CN106852926A - Application of the triterpene glucoside unit in antineoplastic sensitizer is prepared - Google Patents
Application of the triterpene glucoside unit in antineoplastic sensitizer is prepared Download PDFInfo
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- CN106852926A CN106852926A CN201510902357.3A CN201510902357A CN106852926A CN 106852926 A CN106852926 A CN 106852926A CN 201510902357 A CN201510902357 A CN 201510902357A CN 106852926 A CN106852926 A CN 106852926A
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- antineoplastic
- glucoside unit
- triterpene glucoside
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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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
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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Abstract
The invention belongs to cell biology and field of medicaments, it is related to application of the triterpene glucoside unit in antineoplastic sensitizer is prepared.Triterpene glucoside unit is natural products, the effect with reversing multiple medicine resistance of tumor cells, can be as the reversal agent of tumor multi-medicine drug-resistant；Triterpene glucoside unit also has increases the effect of tumor multi-medicine drug-resistant cells against neoplastic drug susceptibility, can be used as chemotherapeutic sensitizer.Present invention also offers the method that the pharmaceutical composition that antineoplastic and triterpene glucoside unit are used in combination suppresses tumor multi-medicine drug-resistant cell propagation.Micromolecular compound triterpene glucoside unit in the present invention develops as new antineoplastic or its auxiliary element, and substantially, environmental protection will provide a kind of new approach and means to tumor killing effect to treat and curing tumour.
Description
Technical field
The invention belongs to cell biology and field of medicaments field, specifically, the present invention relates to triterpene glucoside unit
New application.The invention further relates to corresponding pharmaceutical composition and its application process.
Background technology
Tumour is body under the effect of various carcinogenic factors, and some cell of local organization loses right on gene level
The normal regulation of its growth, the abnormality for causing its clonal abnormality hyperplasia and being formed.The neoplastic disease number of cases of China is quite huge
Greatly, there is data to show and account for the 55% of whole world case load.
Benign tumourInfluence to body is smaller, is mainly shown as local compression and obstructive symptom.Malignant tumour is due to dividing
Change immature, growth very fast, infiltration destroys the 26S Proteasome Structure and Function of organ, and can shift, thus serious on body influence.Dislike
Property tumour can also have in addition to it can cause local compression and the obstructive symptom similar to above-mentioned benign tumourHeating, intractable pain,
Late period may occur in which seriously become thin, it is weak,AnaemiaWith the state of cachexia.
The traditional Chinese medical science thinks that the cause of cancer is equilibrium between yin and yang in human body first, and histocyte is long-term in different carcinogenic factors
Under effect, cell mutation and cause.Cancerous tissue is also a part for human body in fact, only in this imbalance between YIN and YANG of people, five
Raw gram of row multiplies on the premise of insult changes, and the immunosurveillance system of human body can just lose monitoring to it, develop as one pleases.Chinese herbal medicine
Can with recuperating qi-blood, adjustment equilibrium between yin and yang, maintain normal vital signs and save one's life；To train correction gas, produce antibody, cleaning "
Malicious source " and effect a permanent cure.Thus, Chinese herbal medicine extract turns into treatment one important directions of tumour.
Triterpene glucoside unit is natural products, and bioavilability is high, Nature comparison is stable, with Clinical practice value.With
People going deep into its chemistry and biology research, its molecular mechanism of action will progressively clearly, and this will further promote this
The modifying for chemical structure and structure activity study of class compound.
The content of the invention
It is an object of the invention to provide the new medicinal usage of the triterpene glucoside unit of structure shown in formula I.
It is an object of the invention to provide a kind of antineoplastic sensitizer.
On the one hand, the application the invention provides triterpene glucoside unit in antineoplastic sensitizer is prepared.Wherein, sieve
The structure of Chinese fruit sapogenin is as shown in Equation 1.
Described tumour includes carcinoma of mouth, breast cancer, liver cancer, lung cancer, cervical carcinoma, colon cancer or cancer of pancreas.
Described antineoplastic is vincristine, daunorubicin, taxol or 5 FU 5 fluorouracil.
Triterpene glucoside unit can be as tumor multi-drug resistance reversal agents.
On the other hand, the invention provides a kind of antineoplastic pharmaceutical compositions, described antineoplastic pharmaceutical compositions have
Effect composition is antineoplastic and triterpene glucoside unit.
Described antineoplastic is CCSA or cell cycle nonspecific agent (CCNSA).
Described antineoplastic is vincristine, daunorubicin, taxol or 5 FU 5 fluorouracil.
Present invention also offers a kind of method for suppressing tumor cell in vitro growing multiplication, i.e., in the culture medium of tumour cell
Middle addition triterpene glucoside unit and antineoplastic.
Wherein, the final concentration of 1-10 μm of ol/L of triterpene glucoside unit is added.
