350749A (en) | 2019-02-19 |
| CN109350749B CN109350749B (en) | 2020-06-23 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020223770A1 (en) * | 2019-05-08 | 2020-11-12 | Garvan Institute Of Medical Research | Cancer stratification and treatment based on inhibition of nod-2 |
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2018
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020223770A1 (en) * | 2019-05-08 | 2020-11-12 | Garvan Institute Of Medical Research | Cancer stratification and treatment based on inhibition of nod-2 |
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| CN109350749B (en) | 2020-06-23 |
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