CN106265730A - The pyrroloquinoline quinone (PQQ) application in the reverse effect to multi-drug resistance of the tumor - Google Patents
The pyrroloquinoline quinone (PQQ) application in the reverse effect to multi-drug resistance of the tumor Download PDFInfo
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- A61K33/24—Heavy metals; Compounds thereof
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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Abstract
The pyrroloquinoline quinone (PQQ) application in the reverse effect to multi-drug resistance of the tumor.The present invention test result indicate that pyrroloquinoline quinone (PQQ) all has reverse effect to the multidrug resistance of pulmonary carcinoma/cisplatin resistance strain (A549/DDP) and ovarian cancer/taxol resistance strain (A2780/Taxol).
Description
Technical field
The present invention relates to drug world, especially relate to pyrroloquinoline quinone (PQQ) in the reverse to multi-drug resistance of the tumor
Active application.
Background technology
Tumor (tumor, neoplam) be phalangeal cell under carcinogenic factor effect, gene there occurs change, loses it raw
Long normal regulation, causes monoclonicity paraplasm and the neoplasm that formed.And tumor generally can be divided into benign tumor and evil
The property big class of tumor two, benign tumor poor growth, with surrounding tissue boundary clear, does not shifts, to human health damage not
Greatly.Malignant tumor is also referred to as cancer, and malignant growth is rapid, can be transferred to other positions of health, also to produce harmful substance,
Destroy normal organ structure, make body function lack of proper care, life-threatening.Therefore, malignant tumor is the important unit that global disease is lethal
One of fierce, according to statistics, new every 100,000 people of malignant tumor patient in the whole world just there are 173 people, in every 100,000 people of China, have 110 people；
Antitumor drug is widely used as the important means for the treatment of malignant tumor.
And along with the extensive application of antitumor drug, inevitably cause malignant cell that it is produced drug resistance
Property, make chemotherapy effect substantially reduce, this is a great problem of puzzle treating malignant tumor, the most Just because of this, the most also
There is no preferable medicine for the reverse both drug resistance to anti-malignant tumor medicine, and malignant cell is once to antitumor
Medicine forms drug resistance, will numerous First-line chemotherapy medicines such as, anti-swollen malignant tumor medicine that action target spot different different to other structures
Forming multidrug resistance, therefore form multidrug resistance, so its harm is particularly acute, multidrug resistance is to cause anti-infectives
One of major reason that treatment is failed with malignant tumor chemotherapy.
Nowadays, Drug therapy is routine and the treatment means of necessity of each malignant tumor patient, though the most
Develop many cancer therapy drugs and be applied to clinic, can therapeutic effect the most inconspicuous.Trace it to its cause, the secondary work of poison produced except medicine
With outward, the multidrug resistance that malignant cell produces is the key factor affecting therapeutic effect, finds reverse malignancy many
The medicine of medicine drug resistance has become the key of current anti-malignant tumor.
Summary of the invention
In order to overcome the problems referred to above, the present invention provides pyrroloquinoline quinone (PQQ) to multi-drug resistance of the tumor to society
Reverse effect in application.
The technical scheme is that pyrroloquinoline quinone (PQQ) answering in the reverse effect to multi-drug resistance of the tumor
With.
As the improvement of the present invention, described pyrroloquinoline quinone (PQQ) is stock solution；Pyrroloquinoline quinone (PQQ) in described stock solution
It is 100mg-150mg:1000g with the ratio of water.
As the improvement of the present invention, described pyrroloquinoline quinone (PQQ) is 1/3 stock solution；Described 1/3 stock solution weight portion
1 part of stock solution and 2 parts of water preparations.
As the improvement of the present invention, described pyrroloquinoline quinone (PQQ) is 1/10 stock solution；Described 1/10 stock solution is to use weight portion
1 part of stock solution and the preparation of 9 parts of water.
As the improvement of the present invention, described pyrroloquinoline quinone (PQQ) is combined with positive drug.
As the improvement of the present invention, described positive drug is cisplatin or paclitaxel.