Described tumour includes carcinoma of mouth, breast cancer, liver cancer, lung cancer, cervical carcinoma or cancer of pancreas.
When implementing the above method, triterpene glucoside unit is first added, be subsequently adding antineoplastic.Sieve can also simultaneously be added
Chinese fruit sapogenin and antineoplastic.
The invention provides the new application of triterpene glucoside unit, i.e. its application in antineoplastic sensitizer is prepared.
Triterpene glucoside unit is natural products, the effect with reversing multiple medicine resistance of tumor cells, can be as tumor multi-medicine drug-resistant
Reversal agent；Triterpene glucoside unit also has increases the effect of tumor multi-medicine drug-resistant cells against neoplastic drug susceptibility, Ke Yizuo
For chemotherapeutic sensitizer is used.In the present invention micromolecular compound triterpene glucoside unit is as new antineoplastic or its is auxiliary
Co-ingredients is developed, and substantially, environmental protection will provide a kind of new approach and hand to tumor killing effect to treat and curing tumour
Section.
Specific embodiment
The invention provides a kind of antineoplastic, the active component of described antineoplastic is triterpene glucoside unit.
Described tumour can be HCC, stomach cancer cell, cervical cancer cell or blood cell.
Micromolecular compound of the invention can be prepared using various conventional preparation methods.For example, using artificial chemistry
The method of synthesis.
Using micromolecular compound of the present invention, by various conventional screening assays, can filter out and be sent out with triterpene glucoside unit
The raw material for interacting, such as acceptor, inhibitor or antagonist.
The present invention and its inhibitor, antagonist etc., when (administration) is administered in treatment, it is possible to provide different effects.
Generally, these materials can be formulated in nontoxic, inert and pharmaceutically acceptable aqueous carrier medium, wherein pH is usual
About 5-8, preferably pH be about 6-8, pH value can be varied from the property for being formulated material and illness to be treated.Match somebody with somebody
The pharmaceutical composition for making can be administered by conventional route, including (but being not limited to)：Intramuscular, intraperitoneal, skin
Under, intracutaneous or local administration.
By taking triterpene glucoside of the invention unit as an example, it can be combined with suitable pharmaceutically acceptable carrier.This
Class pharmaceutical composition contains the compound and pharmaceutically acceptable carrier or excipient of therapeutically effective amount.This kind of carrier includes
(but being not limited to)：Salt solution, buffer solution, glucose, water, glycerine, ethanol, and combinations thereof.Pharmaceutical preparation should be with administering mode phase
Matching.Triterpene glucoside unit of the invention can be made into injection form, for example with physiological saline or containing glucose and other
The aqueous solution of assistant agent is prepared by conventional method.The pharmaceutical composition of such as tablet and capsule etc, can be by conventional side
Method is prepared.Pharmaceutical composition such as injection, solution, tablet and capsule are preferably aseptically manufactured.The administration of active component
Amount is therapeutically effective amount, such as the daily mg/kg body weight of about 1 microgram/kg body weight-about 5.Additionally, Momordica grosvenori of the invention
Sapogenin can also be used together with other therapeutic agents.Certainly, specific dosage be also contemplated that method of administration, patient health situation etc. because
Element, within the scope of these are all skilled practitioners technical ability.
Experimental technique：
1. cell recovery
1) cryopreservation tube is taken out from liquid nitrogen container, in direct plungeing into 37 DEG C of warm water, and shake makes it melt as early as possible frequently.
2) take out cryopreservation tube from 37 DEG C of water-baths, with suction pipe suction out cell suspension, injection centrifuge tube and addition more than 10 times
Nutrient solution, low-speed centrifugal after mixing, abandons supernatant, repeats and is washed once with nutrient solution.
3) after suitably being diluted with nutrient solution, inoculated and cultured bottle is placed on 37 DEG C of incubator quiescent cultures, and next day changes culture
Liquid, continues to cultivate.Passed on when culture is to finite concentration.PANC-1 cell culture is containing 10%Gibico hyclones
In DMEM high glucose mediums；The cell culture such as K562, HGC, QGY, MCF-7, PC-3 are in 1640 cultures containing 10% hyclone
In base, SK-hep1, HeLa, HepG2, etc. cell culture in the DMEM high glucose mediums containing 10% hyclone, in culture medium
Penicillin containing 100U/ml and 100 μ g/ml streptomysins.
2. passage culture
The situation of daily observation of cell growth, passes on, about every 2-4 when when cell, length is converged to about 90% in blake bottle
Its passage is once.One bottle passes on into three bottles, or a 25cm2Pass in a 75cm2Blake bottle in.Method：
1) with 1 × phosphate buffer washed cell once.
2) digestion of 2-3ml pancreatin digestive juice is added, several minutes in 37 DEG C of incubators are placed in.Tissue Culture Flask is patted with hand,
Make cell separation.