In the present invention, the pyrroloquinoline quinone (PQQ) application in the reverse effect to multi-drug resistance of the tumor, described pyrroles
Quinoline quinone (PQQ) is set to 4 concentration: 1/10 pyrroloquinoline quinone (PQQ) the first stock solution, (PQQ) first is former for 1/3 pyrroloquinoline quinone
Liquid, pyrroloquinoline quinone (PQQ) the first stock solution and pyrroloquinoline quinone (PQQ) the second stock solution, positive drug group is respectively 50 M DDP
With 3 pmol Taxol process groups, and wherein by the pyrroloquinoline quinone (PQQ) of 3 kinds of concentration respectively with 50 M DDP and 3
Pmol Taxol is combined, and test result indicate that pyrroloquinoline quinone (PQQ) is to pulmonary carcinoma/cisplatin resistance strain (A549/ in the present invention
And the multidrug resistance of ovarian cancer/taxol resistance strain (A2780/Taxol) all has reverse effect DDP).
Accompanying drawing explanation
Fig. 1 is the fluorescence picture of Brachydanio rerio A549/DDP transplanted tumor.
Fig. 2 is the pyrroloquinoline quinone (PQQ) growth inhibitory effect (Mean ± SE) to Brachydanio rerio A549/DDP transplanted tumor
Figure.
Fig. 3 is the pyrroloquinoline quinone (PQQ) growth inhibition ratio (Mean ± SE) figure to Brachydanio rerio A549/DDP transplanted tumor.
Fig. 4 is the fluorescence picture of Brachydanio rerio A2780/Taxo transplanted tumor.
Fig. 5 is that pyrroloquinoline quinone (PQQ) is to Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor
Growth inhibitory effect (Mean ± SE) figure.
Fig. 6 is that pyrroloquinoline quinone (PQQ) is to Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor
Growth inhibition ratio (Mean ± SE) figure.
Detailed description of the invention
Embodiment 1 1,/10 first stock solution group
Embodiment 2 1/3 first stock solution group
Embodiment 3 first stock solution group (pyrroloquinoline quinone (PQQ) is 100mg:1000g with the ratio of water)
Embodiment 4 second stock solution group (pyrroloquinoline quinone (PQQ) is 150mg:1000g with the ratio of water)
Embodiment 5 1,/10 first stock solution+50 M cisplatin (DDP) (1,/10 first stock solution combination group)
Embodiment 6 1/3 first stock solution+50 M cisplatin (DDP) (1/3 first stock solution combination group)
Embodiment 7 first stock solution+50 M cisplatin (DDP) (the first stock solution combination group)
Embodiment 8 1,/10 first stock solution+3 pmol paclitaxel (Taxol) (1,/10 first stock solution combination group)
Embodiment 9 1/3 first stock solution+3 pmol paclitaxel (Taxol) (1/3 first stock solution combination group)
Embodiment 10 first stock solution+3 pmol paclitaxel (Taxol) (the first stock solution combination group)
Matched group 1: model control group (Model)
Matched group 2:50 M cisplatin (DDP) (positive drug group)
Matched group 3:3 pmol paclitaxel (Taxol) (positive drug group)
In the present invention, in described stock solution, pyrroloquinoline quinone (PQQ) is 100mg-150mg:1000g with the ratio of water.Described 1/3 stock solution
It is with 1 part of stock solution of weight portion and 2 parts of water preparations；Described 1/10 stock solution is with 1 part of stock solution of weight portion and 9 parts of water preparations
's；In embodiment in the present invention, described stock solution has two concentration, is pyrroloquinoline quinone (PQQ) respectively and the ratio of water is
Second stock solution that ratio is 150mg:1000g of first stock solution of 100mg:1000g and pyrroloquinoline quinone (PQQ) and water.
1, modelling
By red fluorescence dyestuff (CM-Dil) labelling human tumor drug-resistant cell strain (pulmonary carcinoma/cisplatin resistance strain (A549/DDP), ovum
Nest cancer/taxol resistance strain (A2780/Taxol)), in the way of microinjection, it is transplanted in Brachydanio rerio yolk sac (every tail transplanting
About 300 cells), set up Brachydanio rerio tumor drug resistance cell transplantation model.