3) terminate pancreatin with the suitable culture medium of the Gibico hyclones containing 10-15% to digest.Cell is sub-packed in newly
Blake bottle in, continue cultivate.
When suspension cell is passed on, centrifugation in centrifuge tube is collected directly from, abandons old culture medium.General one bottle passes on into three bottles
Ratio is sub-packed in new blake bottle, adds fresh culture to continue to cultivate.
3. cell cryopreservation
1) the cell Trypsin Induced of culture to exponential phase is taken, is collected in centrifuge tube and is counted, be centrifuged.
2) reject trypsase and old nutrient solution, what addition had been configured freezes nutrient solution (containing 10%DMSO, 40%DMEM
With 50%Gibico hyclones), the ultimate density of cell is 0.5-1 × 10 in frozen stock solution7/ml.Gently being blown and beaten with suction pipe makes
Cell is uniform, is then distributed into aseptic cryopreservation tube, often pipe plus 1-1.5ml.
3) cryopreservation tube is put into freezing storing box and puts -80 DEG C of quick-frozen, preservations in immigration liquid nitrogen container after 5 hours.
4. experiment material
Medicine prepares：
Triterpene glucoside unit is dissolved in DMSO (dimethyl sulfoxide (DMSO)), and the mother liquor for being configured to 100mM or 50mM is standby.Its structure is such as
Shown in formula 1.
Verapamil (VPL), vincristine (VCR) and adriamycin (ADR) are purchased from Roche chemical company, and purity is both greater than
99%.
Cell derived:
Human oral cancer cell line KB and its drug-resistant cell strain KB/VCR are provided by Chinese Academy of Sciences's medicine, Breast cancer lines
It is triumphant that MCF-7 and its drug-resistant cell strain MCF-7/ADR, human colon carcinoma HCT-8 and its drug-resistant cell strain HCT-8/VCR are purchased from Nanjing
Base biotech firm.
Kit:
CCK-8 kits are purchased from colleague company.
CCK-8 is tested
KB and KB/VCR cells and MCF-7 and MCF-7/ADR cells are all inoculated into 96 orifice plates according to the density in 3500/ hole
In, the ADR of various concentrations after 24h, VCR, triterpene glucoside unit and VCR and triterpene glucoside unit one are reinstated containing 10% tire ox blood
Clear α-MEM are added in each hole after preparing.After culture 48h, nutrient solution is discarded, cultures of the 90 μ L without serum is added per hole
Base and 10 μ L CCK-8 reagents.After 37 DEG C of reaction 2h, ELIASA reads the light absorption value (OD450) of 450nm wavelength.By calculating
Cell growth fraction to medication group relative to control group.Blank group only adds culture medium to be not added with cell, control group for add with
The DMSO of medicine same volume, cell survival rate=(experimental group OD450- blank group OD450)/(control group OD450- blank groups
OD450).By IC50Value calculates resistance multiple (Resistance Fold, RF) again.
The IC of RF=drug-resistant cell strains50The IC of value/parental cell strain50Value.Each concentration sets 3 repeating holes, and experiment is repeated
3 times.
All mdr cells grow 3 days before tying up to Cell suppression test in without pharmaceutical culture medium.Each numerical value is 3
Independent experiment result, IC50Represented in " means standard deviation " form.VCR, vincristine；ADR, daunorubicin；RF, resistance times
Number.
Embodiment 1
Experimental result：
KB/VCR and MCF-7/ADR are two kinds of conventional multidrug resistance cell strains, in the present embodiment, both cells
Show the characteristic of MDR.As shown in table 1, KB/VCR cells are distinguished the resistance multiple of VCR and ADR relative to KB cells
It is 81.9 times and 94.4 times, and MCF-7/ADR cells are respectively 38.1 compared to the resistance multiple to VCR and ADR with MCF-7 cells
Again with 20.9 times, display experiment mdr cell used has multidrug resistance, and the active results similar to document report of MDR.
Half-inhibition concentration IC of the triterpene glucoside unit to parental cell strain KB and MCF-750Respectively 121 μ Μ and 105 μ
Μ, to the IC of drug-resistant cell strain KB/VCR and MCF-7/ADR50Also be both greater than 100 μ Μ, multidrug resistance cell strain KB/VCR and
MCF-7/ADR does not show the crossing drug resistant to compound triterpene glucoside unit, illustrates that triterpene glucoside unit can escape resistance to
The multidrug resistance of medicine cell.Triterpene glucoside unit is under the concentration of below 10 μ Μ, and cell growth is high without obvious suppression
In the propagation that can suppress cell under the concentration of 100 μ Μ.
Conclusion：Triterpene glucoside unit can overcome the drug resistance of drug-resistant cell strain, and drug-resistant cell strain is to triterpene glucoside unit
Sensitiveness it is essentially identical.