2, experimental technique
Use CM-Dil labelling pulmonary carcinoma/cisplatin resistance strain (A549/DDP) and ovarian cancer/taxol resistance strain (A2780/Taxol)
Cell, is transplanted in 2 dpf Brachydanio rerio yolk sac (every tail transplants about 300 cells) in the way of microinjection, sets up zebra
Fish tumor drug resistance cell transplantation model；The Brachydanio rerio having injected tumor cell is placed 35 DEG C and cultivates 24 hours to 3 dpf；Aobvious
The preferable Brachydanio rerio of implanted tumor cells concordance is picked out under micro mirror, in random assortment to 6 orifice plates, every hole 30 tail.Pyrroles's quinoline
Quinoline quinone (PQQ) sets 4 concentration: 1,/10 first stock solution, 1/3 first stock solution, the first stock solution and the second stock solution, positive drug group is respectively
Being 50 M DDP and 3 pmol Taxol process groups, wherein 50 M DDP are dissolved in the mode of fish culture water and are administered, and 1,/10
One stock solution, 1/3 first stock solution, the first stock solution, the second stock solution and 3 pmol Taxol are blood circulation and are administered；Pyrroloquinoline quinone
(PQQ) wherein 3 concentration are combined as pyrroloquinoline quinone (PQQ) combination group, wherein, pyrroles's quinoline with corresponding positive drug respectively
Quinoline quinone (PQQ) combination group is also blood circulation and is administered.In the present invention, embodiment 1 to embodiment 10 processes 1 hole the most simultaneously
In 30 tails transplanted the Brachydanio rerio of cancerous cell, 35 DEG C of incubators process the 48 hours time (3 dpf to 5 dpf).Experiment knot
Shu Hou, randomly chooses 10 tail Brachydanio rerio respectively from embodiment 1 to embodiment 10 and carries out observing, take pictures and protecting under fluorescence microscope
Deposit picture；Utilize Nikon NIS-Elements D 3.10 high vision to process software and carry out graphical analysis, calculate cancerous cell glimmering
Light intensity (S), the antitumor action of quantitative assessment pyrroloquinoline quinone (PQQ), statistical procedures result represents with ± SE；Pyrroles's quinoline
The antitumor action computing formula of quinoline quinone (PQQ) is as follows:
Growth inhibited percentage rate according to transplanted tumor draws dose effect curve；Statistical analysis use variance analysis and
Dunnett ' s T-checks, and p < 0.05 is significant difference；By comparing the antitumor drug effect of combination group and alone group, evaluate
Whether pyrroloquinoline quinone (PQQ) has reverse multiple drug resistance of tumor effect；Representative experimental patterns is provided.
3, experimental result
3.1 pyrroloquinoline quinone (PQQ) the reverse effect evaluation to pulmonary carcinoma/cisplatin resistance strain (A549/DDP)
Experimental result is as shown in Fig. 1,2,3 and table 1:
In Fig. 1. the fluorescence picture of Brachydanio rerio A549/DDP transplanted tumor., B: matched group 2(50 A: matched group 1(Model)
M DDP), C-E: embodiment 1(1/10 the first stock solution), embodiment 2(1/3 the first stock solution) and embodiment 3(first former
Liquid), F-H: embodiment 5(1/10 the first stock solution and 50 M DDP combinations), embodiment 6(1/3 the first stock solution and 50 M DDP
Combination) and embodiment 7(the first stock solution with 50 M DDP be combined).
The fluorescence intensity of table 1. Brachydanio rerio A549/DDP transplanted tumor collects
With matched group 1(Model) compare: * p < 0.05, * * p < 0.01
In Fig. 2. the pyrroloquinoline quinone (PQQ) growth inhibitory effect (Mean ± SE) to Brachydanio rerio A549/DDP transplanted tumor.
With matched group 1(Model) compare: * p < 0.05, * * p < 0.01
In Fig. 3. the pyrroloquinoline quinone (PQQ) growth inhibition ratio (Mean ± SE) to Brachydanio rerio A549/DDP transplanted tumor.
With matched group 1(Model) compare: * p < 0.05, * * p < 0.01
Interpretation: (1) matched group 2(50 M DDP) to Brachydanio rerio pulmonary carcinoma/cisplatin resistance (A549/DDP) transplanted tumor
Growth inhibition ratio is-0.5%, with matched group 1(Model) compared with, it is not statistically significant (p > 0.05), matched group 2(50 M
DDP) growth to Brachydanio rerio pulmonary carcinoma/cisplatin resistance (A549/DDP) transplanted tumor does not has inhibitory action.Pulmonary carcinoma/cisplatin resistance is described
(A549/DDP) cell has drug-resistant effect to cisplatin (DDP).
(2) in embodiment 1 and embodiment 2, the growth inhibited to Brachydanio rerio pulmonary carcinoma/cisplatin resistance (A549/DDP) transplanted tumor
Rate is respectively 1.0 % and 0.3%, with matched group 1(Model) compared with, all it is not statistically significant (p > 0.05)；In embodiment 3
In, pyrroloquinoline quinone (PQQ) is 16.4% to the growth inhibition ratio of Brachydanio rerio pulmonary carcinoma/cisplatin resistance (A549/DDP) transplanted tumor, with
Matched group 1(Model) compare, statistically significant (p < 0.05)；The most in example 4, pyrroloquinoline quinone (PQQ) is to speckle
The growth inhibition ratio of horse fish pulmonary carcinoma/cisplatin resistance (A549/DDP) transplanted tumor is 16.5%, with matched group 1(Model) compared with, have
Statistical significance (p < 0.05)；.Illustrate that the first stock solution is alone and the second stock solution is alone to Brachydanio rerio pulmonary carcinoma/cisplatin resistance
(A549/DDP) growth of transplanted tumor has inhibitory action.
(3) in embodiment 5 and embodiment 6, the growth inhibited to Brachydanio rerio pulmonary carcinoma/cisplatin resistance (A549/DDP) transplanted tumor
Rate is respectively 1.3 % and 14.0%, with matched group 1(Model) compared with, it is not statistically significant (p > 0.05)；In embodiment 7
In, pyrroloquinoline quinone (PQQ) is 27.5% to the growth inhibition ratio of Brachydanio rerio pulmonary carcinoma/cisplatin resistance (A549/DDP) transplanted tumor, with
Matched group 1(Model) compare, statistically significant (p < 0.01).Illustrate that the first stock solution and 50 M cisplatin (DDP) are combined right
The growth of Brachydanio rerio pulmonary carcinoma/cisplatin resistance (A549/DDP) transplanted tumor has inhibitory action.
In sum, the first stock solution is alone and the second stock solution is alone to Brachydanio rerio pulmonary carcinoma/cisplatin resistance (A549/DDP) shifting
The growth planting tumor has inhibitory action, and the first stock solution is combined Brachydanio rerio pulmonary carcinoma/cisplatin resistance (A549/ with 50 M cisplatin (DDP)
DDP) growth of transplanted tumor has inhibitory action, illustrates that pyrroloquinoline quinone (PQQ) is to Brachydanio rerio pulmonary carcinoma/cisplatin resistance (A549/DDP)
The growth of transplanted tumor has an inhibitory action, and pyrroloquinoline quinone (PQQ) arrives after certain concentration requirement Brachydanio rerio pulmonary carcinoma/cisplatin
The growth of drug resistance (A549/DDP) transplanted tumor just has inhibitory action.
3.2 pyrroloquinoline quinone (PQQ) the reverse effect evaluation to ovarian cancer/taxol resistance strain (A2780/Taxol)
As shown in Fig. 4,5,6 and table 2:
In Fig. 4. the fluorescence picture of Brachydanio rerio A2780/Taxo transplanted tumor., B: matched group 3(3 A: matched group 1(Model)
Pmol Taxol), C-E: embodiment 1(1/10 the first stock solution), embodiment 2(1/3 the first stock solution) and embodiment 3(first
Stock solution), F-H: embodiment 7(1/10 the first stock solution with 3 pmol Taxol combination), embodiment 8(1/3 the first stock solution and 3
Pmol Taxol be combined) and embodiment 9(the first stock solution with 3 pmol Taxol be combined.
The fluorescence intensity of table 2. Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor collects
Compare with matched group 1: * p < 0.05, * * p < 0.01
In Fig. 5. the pyrroloquinoline quinone (PQQ) life to Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor
Long inhibition (Mean ± SE).
Compare with matched group 1: * p < 0.05, * * p < 0.01
In Fig. 6. the pyrroloquinoline quinone (PQQ) life to Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor
Long suppression ratio (Mean ± SE).
Compare with matched group 1: * p < 0.05, * * p < 0.01
(1) matched group 3(3 pmol Taxol) to Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor
Growth inhibition ratio is 10.6%, with matched group 1(Model) compared with, it is not statistically significant (p > 0.05), matched group 3(3
Pmol Taxol) growth of Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor is not had inhibitory action.
Illustrate that ovarian cancer/taxol resistance strain (A2780/Taxol) cell has drug-resistant effect to Taxol.
(2) Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) is moved by embodiment 1, embodiment 2 and embodiment 3
The growth inhibition ratio planting tumor is respectively 19.0%, 19.3% and 28.7%, with matched group 1(Model) compared with, the most statistically significant
(p < 0.05, p < 0.01)；Embodiment 4 is to Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor simultaneously
Growth inhibition ratio be respectively 29.0%, with matched group 1(Model) compared with, statistically significant (p < 0.05, p < 0.01).