Embodiment 2：Reverse effect of the CCK-8 methods detection triterpene glucoside unit to tumor cell multidrug resistance activity
KB/VCR, MCF-7/ADR and HCT-8/VCR cell are inoculated into 96 orifice plates according to the density in 3500/ hole, after 24h
The VCR of various concentrations, and various concentrations VCR and triterpene glucoside unit one reinstate the α-MEM containing 10% hyclone and prepare
After be added in each hole.After culture 48h, nutrient solution is discarded, with method in embodiment 1, survey resistance with CCK-8 kits thin
Born of the same parents' strain and its parental cell plot curve to the activity of VCR and VCR+ triterpene glucosides unit.Each concentration sets 3 repeating holes, real
Test and be repeated 3 times.
Experimental result：
KB/VCR cells are 81.9 times to the resistance multiple of VCR, and MCF-7/ADR is 20.9 times to the resistance multiple of ADR.When
After adding 10 μM of triterpene glucoside unit, KB/VCR cells are made to increased 1.61 times to the sensitiveness of VCR, and ADR is thin to resistance
The sensitiveness of born of the same parents MCF-7/ADR increased 2.17 times.Triterpene glucoside unit can reverse multiple drug resistance of tumor cell to chemotherapeutic
The drug resistance of thing.And this effect shows unobvious in parental cell.
Conclusion：
Triterpene glucoside unit can be with the drug resistance of reverse multiple drug resistance of tumor cell KB/VCR and MCF-7/ADR, Ke Yizuo
It is the sensitizer of antineoplastic, or pharmaceutical composition is made with antineoplastic.
The all documents referred in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after above-mentioned instruction content of the invention has been read, those skilled in the art can
Made various changes or modifications with to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (10)
1. application of the triterpene glucoside unit in antineoplastic sensitizer is prepared.
2. application as claimed in claim 1, it is characterised in that triterpene glucoside unit is tumor multi-drug resistance reversal agents.
3. application as claimed in claim 1, it is characterised in that described tumour includes carcinoma of mouth, nasopharyngeal carcinoma, breast cancer, liver
Cancer, lung cancer, cervical carcinoma, colon cancer or cancer of pancreas.
4. application as claimed in claim 1, it is characterised in that described antineoplastic is vincristine, daunorubicin, purple
China fir alcohol or 5 FU 5 fluorouracil.
5. a kind of antineoplastic pharmaceutical compositions, it is characterised in that the active ingredient of described antineoplastic pharmaceutical compositions is anti-swollen
Tumor medicine and triterpene glucoside unit.
6. antineoplastic pharmaceutical compositions as claimed in claim 5, it is characterised in that described antineoplastic is the cell cycle
Specific drug or cell cycle nonspecific agent (CCNSA).
7. antineoplastic pharmaceutical compositions as claimed in claim 5, it is characterised in that described antineoplastic is new Changchun
Alkali, daunorubicin, taxol or 5 FU 5 fluorouracil.
8. it is a kind of suppress tumor cell in vitro growing multiplication method, it is characterised in that in the culture medium of tumour cell add
Triterpene glucoside unit and antineoplastic.
9. method as claimed in claim 8, it is characterised in that described tumour includes carcinoma of mouth, breast cancer, nasopharyngeal carcinoma, liver
Cancer, lung cancer, cervical carcinoma or cancer of pancreas.
10. method as claimed in claim 8, it is characterised in that first add triterpene glucoside unit, be subsequently adding antineoplastic
Thing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510902357.3A CN106852926A (en) | 2015-12-08 | 2015-12-08 | Application of the triterpene glucoside unit in antineoplastic sensitizer is prepared |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510902357.3A CN106852926A (en) | 2015-12-08 | 2015-12-08 | Application of the triterpene glucoside unit in antineoplastic sensitizer is prepared |
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| CN106852926A true CN106852926A (en) | 2017-06-16 |
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| CN201510902357.3A Pending CN106852926A (en) | 2015-12-08 | 2015-12-08 | Application of the triterpene glucoside unit in antineoplastic sensitizer is prepared |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108315294A (en) * | 2018-04-10 | 2018-07-24 | 广西大学 | Applications of the Fructus Monordicae extract Mogroside V in terms of promoting oocyte in vitro maturation |
-
2015
- 2015-12-08 CN CN201510902357.3A patent/CN106852926A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108315294A (en) * | 2018-04-10 | 2018-07-24 | 广西大学 | Applications of the Fructus Monordicae extract Mogroside V in terms of promoting oocyte in vitro maturation |
| CN108315294B (en) * | 2018-04-10 | 2020-12-08 | 广西大学 | Application of momordica grosvenori extract Mogroside V in promoting oocyte in-vitro maturation |
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Application publication date: 20170616 |
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