Illustrating in the range of 1,/10 first stock solution to the first original liquid concentration, the first stock solution is alone and the second stock solution is alone to Brachydanio rerio ovary
The growth of cancer/taxol resistance strain (A2780/Taxol) transplanted tumor has inhibitory action, and in concentration dependence.
(3) embodiment 7 growth inhibition ratio to Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor
It is 8.1%, with matched group 1(Model) compared with, it is not statistically significant (p > 0.05)；Embodiment 8 and embodiment 9 are to Brachydanio rerio
The growth inhibition ratio of ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor is respectively 19.7% and 27.7%, with matched group
1(Model) compare, statistically significant (p < 0.01).Illustrate pyrroloquinoline quinone (PQQ) concentration be 1/3 first stock solution extremely
In the range of first original liquid concentration, pyrroloquinoline quinone (PQQ) is combined 3 pmol paclitaxels (Taxol) to Brachydanio rerio ovarian cancer/Ramulus et folium taxi cuspidatae
The growth of alcohol persister (A2780/Taxol) transplanted tumor has inhibitory action, and in concentration dependence.
In sum, Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) is transplanted by pyrroloquinoline quinone (PQQ)
The growth of tumor has inhibitory action；In the range of 1,/10 first stock solution to the first original liquid concentration, pyrroloquinoline quinone (PQQ) is alone to speckle
The growth of horse fish ovaries cancer/taxol resistance strain (A2780/Taxol) transplanted tumor has inhibitory action, and in concentration dependence.Separately
Outward, in the range of pyrroloquinoline quinone (PQQ) concentration is 1/3 first stock solution to the first original liquid concentration, pyrroloquinoline quinone (PQQ) is combined
The growth of Brachydanio rerio ovarian cancer/taxol resistance strain (A2780/Taxol) transplanted tumor is also had by 3 pmol paclitaxels (Taxol)
Inhibitory action, is also in concentration dependence simultaneously.
Above experimental result shows, pyrroloquinoline quinone (PQQ) to pulmonary carcinoma/cisplatin resistance strain (A549/DDP) and ovarian cancer/
The multidrug resistance of taxol resistance strain (A2780/Taxol) all has reverse effect.
Claims (6)
1. the pyrroloquinoline quinone (PQQ) application in the reverse effect to multi-drug resistance of the tumor.
Application the most according to claim 1, it is characterised in that described pyrroloquinoline quinone (PQQ) is stock solution；In described stock solution
Pyrroloquinoline quinone (PQQ) is 100mg-150mg:1000g with the ratio of water.
Application the most according to claim 2, it is characterised in that described pyrroloquinoline quinone (PQQ) is 1/3 stock solution；Described 1/3
Stock solution is with 1 part of stock solution of weight portion and 2 parts of water preparations.
Application the most according to claim 2, it is characterised in that described pyrroloquinoline quinone (PQQ) is 1/10 stock solution；Described 1/
10 stock solutions are with 1 part of stock solution of weight portion and 9 parts of water preparations.
5. according to the application described in any one claim in Claims 1-4, it is characterised in that described pyrroloquinoline quinone
(PQQ) it is combined with positive drug.
Application the most according to claim 5, it is characterised in that described positive drug is cisplatin or paclitaxel.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2596849A (en) * | 2020-07-10 | 2022-01-12 | Jardine Romy | Nutritional supplement composition for treating coronavirus infections, cancer, ME, post viral & Chronic fatigue syndrome & neurodegeneration in an individual |
| WO2022166599A1 (en) | 2021-02-02 | 2022-08-11 | 广州沪同有梧生物科技有限公司 | New use of pqq and derivative thereof |
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| CN103536593A (en) * | 2012-07-12 | 2014-01-29 | 常茂生物化学工程股份有限公司 | Use of pyrroloquinoline quinone in preparing medicines for preventing and treating tumors |
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| CN103536593A (en) * | 2012-07-12 | 2014-01-29 | 常茂生物化学工程股份有限公司 | Use of pyrroloquinoline quinone in preparing medicines for preventing and treating tumors |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2596849A (en) * | 2020-07-10 | 2022-01-12 | Jardine Romy | Nutritional supplement composition for treating coronavirus infections, cancer, ME, post viral & Chronic fatigue syndrome & neurodegeneration in an individual |
| WO2022166599A1 (en) | 2021-02-02 | 2022-08-11 | 广州沪同有梧生物科技有限公司 | New use of pqq and derivative thereof |
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Application publication date: 20170104 |